review article genetics of type 2 diabetes: insights into...

Review ArticleGenetics of Type 2 Diabetes Insights into the Pathogenesis andIts Clinical Application

Xue Sun1 Weihui Yu2 and Cheng Hu13

1 Shanghai Diabetes Institute Shanghai Clinical Center for Diabetes Shanghai Key Clinical Center for Metabolic Disease ShanghaiKey Laboratory of Diabetes Mellitus Shanghai Jiao Tong University Affiliated Sixth Peoplersquos Hospital Shanghai 200233 China

2Department of Endocrinology and Metabolism Wenzhou Medical University Affiliated First Hospital Wenzhou 325000 China3 Shanghai Jiao Tong University Affiliated Sixth Peoplersquos Hospital South Branch Shanghai 200233 China

Correspondence should be addressed to Cheng Hu alfredhcsjtueducn

Received 7 March 2014 Accepted 22 March 2014 Published 17 April 2014

Academic Editor Jiarui Wu

Copyright copy 2014 Xue Sun et alThis is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

With rapidly increasing prevalence diabetes has become one of the major causes of mortality worldwide According to the lateststudies genetic informationmakes substantial contributions towards the prediction of diabetes risk and individualized antidiabetictreatment To date approximately 70 susceptibility genes have been identified as being associated with type 2 diabetes (T2D) at agenome-wide significant level (119875 lt 5times10minus8) However all the genetic loci identified so far account for only about 10 of the overallheritability of T2D In addition how these novel susceptibility loci correlate with the pathophysiology of the disease remains largelyunknown This review covers the major genetic studies on the risk of T2D based on ethnicity and briefly discusses the potentialmechanisms and clinical utility of the genetic information underlying T2D

1 Introduction

The prevalence of type 2 diabetes (T2D) is rising rapidlyowing to increased economic growth and lifestyle changesin both developed and developing countries According to arecent report the number of diabetics is estimated to reach439 million by 2030 worldwide [1] Therefore strategies toprevent and treat diabetes are urgently needed in order tostem this global pandemic It is well known that T2D is causedby 120573-cell dysfunction andor insulin resistance which ispromoted by multifactorial genetic or environmental factorsOver the years linkage analysis candidate gene approachlarge-scale association studies and genome-wide associationstudies (GWAS) have successfully identified multiple genesthat contribute to T2D susceptibility Combined analyses ofthese loci such as construction of genetic risk scores havecontributed significantly to the prediction of T2D diabetesand thus facilitated the adoption of early diagnosis andpreventative strategies to reduce this growing disease burden[2ndash5]

Pharmacogenomics is an emerging discipline that high-lights the role of inherited and acquired genetic variations

in drug response and which is beneficial for appropriateselection of antidiabetic drugs [6] So far pharmacogenomicshas proven to be valuable in guiding therapeutic choicesin maturity onset diabetes in the young (MODY) and inneonatal diabetes however its extension to T2D still needsdetailed studies [7] The present review summarizes recentgenetic research on T2D in both ethnic and chronologiccontexts and briefly discusses the potential mechanisms andclinical utilities of genetic information in T2D

2 Advances in Type 2 DiabetesGenetic Research

Linkage analysis candidate gene approach large-scale asso-ciation studies and GWAS have identified approximately70 loci conferring susceptibility to T2D Among them 45loci were identified in European populations (Table 1) andthe other 29 loci were identified in Asian populationsespecially in East and South Asians (Tables 2 and 3) Theimmediate benefit derived from these findings was the betterunderstanding of the pathophysiology of T2D

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 926713 15 pageshttpdxdoiorg1011552014926713

2 BioMed Research International

Table 1 European-derived susceptibility loci for type 2 diabetes

Locus SNP Chr Position Allele(riskother) RAFlowast OR Probable

mechanism

2000 PPAR120574 [8] rs1801282 3 12368125 CG 092 114 Insulin actionCandidate andlarge-scale

association study

2003 KCNJ11 [9] rs5219 11 17366148 TC 05 114 120573-Cell functionCandidate andlarge-scale

association study

2006 TCF7L2 [10] rs7903146 10 114748339 TC 025 137 120573-Cell functionCandidate andlarge-scale

association study

2007 WFS1 [11] rs10010131 4 6343816 GA 06 111 120573-Cell functionCandidate andlarge-scale

association study

2007 HNF1B [12] rs4430796 17 rs4430796 AG 047 11 120573-Cell functionCandidate andlarge-scale

association study2007 IGF2BP2 [13ndash15] rs4402960 3 186994381 TG 029 114 120573-Cell function GWAS2007 CDKN2A-CDKN2B [13ndash15] rs10811661 9 rs10811661 TC 079 12 120573-Cell function GWAS2007 CDKAL1 [13ndash16] rs10946398 6 20769013 CA 031 112 120573-Cell function GWAS2007 SLC30A8 [17] rs13266634 8 118253964 CT 075 112 120573-Cell function GWAS2007 HHEXIDE [17] rs1111875 10 94452862 CT 056 113 120573-Cell function GWAS2007 FTO [13 15 18] rs8050136 16 rs8050136 AC 045 117 Obesity GWAS2008 NOTCH2 [19] rs10923931 1 120230001 TG 0106 113 Unknown GWAS2008 ADAMTS9 [19] rs4607103 3 64686944 CT 0761 109 Insulin action GWAS2008 THADA [19] rs7578597 2 43644474 TC 0902 115 120573-Cell function GWAS2008 TSPAN8LGR5 [19] rs7961581 12 69949369 CT 0269 109 120573-Cell function GWAS2008 CDC123CAMK1D [19] rs12779790 10 12368016 GA 0183 111 120573-Cell function GWAS2008 JAZF1 [19] rs864745 7 28147081 TC 0501 11 120573-Cell function GWAS2009 MTNR1B [20] rs1387153 11 92313476 TC 0283 115 120573-Cell function GWAS2009 IRS1 [21] rs2943641 2 226801989 CT 0633 119 Insulin action GWAS2010 DGKBTMEM195 [22] rs2191349 7 15030834 TG 0333 106 120573-Cell function GWAS2010 GCKR [22] rs780094 2 27594741 CT 0394 106 Insulin action GWAS2010 GCK [22] rs4607517 7 44202193 AG 0195 107 120573-Cell function GWAS2010 PROX1 [22] rs340874 1 212225879 CT 0492 107 120573-Cell function GWAS2010 ADCY5 [22] rs11708067 3 124548468 AG 0226 112 120573-Cell function GWAS2010 RBMS1ITGB6 [23] rs7593730 2 160879700 CT 023 09 Insulin action GWAS2010 KCNQ1 [24] rs231362 11 2648047 GA 052 108 120573-Cell function GWAS2010 DUSP9 [24] rs5945326 X 152553116 AG 079 127 Insulin action GWAS2010 PRC1 [24] rs8042680 15 89322341 AC 022 107 Unknown GWAS2010 ZFAND6 [24] rs11634397 15 78219277 GA 06 106 Unknown GWAS2010 HNF1A [24] rs7957197 12 119945069 TA 085 107 Unknown GWAS2010 HMGA2 [24] rs1531343 12 64461161 CG 01 11 Insulin action GWAS2010 CENTD2 [24] rs1552224 11 72110746 AC 088 114 120573-Cell function GWAS2010 CHCHD9 [24] rs13292136 9 81141948 CT 093 111 Unknown GWAS2010 TP53INP1 [24] rs896854 8 96029687 TC 048 106 Unknown GWAS2010 KLF14 [24] rs972283 7 130117394 GA 055 107 Insulin action GWAS2010 ZBED3 [24] rs4457053 5 76460705 GA 026 108 Unknown GWAS2010 BCL11A [24] rs243021 2 60438323 AG 046 108 Unknown GWAS

BioMed Research International 3

Table 1 Continued


mechanism2012 HMG20A [25] rs7177055 15 75619817 AG 068 108 Unknown GWAS2012 GRB14 [25] rs13389219 2 165237122 CT 06 107 Insulin action GWAS2012 ZMIZ1 [25] rs12571751 10 80612637 AG 052 108 Unknown GWAS2012 ANK1 [25] rs516946 8 41638405 CT 076 109 120573-cell function GWAS2012 KLHDC5 [25] rs10842994 12 27856417 CT 08 11 Unknown GWAS2012 TLE1 [25] rs2796441 9 83498768 GA 057 107 Unknown GWAS2012 ANKRD55 [25] rs459193 5 55842508 GA 07 108 Insulin action GWAS2012 CILP2 [25] rs10401969 19 19268718 CT 008 113 Unknown GWAS2012 MC4R [25] rs12970134 18 56035730 AG 027 108 Unknown GWAS2012 BCAR1 [25] rs7202877 16 73804746 TG 089 112 120573-Cell function GWASlowastData were derived from HapMap East Asian or original studies Position is given for NCBI Build 36SNP single nucleotide polymorphism Chr chromosome RAF risk allele frequency OR odds ratio

Table 2 Type 2 diabetes susceptibility loci identified in East Asians


mechanism2009 KCNQ1 [26] rs2237892 11 2796327 CT 0683 143 120573-Cell function GWAS2010 UBE2E2 [27] rs7612463 3 23311454 AC 0134 119 Unknown GWAS2010 C2CD4A-C2CD4B [27] rs7172432 15 60183681 AG 042 113 Unknown GWAS2010 SPRY2 [28] rs1359790 13 79615157 GA 0273 115 Unknown GWAS2010 CDC123CAM K1D [28] rs10906115 10 12355003 AG 0561 113 Unknown GWAS2010 SRR [29] rs391300 17 2163008 GA 0367 128 120573-Cell function GWAS2010 PTPRD [29] rs17584499 9 8869118 TC 0226 157 Insulin action GWAS2011 MAEA [30] rs6815464 4 1299901 CG 0640 113 Unknown GWAS2011 PSMD6 [30] rs831571 3 64023337 CT 0688 109 Unknown GWAS2011 ZFAND3 [30] rs9470794 6 38214822 CT 0203 112 Unknown GWAS2011 GCC1-PAX4 [30] rs6467136 7 126952194 GA 0182 111 Unknown GWAS2011 KCNK16 [30] rs1535500 6 39392028 TG 0398 108 120573-Cell function GWAS2011 PEPD [30] rs3786897 19 38584848 AG 0547 11 Unknown GWAS2011 FITM2-R3HD [30] rs6017317 20 42380380 GT 0545 109 120573-Cell function GWAS2011 GLIS3 [30] rs7041847 9 4277466 AG 0529 11 120573-Cell function GWAS2012 ANK1 [31] rs515071 8 41638405 CT 08 118 Unknown GWAS2013 GRK5 [32] rs10886471 10 121139393 CT 0756 112 Insulin action GWAS2013 RASGRP1 [32] rs7403531 15 36610197 TC 0317 11 120573-Cell function GWAS2013 PAX4 [33] rs10229583 7 127034139 GA 0829 118 Unknown GWAS2013 MIR129-LEP [34] rs791595 7 127650038 AG 008 117 Unknown GWAS2013 SLC16A13 [34] rs312457 17 6881117 GA 0078 12 Unknown GWAS2013 GPSM1 [34] rs11787792 9 138371969 AG 0874 115 Unknown GWASlowastData were derived from HapMap East Asian or original studies Position is given for NCBI Build 36SNP single nucleotide polymorphism Chr chromosome RAF risk allele frequency OR odds ratio

21 Genetics of Type 2 Diabetes in European Populations

211 Linkage Analysis Candidate Gene Approach and Large-Scale Association Studies Linkage analysis has proved to bevaluable in the exploration of genetic factors of monogenicdiseases such as MODY neonatal mitochondrial diabetes

insulin resistance and Wolfram syndromes [38ndash40] How-ever it has not been particularly useful in identifying thegenetic factors for common forms of T2D Over the yearslinkage studies have reportedmany predisposing associationswith chromosomal regions for T2D including segments inchromosomes 5 and 10 and have identified putative causative


Table 3 Type 2 diabetes susceptibility loci identified in South Asians

Locus SNP Chr Position Allele(riskother) RAFlowast OR Probable mechanism

2011 ST6GAL1 [35] rs16861329 3 188149155 GA 086 109 120573-Cell function GWAS2011 HNF4A [35] rs4812829 20 42422681 AG 029 109 120573-Cell function GWAS2011 VPS26A [35] rs1802295 10 70601480 AG 026 108 Unknown GWAS2011 AP3S2 [35] rs2028299 15 88175261 CA 031 11 Unknown GWAS2011 HMG20A [35] rs7178572 15 75534245 GA 052 109 Unknown GWAS2011 GRB14 [35] rs3923113 2 165210095 AC 074 109 Insulin action GWAS2013 TMEM163 [36] rs998451 2 135145758 GA 1 156 120573-Cell function GWAS2013 SGCG [37] rs9552911 13 22762657 AG 007 067 Unknown GWASlowastData were derived from HapMap East Asian or original studies Position is given for NCBI Build 36SNP single nucleotide polymorphism Chr chromosome RAF risk allele frequency OR odds ratio

genetic variants in CAPN10 [41] ENPP1 [42] HNF4A [4344] and ACDC (also called ADIPOQ) [45] but most of thefindings from these reports could not be replicated

During the past several decades only a few loci con-ferring risk of T2D were identified through candidate geneapproachwith PPAR120574 Pro12Ala polymorphism being the firstreported locus [8] PPAR120574 is a transcription factor that playsa pivotal role in adipocyte differentiation It was reportedthat PPAR120574 Pro12Ala variant was associated with increasedinsulin sensitivity in the general population and thus mayprotect an individual from T2D [46]The KCNJ11 (potassiuminwardly rectifying channel subfamily J member 11) encodespotassium inwardly rectifier 62 subunit (Kir62) of the ATP-sensitive potassium (KATP) channel which has an impacton glucose-dependent insulin secretion in pancreatic 120573-cells[9] The E23K variant in this gene demonstrated a robustassociation with T2D using the candidate gene approach [9]WFS1 and HNF1B were also uncovered as established genesassociated with T2D [11 12] WFS1 encodes wolframin amembrane glycoprotein that maintains calcium homeostasisof the endoplasmic reticulum Rare mutations inWFS1 causeWolfram syndrome which is characterized by a significant120573-cell loss as a result of enhanced endoplasmic reticulumstress [47ndash49] HNF1B encodes hepatocyte nuclear factor 1homeoboxBwhich is a liver-specific factor of the homeobox-containing basic helix-turn-helix family Mutation of thisgene was demonstrated to cause MODY5 [38]

In 2006 a large-scale association study identifiedTCF7L2as an important genetic factor for T2D in Icelandic individ-uals [10] This discovery was a significant breakthrough asthis association was then widely confirmed in populations ofEuropean origin and other ethnic groups such as Japaneseand American individuals [50ndash57] Therefore TCF7L2 wasregarded as the most significant T2D susceptibility geneidentified to date

212 Genome-Wide Association Study (GWAS) With theadvent of GWAS exploration of the genetic basis for T2Dsusceptibility has made significant breakthroughs In 2007the results of five genome-wide association studies werepublished These studies increased the number of confirmedT2D susceptibility loci to nine (PPAR120574 KCNJ11 TCF7L2

CDKAL1 CDKN2AB IGF2BP2 HHEXIDE FTO andSLC30A8) [13ndash18] Except for PPAR120574 and FTO which mainlyaffect insulin sensitivity all the other genes may affect 120573-cell function although the exact mechanisms remain largelyunknown [16] HHEX which is located on chromosome10q is a member of the homeobox family and encodes atranscription factor that maybe involved in Wnt signaling[58] Nevertheless these studies established the utility ofGWAS approach in elucidating complex genetic traits

In 2008 to increase the power of identifying variants withmodest effects a meta-analysis of three GWAS includingDiabetes Genetics Initiative (DGI) Finland-United StatesInvestigation of NIDDMGenetics (FUSION) andWellcomeTrust Case Control Consortium (WTCCC) were conductedThis study detected at least six previously unknown loci thatreached genome-wide significance for association with T2D(119875 lt 5times10minus8) with the loci being JAZF1 CDC123-CAMK1DTSPAN8-LGR5 THADA ADAMTS9 and NOTCH2 [19]Genetic variants in JAZF1 CDC123-CAMK1D TSPAN8-LGR5 and THADA have been reported to affect pancreatic120573-cell functions [59 60]

In 2009 a novel genetic variant rs2943641 which islocated adjacent to the insulin receptor substrate 1 gene(IRS1) was shown to have a significant association withinsulin resistance and hyperinsulinemia and further stud-ies also showed that this variant is implicated in reducedbasal IRS1 protein level and decreased IRS1-associatedphosphatidylinositol-3-OH kinase activity in human skeletalmuscle biopsies [21] In the same year a variant nearMTNR1Bwas found to be associated with increased fasting plasmaglucose level and higher risk of T2D (odds ratio = 115 95CI= 108ndash122 119875 = 63 times 10minus5) [20] Ten GWAS involving a totalof 36610 individuals of European descent and ameta-analysisof 13 case-control studies replicated this result and foundthat risk alleles in this gene are associated with reduced 120573-cell function as measured by homeostasis model assessment(HOMA-120573 119875 = 11 times 10minus15) [61]

In 2010 a meta-analysis of 21 genome-wide associa-tion studies performed by Dupuis and colleagues identifiedADCY5 PROX1 GCK GCKR and DGKBTMEM195 as newgenetic loci for T2D susceptibility [22] Among these lociDGKBTMEM195 GCK PROX1 and ADCY5 mainly affect


120573-cell functions whereas the locus mapped in GCKR showsa primary effect on insulin action [22] In the same yearanother genome-wide association study by Qi and colleaguesdiscovered new variants near RBMS1 and ITGB6 genesat 2q24 and these variants were found to affect glucosemetabolism and insulin resistance [23] In addition anexpanded meta-analysis of existing GWAS by Voight andcolleagues identified 12 new signals with a combined 119875 lt5times10

minus8 including BCL11A ZBED3KLF14 TP53INP1 TLE4CENTD2 HMGA2 HNF1A PRC1 ZFAND6 DUSP9 andKCNQ1 [24]HNF1A was previously recognized as the causalgene of MODY3 [62] and also harbored the common variant(G319S) that contributes to early-onset T2D [63 64]DUSP9mapped on chromosome X encodes a member of the familyof mitogen-activated protein kinase phosphatase 4 MKP4which is important in cell cycle regulation and plays pivotalroles in regulating insulin action [65ndash67]

In 2012 a meta-analysis conducted by Morris and col-leagues identified additional ten previously unreported T2Dsusceptible loci including BCAR1MC4R CILP2ANKRD55TLE1 KLHDC5MGC21675 ANK1 ZMIZ1 and GRB14 [25]To assess the potential function of these loci OGTT wasemployed to test insulin release and insulin sensitivity ANK1was found to be associatedwith insulinogenic and dispositionindices indicating that this gene probably had an effect oninsulin secretion [68] In this study GRB14 and AKNRD55were associated with decreased Matsuda index an index ofinsulin sensitivity [68]

As described above genetic studies of T2D in Europeanpopulations have made significant progress in our under-standing of T2D susceptibility However existing data canonly provide partial explanation for the heritability of T2DIt is well known that discrepancies exist in allelic frequenciesand effect sizes in different ethnic groups It is thereforeimportant to understand whether these variants are alsoapplicable to other ethnic populations

22 Genetics of T2D in East Asians Epidemiological studieshave documented consistent increases in the prevalence ofdiabetes in Asia especially in China with diabetes prevalencehaving increased from 26 in 2000 to 97 in 2010 [69]However our understanding of the genetic basis of T2Din East Asia remains limited It is therefore imperative toidentify specific genes associated with this disease in EastAsians

In 2008 two papers provided the first reports of GWASfor T2D in East Asian populations and ascertained KCNQ1as a new susceptibility locus [70 71] KCNQ1 encodes thepore-forming 120572-subunit of the voltage-gated K+ channel(KvLQT1) which is expressed mainly in the heart andpancreas Its association with T2D was further replicated inKorean [72] Chinese [26] and Singaporean [73] populationsas well as individuals of European descent [70] ThereforeKCNQ1 is regarded as the most significant locus for T2Din East Asians This genetic variant is implicated in insulinsecretion which may be the explanation for its associationwith T2D [73 74]

In 2010 another GWAS conducted in a Japanese groupidentified two new loci in UBE2E2 and C2CD4A-C2CD4BGenetic variants in C2CD4A-C2CD4Bwere then validated inEuropean populations [27] When the GWAS reports sprungup in East Asians Chinese investigators performed their firstGWAS in the Han Chinese residing in Taiwan and identifiedtwo new susceptible loci for T2D in PTPRD (protein tyrosinephosphatase receptor type D) and SRR (serine racemase)[29] PTPRD is a protein tyrosine phosphatase and mayplay a role in the pathogenesis of T2D through increasedinsulin resistance [75] SRR encodes a serine racemase thatsynthesizesD-serine fromL-serine andwhich confers risk forT2D via the glutamate signaling pathway [76 77] In the sameyear a fast-track multiple-stage study conducted in HanChinese population by Shu and colleagues discovered a novelgenetic susceptibility locus rs1359790 at 13q311 for T2Dand this variant was also validated in European AmericansKoreans and Singapore Chinese [28]

In 2011 in order to identify additional genes in EastAsians Cho and colleagues carried out a meta-analysis ofthree-stage GWAS in populations of East Asian descentCompelling evidence for association with T2D of eight novelloci was demonstrated by this study All of these loci aremapped in or near GLIS3 PEPD FITM2-R3HDML-HNF4AKCNK16MAEA GCC1-PAX4 PSMD6 and ZFAND [30]

In 2012 another GWAS in Japanese populations revealedthat rs515071 in ANK1 was associated with T2D at thegenome-wide significance level [31] ANK1 which encodesa member of the ankyrin family is also reported to beassociated with impaired insulin secretion and abnormallevel of HbA

1c [68 78] In addition GWAS in Beijing andShanghai populations added two new loci to the list GRK5and RASGRP1 and the association signal for GRK5 seems tobe specific to East Asians [32] GRK5 is regarded as a positiveregulator of insulin sensitivity and this protein is a potentialtherapeutic target for the treatment of insulin resistance [79]

In 2013 a novel variant rs10229583 at 7q32 near PAX4wasidentified in a meta-analysis of three GWAS from SouthernHan Chinese descents [33] As a member of the paired boxfamily of transcription factors PAX4 plays a critical rolein pancreatic 120573-cell development and 120573-cell functions [80]Further three new predisposing loci MIR129-LEP GPSM1and SLC16A13 with genome-wide significance for T2D wereidentified [34] Rs791595 is located between MIR129-1 andLEP The coding product of LEP leptin is closely related tobody weight regulation and its deficiency in mice and humancauses morbid obesity and diabetes while the role ofMIR129in diabetes remains unknown [81]

Besides these newly identified loci some susceptiblegenes identified in Caucasians were also replicated in EastAsians such as PPAR120574 KCNJ11 TCF2 TCF7L2 CDKAL1CDKN2A-CDKN2B IDE-KIF11-HHEX IGF2BP2 MTNR1BSLC30A8 KCNQ1 CDC123 GLIS3 HNF1B and DUSP9 [3282ndash93]

Together all these T2D risk loci initially identified orreplicated in East Asians provide new perspectives on theetiology of T2D and uncover the need for further studies toexplore additional loci with strong effects on T2D


23 Genetics of T2D in South Asians South Asia with morethan a quarter of the worldrsquos population harbors the highestnumber of patients suffering from T2D [94] Currently thenumber of diabetic patients is reaching 624 million and thenumber of prediabetic individuals is reaching 772 million[95] Compared to European populations South Asians are ata fourfold higher risk of T2D [96 97] Therefore significantefforts should be made to identify common genetic variantsunderlying the T2D risk in individuals of South Asianancestry

In 2011 a GWAS in South Asians identified six novel lociharboring disease-predisposing variants including GRB14ST6GAL1 VPS26A HMG20A AP3S2 and HNF4A Singlenucleotide polymorphisms (SNPs) at GRB14 were associatedwith insulin sensitivity and SNPs at ST6GAL1 and HNF4Awere associated with pancreatic 120573-cell function [35]

In 2013 a GWAS performed in Indians identifiedTMEM163 on chromosome 2q21 as a new signal for T2DTMEM163 encodes a putative vesicular transporter in nerveterminals and shows a plausible effect on T2D by impairinginsulin secretion [36] Concurrently a novel locus at 13q12 inthe SGCG gene was identified to confer T2D susceptibilityin Punjabi Sikhs from Northern India This associationdemonstrated excellent consistency across the three Sikhsamples but no significant association was observed in alarge East Asian replication study indicating that the detectedlocus is specific to the Indian Punjabi Sikh population [37]

In consideration of Indiarsquos complex demographic historycultural diversity differences in risk allele frequency andpattern of linkage disequilibrium existing between Europeanand South Asian populations large replication studies wereconducted to evaluate the contribution of European-derivedloci in South Asian populations SNPs in or near PPARGKCNJ11 TCF7L2 SLC30A8 HHEX CDKN2AB IGF2BP2CDKAL1 FTO KCNQ1 JAZF1 IRS1 KLF14 CHCHD9 andDUSP9 displayed significant associations with T2D in Pak-istani populations with similar effect sizes as those seen inEuropean populations [98ndash102]

24 Genetics of Type 2 Diabetes in Other Populations Thediscovery of new susceptibility loci for T2D by GWAS indifferent ethnic groups emphasizes the need to conduct moreGWAS based on ethnic background In addition to Europeanand Asian populations researchers also conducted studies inPima Indians and Mexican Americans aimed at identifyingnew risk loci

In Pima Indians a few genes have been reported to conferrisk of T2D In 2007 researchers found that variants withinARHGEF11 nominally increased the risk of T2D possibly as aresult of increased insulin resistance [103] In 2008 variationwithin PCLOwas confirmed to have a modest effect on early-onset T2D possibly by reduction of insulin action [104]In 2010 ACAD10 variation was found to increase T2D riskby impairing insulin sensitivity via abnormal lipid oxidation[105] Soon afterwards an ASK1 variant was identified toconfer susceptibility to T2D by decreasing insulin sensitivityowing to reduced ASK1 expression in skeletal muscle [106]However a replication study which genotyped SNPsmapped

in CDKAL SLC30A8 HHEX EXT2 IGF2BP2 LOC387761and FTO previously associated with T2D in Caucasians didnot provide any evidence for association with T2D or obesityamong full-heritage Pima Indians Instead they found thatCDKAL1 HHEX and EXT2 were evidently associated witheither insulin secretion or insulin action in Pima Indians withnormal glucose tolerance [107]

Similarly analysis of T2D risk genes in Mexican Amer-ican populations had identified several novel candidate locifor T2D such as rs979752 and rs10500641 nearUBQLNL andOR52H1 on chromosome 11 rs2773080 and rs3922812 in ornear RALGPS2 on chromosome 1 and rs1509957 near EGR2on chromosome 10 [108] In 2011 the largestGWAS andmeta-analysis of T2D in Mexican populations identified 49 SNPsin eight gene regions (PER3 PARD3B EPHA4 TOMM7PTPRD HNT LOC729993 and IL34) and six intergenicregions with an unadjusted 119875 value lt 1 times 10minus5 [109] Inconsideration of the fact that all the above loci did notreach genome-wide significance (119875 lt 5 times 10minus8) Williamsand colleagues analyzed 92 million SNPs in 8214 Mexicansand other Latin Americans and identified a novel locusassociated with T2D spanning the solute carriers SLC16A11(119875 = 39 times 10minus13 odds ratio (OR) = 129) They observed thatSLC16A11 mainly localizes with the endoplasmic reticulummembrane protein calnexin in liver salivary gland and thy-roid Importantly overexpression of SLC16A11 in HeLa cellsresulted in substantial increases in triacylglycerol suggestingthat SLC16A11 may have a role in hepatic lipid metabolism[16 110] Nevertheless the role of all these risk loci in thepathogenesis of diabetes remains unclear and needs furtherinvestigations

3 Correlation of the SusceptibilityLoci with the Pathogenesis of T2D

With the large number of aforementioned genetic locisusceptible to T2D the question pertains to how theyparticipate in the pathogenesis of T2D A great numberof studies have suggested that genetic variants in ornear KCNJ11 TCF7L2 WFS1 HNF1B IGF2BP2 CDKN2A-CDKN2B CDKAL1 SLC30A8HHEXIDE KCNQ1 THADATSPAN8LGR5 CDC123CAMK1D JAZF1 MTNR1BDGKBTMEM195 GCK PROX1 ADCY5 SRR CENTD2ST6GAL1 HNF4A KCNK16 FITM2-R3HDML-HNF4AGLIS3 GRB14 ANK1 BCAR1 RASGRP1 and TMEM163mayconfer T2D risk through impaired 120573-cell function [16 2444 68 111ndash114] whereas PPAR120574 ADAMTS9 IRS1 GCKRRBMS1ITGB6 PTPRD DUSP9 HMGA2 KLF14 GRB14ANKRD55 and GRK5 have an impact on insulin action [2124 115 116] (Tables 1 2 and 3) FTO and MC4R previouslyidentified genes associatedwith obesity appear to confer T2Drisk through their primary effects on BMI but recent GWAShave shown that their effects on T2D were independent ofBMI though FTOmay have a small but detectable influenceon T2D risk through insulin action [117 118]

31 Impact of TCF7L2 on the Risk of T2D TCF7L2 is themost intensively studied locus for T2D risk so far The risk


alleles of TCF7L2 were associated with enhanced expressionof this gene in human islets as well as impaired insulinsecretion both in vitro and in vivo The authors also observedan impaired incretin effect in subjects carrying risk alleles ofTCF7L2 and proposed the engagement of the enteroinsularaxis in T2D [119] Dennis and colleagues then verified thisresult and indicated that TCF7L2 variant rs7903146 affectedrisk of T2D at least in part through modifying the effect ofincretins on insulin secretion This was not due to reducedsecretion of glucose-dependent insulinotropic polypeptide(GIP) and glucagon-like peptide 1 (GLP-1) which exhibit animportant physiological role in boosting insulin secretionfollowing meals but rather due to the effect of TCF7L2on the sensitivity of 120573-cells to incretins [120] TCF7L2 hasalso been linked to altered pancreatic islet morphology asexemplified by increased individual islet size and alteredalpha and beta cell ratiodistribution within human islets[121] This phenomenon is also observed in other in vivoor in vitro studies [122ndash124] This further strengthened theevidence for the role of TCF7L2-associated alteration of celltypes in islets in the pathogenesis of T2D

TCF7L2 encodes the transcription factor TCF4 whichis related to Wnt signaling pathway and which plays acritical role in the pathogenesis of T2D The major effectorof the canonical Wnt signaling pathway is known as 120573-cateninTCF This bipartite transcription factor is formed byfree 120573-catenin (120573-cat) and a member of the TCF proteinfamily includingTCF7L2 (previously known as TCF-4) [125]GWAS have revealed the involvement of a Wnt ligand (Wnt-5b) Wnt coreceptor (LRP-5) and the Wnt pathway effectorTCF7L2 in the development of diabetes [126] Several pre-vious studies also provide evidence that the 120573-cateninTCFaxis participates in pancreatic cell proliferation and differ-entiation [127ndash131] Treatment of 120573-cells with purified Wntprotein or activated 120573-catenin augmented the proliferationof these cells [132] Intriguingly deletion of 120573-catenin withinthe pancreatic epithelium resulted in an almost completelack of acinar cells whereas deletion of 120573-catenin specifi-cally in differentiated acinar cells had no such effect [128]suggesting that the TCF7L2-related Wnt signaling mainlyperturbs pancreatic growth but not pancreatic functionHowever deletion of islet TCF7L2 expression from 120573-cellsdid not show any demonstrable effects on glucose-stimulatedinsulin secretion (GSIS) in adult mice whereas manipulatingTCF7L2 levels in the liver caused hypoglycemia and reducedhepatic glucose production [133] In concordance with theseresults risk alleles in TCF7L2 were associated with hepaticbut not peripheral insulin resistance and enhanced rateof hepatic glucose production in human [119] ThereforeTCF7L2-related disruption of 120573-cell function is probably theindirect consequence of primary events in liver or otherorganssystems

32 Impact of SCL30A8 on the Risk of T2D Besides TCF7L2solute carrier family 30 member 8 gene (SCL30A8) hasalso been explored in depth SCL30A8 encodes the islet-specific zinc transporter ZnT-8 which delivers zinc ions fromcytoplasm into intracellular insulin-containing granules and

is implicated in insulin maturation andor storage processesin 120573-cells [134] Expression level of ZnT-8 was remarkablydownregulated in the pancreas of dbdb andAkitamice in theearly stage of diabetes [135] Global SCL30A8 knockout micedemonstrated reduced plasma insulin impaired GSIS andmarkedly reduced islet zinc content [136] Remarkably bothZnT-8 knockout mice and human individuals carrying riskalleles of SLC30A8 exhibited increased hepatic insulin clear-ance with significantly increased c-peptideinsulin ratios[137] Contrary to the previous findings overexpressionof ZnT-8 in INS-1 cells stimulated zinc accumulation andenhancedGSIS of these cells [138] Importantly a recent studydiscovered that SCL30A8 gene transcription was regulatedby Pdx-1 a 120573-cell-enriched transcription factor and involvedin the development of islets through an intrinsic enhancerRestriction of Pdx-1 in pancreatic islet 120573-cells correlated withthe induction of SCL30A8 gene and ZnT-8 protein expression[139] Therefore the specific pathways by which SL30A8correlates with the pathogenesis of T2D still need furtherexploration

It should be noted that a great number of low frequencyvariants might not be identified by GWAS owing to therequired genome-wide significance level According to theexisting studies many important loci are also obscured as aresult of borderline associationsThe known variants accountfor only a small amount of the overall estimated geneticheritability therefore there is still a long way to go in termsof understanding the pathogenesis of type 2 diabetes

4 Clinical Utility of Genetic InformationPrediction of Type 2 Diabetes

One of most important clinical utilities of genetic informa-tion is to predict the risk of developing T2D among nondia-betic individuals This will facilitate the early interventionalstrategies to prevent or delay the onset of the disease A vastnumber of recent studies have constructed genetic risk scoremodels by summing up numerous independently inheritedsusceptible variants for T2D to evaluate the predictive abilityfrom the current genetic information For example the areaunder the receiver operating characteristic (ROC) curves(AUCs) is used to assess discriminative accuracy of thisapproach The AUC value can range from 05 to 10 wherethe AUC of 05 stands for the lack of discrimination andAUC of 1 stands for perfect discrimination An AUC valueof greater than 075 is considered to be clinically useful [140]Imamura and colleagues created a genetic risk score modelusing 49 susceptibility alleles (GRS-49) for T2D in a Japanesepopulation and discovered an increased level of AUC withcombined GRS-49 and clinical factors (including age sexand BMI) compared with each individually But the AUCvalue is only 0773 which shows a clinically modest butstatistically significant effect on T2D [141]This phenomenonis also observed in many other studies from different ethnicgroups [142 143] Controversially it was proposed thatphenotype-based risk models are superior to models basedon 20 common independently inherited diabetes risk allelesin discrimination for T2D with the observation of only


minimal improvement in accuracy of risk estimation whenadding genotypes to phenotype-based risk models [144] Thediscrepancy may result from the fact that prediction forT2D using genetic information is largely affected by age Forexample the Framingham Offspring Study conducted with3471 subjects followed over 34 years found out that commongenetic variations appropriately reclassified younger peoplefor T2D risk beyond clinical risk factors but it failed in olderpeople [145] In addition along with the rapid economicgrowth and lifestyle changes we may underscore the role ofenvironmental factors in the pathogenesis of T2D A recentstudy suggested that the potential deleterious effect of severalT2D loci may be abolished or at least attenuated by higherphysical activity levels or healthy lifestyle whereas they maybe augmented by low physical activity and dietary factors thatare similar to aWestern dietary pattern [146]Therefore theseinconsistencies will need further investigations

5 Pharmacogenomics of Type 2 Diabetes

With the advent of GWAS studies on the roles of inher-ited and acquired genetic variations in drug response haveundergone an evolution from pharmacogenetics into phar-macogenomics with a shift from the focus on individualcandidate genes toGWAS [147] Clinically it is often observedthat even patients who receive similar antidiabetic regimensdemonstrate large variability in drug disposition glycemicresponse tolerability and incidence of adverse effects [148]This interindividual variability can be attributed to specificgene polymorphisms involved in the metabolism trans-portation and therapeutic mechanisms of oral antidiabeticdrugs Pharmacogenomics is on the agenda to explore fea-sible genetic testing to predict treatment outcome so thatappropriate steps could be taken to treat type 2 diabetes moreefficiently

In general the oral antidiabetic drug (OAD) is the firstline treatment for T2D after failure of lifestyle interventionThe most commonly prescribed OADs include sulfonylureas(SU) biguanides thiazolidinediones (TZDs) glinides and120572-glucosidase inhibitors To date numerous pharmacogeneticstudies comparing these drugs have been conducted inpopulations with different ethnic backgrounds With respectto sulfonylureas genetic variants at multiple loci such asKCNJ11 ABCC8 IRIS1 TCF7L2 NOS1AP KCNQ1 CDKAL1and CAPN10 affect pharmacokinetics andor pharmacody-namics of these drugs [149ndash157] Among them KCNJ11encodes a major subunit of the ATP-sensitive K+ channelandABCC8 encodes amodulator of ATP-sensitive potassiumchannels (SUR1) They both play pivotal roles in insulinsecretion and are both shown in pharmacogenomic studiesto impact sulfonylureas efficacy [151 158] The Arg (972)IRS-1 variant is associated with increased risk for secondaryfailure to sulfonylurea and it is noteworthy that the genotypefrequency of this variant is twice as high in patients withsecondary failure to sulfonylurea compared to the diabeticpatients whose blood glucose levels were well controlledwith oral therapy [157] In diabetic patients carrying riskalleles in NOS1AP gene glibenclamide is less effective in

reducing glucose levels The increased mortality in usersof sulfonylurea was also shown in this paper remindingus of the fact that genetic variation could alter responsesto T2D therapy [155] Consistent with this notion studieshave shown that genetic variants in SLC22A1 SLC22A2SLC47A1 SLC47A2 and ATM [159ndash167] were found to affectmetformin efficacy SLC22A1 encodes organic cation trans-porter 1 (OCT1) which participates in the transportation ofmetformin into hepatocytes SLC47A1 encodes themultidrugand toxin extrusion 1 protein (MATE1) which facilitatesmetformin excretion from hepatocytes into bileATM a geneknown to be involved in DNA repair and cell cycle controlplays a role in metformin efficacy upstream of AMPK andvariation in this gene alters glycemic responses to metformin[167]

Gene polymorphisms associated with glinide (repaglin-ide and nateglinide) responses were mapped in CYP2C8SLCO1B1 TCF7L2 CYP3A4 IGF2BP2 SLC30A8 KCNQ1KCNJ11 NAMPT UCP2 MDR1 NeuroD1 and PAX4 [168ndash174] Among them SLCO1B1 is mainly expressed in thebasolateral membrane of hepatocytes and can facilitate hep-atic uptake of repaglinide [175] polymorphisms of thisgene have significant influence on the pharmacokinetics ofrepaglinide with reduced pharmacokinetic exposure after asingle oral dose administration of 2mg repaglinide [176]Thiazolidinediones also known as glitazones act as agonistsfor their molecular target peroxisome proliferator-activatedreceptor-120574 (PPAR-120574) The direct antioxidant action of glita-zones may contribute to its effect on insulin resistance [177]Recent studies have also reported several loci involved in thepharmacogenetics of thiazolidinediones including PGC-1120572resistin adiponectin leptin TNF-alpha and CYP2C8 [178ndash183]

Pharmacogenetic research provides a means to bet-ter understand and improve pharmacotherapy Despite allthese advances in the field of pharmacogenetics adequatelydesigned and rigorously conducted clinical trials are stillneeded for guiding therapeutic decisions in T2D treatment

6 Conclusion

To date approximately 70 loci associated with T2D havebeen identified Despite this excellent progress the currentknowledge from these genetic data is still not sufficient tosupport the clinical utility for the prediction early identi-fication and prevention of diabetes As an emerging fieldpharmacogenomics aims at exploring possible molecularmechanisms of drugs and specific genetic variants associatedwith drug efficacy and thus can make contributions fordecisions regarding drug selection dose titration treatmentduration and avoidance of adverse drug reactions Howeverthe loci identified so far explain only a small amount ofthe estimated heritability of type 2 diabetes and the clinicalutility of genetic information is still in its preliminary stageThere is no doubt that intensive studies should be conductedto further identify T2D inheritability factors and promotethe translation of novel findings from GWAS to clinicalapplication


Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Xue Sun and Weihui Yu contributed equally to this paper

Acknowledgments

The authors thank all the individuals who participated inthis study and are appreciative of the doctors and nurses atthe Shanghai Clinical Center for DiabetesThey acknowledgeGrants from NSFC (81322010) the Excellent Young Medi-cal Expert of Shanghai (XYQ2011041) the Shanghai TalentDevelopment Grant (2012041) and the National Young TopTalent Supporting Program

References

[1] J E Shaw R A Sicree and P Z Zimmet ldquoGlobal estimates ofthe prevalence of diabetes for 2010 and 2030rdquoDiabetes Researchand Clinical Practice vol 87 no 1 pp 4ndash14 2010

[2] J B Meigs P Shrader L M Sullivan et al ldquoGenotype scorein addition to common risk factors for prediction of type 2diabetesrdquoThe New England Journal of Medicine vol 359 no 21pp 2208ndash2219 2008

[3] M van Hoek A Dehghan J C MWitteman et al ldquoPredictingtype 2 diabetes based on polymorphisms from genome-wideassociation studies a population-based studyrdquoDiabetes vol 57no 11 pp 3122ndash3128 2008

[4] M C Cornelis L Qi C Zhang et al ldquoJoint effects of commongenetic variants on the risk for type 2 diabetes in US men andwomen of European ancestryrdquo Annals of Internal Medicine vol150 no 8 pp 541ndash550 2009

[5] V Lyssenko A Jonsson P Almgren et al ldquoClinical risk factorsDNAvariants and the development of type 2 diabetesrdquoTheNewEngland Journal of Medicine vol 359 no 21 pp 2220ndash22322008

[6] V G Manolopoulos G Ragia and A Tavridou ldquoPharma-cogenomics of oral antidiabetic medications current data andpharmacoepigenomic perspectiverdquo Pharmacogenomics vol 12no 8 pp 1161ndash1191 2011

[7] CHuang and J C Florez ldquoPharmacogenetics in type 2 diabetespotential implications for clinical practicerdquo Genome Medicinevol 3 no 11 article 76 2011

[8] D Altshuler J N Hirschhorn M Klannemark et al ldquoThecommon PPAR120574 Pro12Ala polymorphism is associated withdecreased risk of type 2 diabetesrdquo Nature Genetics vol 26 no1 pp 76ndash80 2000

[9] A L GloynMNWeedon K R Owen et al ldquoLarge-scale asso-ciation studies of variants in genes encoding the pancreatic 120573-cell K

119860119879119875

channel subunits Kir62 (KCNJ11) and SUR1 (ABCC8)confirm that the KCNJ11 E23K variant is associated with type 2diabetesrdquo Diabetes vol 52 no 2 pp 568ndash572 2003

[10] S F A Grant G Thorleifsson I Reynisdottir et al ldquoVariant oftranscription factor 7-like 2 (TCF7L2) gene confers risk of type2 diabetesrdquo Nature Genetics vol 38 no 3 pp 320ndash323 2006

[11] M S Sandhu M N Weedon K A Fawcett et al ldquoCommonvariants inWFS1 confer risk of type 2 diabetesrdquoNature Geneticsvol 39 no 8 pp 951ndash953 2007

[12] J Gudmundsson P Sulem V Steinthorsdottir et al ldquoTwovariants on chromosome 17 confer prostate cancer risk and theone in TCF2 protects against type 2 diabetesrdquo Nature Geneticsvol 39 no 8 pp 977ndash983 2007

[13] E Zeggini M N Weedon C M Lindgren et al ldquoReplicationof genome-wide association signals in UK samples reveals riskloci for type 2 diabetesrdquo Science vol 316 no 5829 pp 1336ndash13412007

[14] R Saxena B F Voight V Lyssenko et al ldquoGenome-wideassociation analysis identifies loci for type 2 diabetes andtriglyceride levelsrdquo Science vol 316 no 5829 pp 1331ndash13362007

[15] L J Scott K LMohlke L L Bonnycastle et al ldquoA genome-wideassociation study of type 2 diabetes in Finns detects multiplesusceptibility variantsrdquo Science vol 316 no 5829 pp 1341ndash13452007

[16] V Steinthorsdottir G Thorleifsson I Reynisdottir et al ldquoAvariant in CDKAL1 influences insulin response and risk of type2 diabetesrdquo Nature Genetics vol 39 no 6 pp 770ndash775 2007

[17] R Sladek G Rocheleau J Rung et al ldquoA genome-wideassociation study identifies novel risk loci for type 2 diabetesrdquoNature vol 445 no 7130 pp 881ndash885 2007

[18] P R Burton D G Clayton L R Cardon et al ldquoGenome-wideassociation study of 14000 cases of seven common diseases and3000 shared controlsrdquo Nature vol 447 no 7145 pp 661ndash6782007

[19] E Zeggini L J Scott R Saxena andB F Voight ldquoMeta-analysisof genome-wide association data and large-scale replicationidentifies additional susceptibility loci for type 2 diabetesrdquoNature Genetics vol 40 no 5 pp 638ndash645 2008

[20] N Bouatia-Naji A Bonnefond C Cavalcanti-Proenca et alldquoA variant near MTNR1B is associated with increased fastingplasma glucose levels and type 2 diabetes riskrdquoNature Geneticsvol 41 no 1 pp 89ndash94 2009

[21] J Rung S Cauchi A Albrechtsen et al ldquoGenetic variant nearIRS1 is associated with type 2 diabetes insulin resistance andhyperinsulinemiardquoNature Genetics vol 41 no 10 pp 1110ndash11152009

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[24] B F Voight L J Scott V Steinthorsdottir et al ldquoTwelvetype 2 diabetes susceptibility loci identified through large-scaleassociation analysisrdquoNature Genetics vol 42 no 7 pp 579ndash5892010

[25] A P Morris B F Voight T M Teslovich et al ldquoLarge-scale association analysis provides insights into the geneticarchitecture and pathophysiology of type 2 diabetesrdquo NatureGenetics vol 44 no 9 pp 981ndash990 2012

[26] C Hu C Wang R Zhang et al ldquoVariations in KCNQ1 areassociated with type 2 diabetes and beta cell function in aChinese populationrdquo Diabetologia vol 52 no 7 pp 1322ndash13252009


[27] T Yamauchi K Hara S Maeda et al ldquoA genome-wide associ-ation study in the Japanese population identifies susceptibilityloci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4BrdquoNature Genetics vol 42 no 10 pp 864ndash868 2010

[28] X O Shu J Long Q Cai et al ldquoIdentification of new geneticrisk variants for type 2 diabetesrdquo PLoS Genetics vol 6 no 9Article ID e1001127 2010

[29] F-J Tsai C-F Yang C-C Chen et al ldquoA genome-wideassociation study identifies susceptibility variants for type 2diabetes in Han Chineserdquo PLoS Genetics vol 6 no 2 ArticleID e1000847 2010

[30] Y S Cho C H Chen C Hu et al ldquoMeta-analysis of genome-wide association studies identifies eight new loci for type 2diabetes in east AsiansrdquoNatureGenetics vol 44 no 1 pp 67ndash722012

[31] M Imamura S Maeda T Yamauchi et al ldquoA single-nucleotidepolymorphism in ANK1 is associated with susceptibility to type2 diabetes in Japanese populationsrdquoHumanMolecular Geneticsvol 21 no 13 pp 3042ndash3049 2012

[32] H Li W Gan L Lu et al ldquoA genome-wide association studyidentifiesGRK5 andRASGRP1 as type 2 diabetes loci in ChineseHansrdquo Diabetes vol 62 no 1 pp 291ndash298 2013

[33] R C Ma C Hu C H Tam et al ldquoGenome-wide associationstudy in a Chinese population identifies a susceptibility locusfor type 2 diabetes at 7q32 near PAX4rdquoDiabetologia vol 56 no6 pp 1291ndash1305 2013

[34] K Hara H Fujita T A Johnson et al ldquoGenome-wide associa-tion study identifies three novel loci for type 2 diabetesrdquoHumanMolecular Genetics vol 23 no 1 pp 239ndash246 2014

[35] J S Kooner D Saleheen X Sim et al ldquoGenome-wide associa-tion study in individuals of South Asian ancestry identifies sixnew type 2 diabetes susceptibility locirdquoNature Genetics vol 43no 10 pp 984ndash989 2011

[36] R Tabassum G Chauhan O P Dwivedi et al ldquoGenome-wideassociation study for type 2 diabetes in Indians identifies a newsusceptibility locus at 2q21rdquoDiabetes vol 62 no 3 pp 977ndash9862013

[37] R Saxena D Saleheen L F Been et al ldquoGenome-wideassociation study identifies a novel locus contributing to type2 diabetes susceptibility in Sikhs of Punjabi origin from IndiardquoDiabetes vol 62 no 5 pp 1746ndash1755 2013

[38] S S Fajans G I Bell and K S Polonsky ldquoMolecular mecha-nisms and clinical pathophysiology of maturity-onset diabetesof the youngrdquo The New England Journal of Medicine vol 345no 13 pp 971ndash980 2001

[39] I Barroso ldquoGenetics of type 2 diabetesrdquo Diabetic Medicine vol22 no 5 pp 517ndash535 2005

[40] M Vaxillaire and P Froguel ldquoMonogenic diabetes in the youngpharmacogenetics and relevance to multifactorial forms of type2 diabetesrdquo Endocrine Reviews vol 29 no 3 pp 254ndash264 2008

[41] Y Horikawa N Oda N J Cox et al ldquoGenetic variation inthe gene encoding calpain-10 is associated with type 2 diabetesmellitusrdquo Nature Genetics vol 26 no 2 pp 163ndash175 2000

[42] DMeyre N Bouatia-Naji A Tounian et al ldquoVariants of ENPP1are associatedwith childhood and adult obesity and increase therisk of glucose intolerance and type 2 diabetesrdquoNature Geneticsvol 37 no 8 pp 863ndash867 2005

[43] L D Love-Gregory J Wasson J Ma et al ldquoA common poly-morphism in the upstream promoter region of the hepatocytenuclear factor-4120572 gene on chromosome 20 q is associated withtype 2 diabetes and appears to contribute to the evidence for

linkage in an Ashkenazi Jewish populationrdquo Diabetes vol 53no 4 pp 1134ndash1140 2004

[44] K Silander K L Mohlke L J Scott et al ldquoGenetic variationnear the hepatocyte nuclear factor-4120572 gene predicts suscepti-bility to type 2 diabetesrdquo Diabetes vol 53 no 4 pp 1141ndash11492004

[45] F Vasseur N Helbecque C Dina et al ldquoSingle-nucleotidepolymorphism haplotypes in the both proximal promoterand exon 3 of the APM1 gene modulate adipocyte-secretedadiponectin hormone levels and contribute to the genetic riskfor type 2 diabetes in French Caucasiansrdquo Human MolecularGenetics vol 11 no 21 pp 2607ndash2614 2002

[46] S S Deeb L FajasMNemoto et al ldquoAPro12Ala substitution inPPAR1205742 associated with decreased receptor activity lower bodymass index and improved insulin sensitivityrdquo Nature Geneticsvol 20 no 3 pp 284ndash287 1998

[47] A Karasik C OrsquoHara S Srikanta et al ldquoGenetically pro-grammed selective islet 120573-cell loss in diabetic subjects withWolframrsquos syndromerdquo Diabetes Care vol 12 no 2 pp 135ndash1381989

[48] A C Riggs E Bernal-Mizrachi M Ohsugi et al ldquoMiceconditionally lacking the Wolfram gene in pancreatic islet betacells exhibit diabetes as a result of enhanced endoplasmicreticulum stress and apoptosisrdquoDiabetologia vol 48 no 11 pp2313ndash2321 2005

[49] T Yamada H Ishihara A Tamura et al ldquoWFS1-deficiencyincreases endoplasmic reticulum stress impairs cell cycle pro-gression and triggers the apoptotic pathway specifically inpancreatic 120573-cellsrdquo Human Molecular Genetics vol 15 no 10pp 1600ndash1609 2006

[50] C J Groves E Zeggini J Minton et al ldquoAssociation analysis of6736 UK subjects provides replication and confirmsTCF7L2 asa type 2 diabetes susceptibility gene with a substantial effect onindividual riskrdquo Diabetes vol 55 no 9 pp 2640ndash2644 2006

[51] C Zhang L Qi D J Hunter et al ldquoVariant of transcriptionfactor 7-like 2 (TCF7L2) gene and the risk of type 2 diabetes inlarge cohorts of US women and menrdquo Diabetes vol 55 no 9pp 2645ndash2648 2006

[52] L J Scott L L Bonnycastle C J Willer et al ldquoAssociationof transcription factor 7-like 2 (TCF7L2) variants with type 2diabetes in a Finnish samplerdquo Diabetes vol 55 no 9 pp 2649ndash2653 2006

[53] CM Damcott T I Pollin L J Reinhart et al ldquoPolymorphismsin the transcription factor 7-like 2 (TCF7L2) gene are associatedwith type 2 diabetes in the Amish replication and evidence fora role in both insulin secretion and insulin resistancerdquoDiabetesvol 55 no 9 pp 2654ndash2659 2006

[54] R Saxena L Gianniny N P Burtt et al ldquoCommon singlenucleotide polymorphisms in TCF7L2 are reproducibly asso-ciated with type 2 diabetes and reduce the insulin response toglucose in nondiabetic individualsrdquoDiabetes vol 55 no 10 pp2890ndash2895 2006

[55] S Cauchi D Meyre C Dina et al ldquoTranscription factorTCF7L2 genetic study in the French population expression inhuman 120573-cells and adipose tissue and strong association withtype 2 diabetesrdquo Diabetes vol 55 no 10 pp 2903ndash2908 2006

[56] T Hayashi Y Iwamoto K Kaku H Hirose and S MaedaldquoReplication study for the association of TCF7L2 with suscepti-bility to type 2 diabetes in a Japanese populationrdquoDiabetologiavol 50 no 5 pp 980ndash984 2007

[57] M Horikoshi K Hara C Ito R Nagai P Froguel and TKadowaki ldquoA genetic variation of the transcription factor 7-like


2 gene is associated with risk of type 2 diabetes in the Japanesepopulationrdquo Diabetologia vol 50 no 4 pp 747ndash751 2007

[58] A C Foley and M Mercola ldquoHeart induction by Wnt antago-nists depends on the homeodomain transcription factor HexrdquoGenes amp Development vol 19 no 3 pp 387ndash396 2005

[59] A M Simonis-Bik G Nijpels T W van Haeften et al ldquoGenevariants in the novel type 2 diabetes loci CDC123CAMK1DTHADA ADAMTS9 BCL11A and MTNR1B affect differentaspects of pancreatic 120573-cell functionrdquo Diabetes vol 59 no 1pp 293ndash301 2010

[60] N Grarup G Andersen N T Krarup et al ldquoAssocia-tion testing of novel type 2 diabetes risk alleles in theJAZF1 CDC123CAMK1D TSPAN8 THADA ADAMTS9 andNOTCH2 Loci with insulin release insulin sensitivity andobesity in a population-based sample of 4516 glucose-tolerantmiddle-aged danesrdquo Diabetes vol 57 no 9 pp 2534ndash25402008

[61] I Prokopenko C Langenberg J C Florez et al ldquoVariants inMTNR1B influence fasting glucose levelsrdquo Nature Genetics vol41 no 1 pp 77ndash81 2009

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3

family with a novelHNF1A germline mutationrdquo Journal of Hepatology vol 59 no4 pp 904ndash907 2013

[63] DM LimNHuh andK Y Park ldquoHepatocyte nuclear factor 1-120572mutation in normal glucose-tolerant subjects and early-onsettype 2 diabetic patientsrdquo Korean Journal of Internal Medicinevol 23 no 4 pp 165ndash169 2008

[64] R A Hegele H Cao S B Harris A J G Hanley andB Zinman ldquoThe hepatic nuclear factor-1120572 G319S variant isassociated with early-onset type 2 diabetes in Canadian Oji-CreerdquoThe Journal of Clinical Endocrinology amp Metabolism vol84 no 3 pp 1077ndash1082 1999

[65] H Xu M Dembski Q Yang et al ldquoDual specificity mitogen-activated protein (MAP) kinase phosphatase-4 plays a potentialrole in insulin resistancerdquo The Journal of Biological Chemistryvol 278 no 32 pp 30187ndash30192 2003

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[67] B Emanuelli D Eberle R Suzuki and C R Kahn ldquoOverex-pression of the dual-specificity phosphatase MKP-4DUSP-9protects against stress-induced insulin resistancerdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 105 no 9 pp 3545ndash3550 2008

[68] M N Harder R Ribel-Madsen J M Justesen et al ldquoType 2diabetes risk alleles near BCAR1 and in ANK1 associate withdecreased 120573-cell function whereas risk alleles near ANKRD55and GRB14 associate with decreased insulin sensitivity in theDanish Inter99 cohortrdquoThe Journal of Clinical Endocrinology ampMetabolism vol 98 no 4 pp E801ndashE806 2013

[69] H Li BOldenburg C Chamberlain et al ldquoDiabetes prevalenceand determinants in adults in China mainland from 2000to 2010 a systematic reviewrdquo Diabetes Research and ClinicalPractice vol 98 no 2 pp 226ndash235 2012

[70] K Yasuda KMiyake YHorikawa et al ldquoVariants inKCNQ1 areassociatedwith susceptibility to type 2 diabetesmellitusrdquoNatureGenetics vol 40 no 9 pp 1092ndash1097 2008

[71] H Unoki A Takahashi T Kawaguchi et al ldquoSNPs in KCNQ1are associatedwith susceptibility to type 2 diabetes in East Asianand European populationsrdquo Nature Genetics vol 40 no 9 pp1098ndash1102 2008

[72] Y-H Lee E S Kang S H Kim et al ldquoAssociation betweenpolymorphisms in SLC30A8 HHEX CDKN2AB IGF2BP2FTOWFS1CDKAL1KCNQ1 and type 2 diabetes in the Koreanpopulationrdquo Journal of Human Genetics vol 53 no 11-12 pp991ndash998 2008

[73] J T Tan S Nurbaya D Gardner S Ye E S Tai and D P KNg ldquoGenetic variation inKCNQ1 associates with fasting glucoseand 120573-cell function a study of 3734 subjects comprising threeethnicities living in SingaporerdquoDiabetes vol 58 no 6 pp 1445ndash1449 2009

[74] K Mussig H Staiger F Machicao et al ldquoAssociation of type 2diabetes candidate polymorphisms inKCNQ1with incretin andinsulin secretionrdquo Diabetes vol 58 no 7 pp 1715ndash1720 2009

[75] Y C Chang Y F Chiu P H Liu et al ldquoReplication of genome-wide association signals of type 2 diabetes in Han Chinese ina prospective cohortrdquo Clinical Endocrinology vol 76 no 3 pp365ndash372 2012

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[77] H Wolosker K N Sheth M Takahashi et al ldquoPurification ofserine racemase biosynthesis of the neuromodulator D-serinerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 96 no 2 pp 721ndash725 1999

[78] N Soranzo S Sanna E Wheeler et al ldquoCommon variants at 10genomic loci influence hemoglobin A

1119862

levels via glycemic andnonglycemic pathwaysrdquoDiabetes vol 59 no 12 pp 3229ndash32392010

[79] L Wang M Shen F Wang et al ldquoGRK5 ablation contributesto insulin resistancerdquo Biochemical and Biophysical ResearchCommunications vol 429 no 1-2 pp 99ndash104 2012

[80] J Wang L Elghazi S E Parker et al ldquoThe concerted activitiesof PAX4 and Nkx22 are essential to initiate pancreatic 120573-celldifferentiationrdquo Developmental Biology vol 266 no 1 pp 178ndash189 2004

[81] Y Zhang R Proenca M Maffei M Barone L Leopold and JM Friedman ldquoPositional cloning of the mouse obese gene andits human homologuerdquo Nature vol 372 no 6505 pp 425ndash4321994

[82] Y Liu L Yu D Zhang et al ldquoPositive association betweenvariations in CDKAL1 and type 2 diabetes in Han Chineseindividualsrdquo Diabetologia vol 51 no 11 pp 2134ndash2137 2008

[83] M Xu Y Bi Y Xu et al ldquoCombined effects of 19 commonvariations on type 2 diabetes in Chinese results from twocommunity-based studiesrdquo PLoS ONE vol 5 no 11 Article IDe14022 2010

[84] Y Wu H Li R J F Loos et al ldquoCommon variants in CDKAL1CDKN2AB IGF2BP2 SLC30A8 and HHEXIDE genes areassociated with type 2 diabetes and impaired fasting glucose ina Chinese Han populationrdquo Diabetes vol 57 no 10 pp 2834ndash2842 2008

[85] Y Liu Z Liu Y Song et al ldquoMeta-analysis added power toidentify variants in FTO associated with type 2 diabetes andobesity in the Asian populationrdquoObesity vol 18 no 8 pp 1619ndash1624 2010


[86] J Wen T Ronn A Olsson et al ldquoInvestigation of type 2diabetes risk alleles supportCDKN2ABCDKAL1 and TCF7L2as susceptibility genes in aHanChinese cohortrdquo PLoSONE vol5 no 2 Article ID e9153 2010

[87] C Hu R Zhang C Wang et al ldquoPPARG KCNJ11 CDKAL1CDKN2A-CDKN2B IDE-KIF11-HHEX IGF2BP2 and SLC30A8are associated with type 2 diabetes in a chinese populationrdquoPLoS ONE vol 4 no 10 Article ID e7643 2009

[88] J Xiang X-Y Li M Xu et al ldquoZinc transporter-8 gene(SLC30A8) is associated with type 2 diabetes in Chineserdquo TheJournal of Clinical Endocrinology amp Metabolism vol 93 no 10pp 4107ndash4112 2008

[89] T Ronn J Wen Z Yang et al ldquoA common variant inMTNR1Bencoding melatonin receptor 1B is associated with type 2 dia-betes and fasting plasma glucose in Han Chinese individualsrdquoDiabetologia vol 52 no 5 pp 830ndash833 2009

[90] M C Y Ng C H T Tam V K L Lam W-Y So R CW Ma and J C N Chan ldquoReplication and identification ofnovel variants at TCF7L2 associated with type 2 diabetes inHong Kong Chineserdquo The Journal of Clinical Endocrinology ampMetabolism vol 92 no 9 pp 3733ndash3737 2007

[91] M C Y Ng K S Park B Oh et al ldquoImplication of geneticvariants nearTCF7L2 SLC30A8HHEXCDKAL1CDKN2ABIGF2BP2 and FTO in type 2 diabetes and obesity in 6719Asiansrdquo Diabetes vol 57 no 8 pp 2226ndash2233 2008

[92] Y-C Chang T-J Chang Y-D Jiang et al ldquoAssociation studyof the genetic polymorphisms of the transcription factor 7-like2 (TCF7L2) gene and type 2 diabetes in theChinese populationrdquoDiabetes vol 56 no 10 pp 2631ndash2637 2007

[93] H Fukuda M Imamura Y Tanaka et al ldquoA single nucleotidepolymorphism within DUSP9 is associated with susceptibilityto type 2 diabetes in a Japanese populationrdquo PLoS One vol 7no 9 Article ID e46263 2012

[94] B Basnyat and L C Rajapaksa ldquoCardiovascular and infectiousdiseases in South Asia the double whammyrdquo British MedicalJournal vol 328 no 7443 p 781 2004

[95] R M Anjana R Pradeepa M Deepa et al ldquoPrevalenceof diabetes and prediabetes (impaired fasting glucose andorimpaired glucose tolerance) in urban and rural India phasei results of the Indian Council of Medical Research-INdiaDIABetes (ICMR-INDIAB) studyrdquo Diabetologia vol 54 no 12pp 3022ndash3027 2011

[96] A Ramachandran R C Ma and C Snehalatha ldquoDiabetes inAsiardquoThe Lancet vol 375 no 9712 pp 408ndash418 2010

[97] J C Chambers O A Obeid H Refsum et al ldquoPlasmahomocysteine concentrations and risk of coronary heart diseasein UK Indian Asian and European menrdquo The Lancet vol 355no 9203 pp 523ndash527 2000

[98] D K Sanghera L Ortega S Han et al ldquoImpact of ninecommon type 2 diabetes risk polymorphisms in Asian IndianSikhsPPARG2 (Pro12Ala) IGF2BP2TCF7L2 and FTO variantsconfer a significant riskrdquo BMC Medical Genetics vol 9 article59 2008

[99] C S Yajnik C S Janipalli S Bhaskar et al ldquoFTO gene variantsare strongly associated with type 2 diabetes in South AsianIndiansrdquo Diabetologia vol 52 no 2 pp 247ndash252 2009

[100] M Chidambaram V Radha and V Mohan ldquoReplication ofrecently described type 2 diabetes gene variants in a SouthIndian populationrdquo Metabolism vol 59 no 12 pp 1760ndash17662010

[101] G Chauhan C J Spurgeon R Tabassum et al ldquoImpactof common variants of PPARG KCNJ11 TCF7L2 SLC30A8

HHEX CDKN2A IGF2BP2 and CDKAL1 on the risk of type2 diabetes in 5164 Indiansrdquo Diabetes vol 59 no 8 pp 2068ndash2074 2010

[102] S D Rees M Z I Hydrie A S Shera et al ldquoReplication of13 genome-wide association (GWA)-validated risk variants fortype 2 diabetes in Pakistani populationsrdquo Diabetologia vol 54no 6 pp 1368ndash1374 2011

[103] L Ma R L Hanson L N Que et al ldquoVariants in ARHGEF11a candidate gene for the linkage to type 2 diabetes on chromo-some 1q are nominally associated with insulin resistance andtype 2 diabetes in Pima Indiansrdquo Diabetes vol 56 no 5 pp1454ndash1459 2007

[104] L Ma R L Hanson L N Que et al ldquoPCLO variants arenominally associated with early-onset type 2 diabetes andinsulin resistance in Pima Indiansrdquo Diabetes vol 57 no 11 pp3156ndash3160 2008

[105] L Bian R L Hanson Y L Muller et al ldquoVariants in ACAD10are associated with type 2 diabetes insulin resistance and lipidoxidation in Pima IndiansrdquoDiabetologia vol 53 no 7 pp 1349ndash1353 2010

[106] L Bian R L Hanson V Ossowski et al ldquoVariants in ASK1 areassociated with skeletal muscleASK1 expression in vivo insulinresistance and type 2 diabetes in Pima Indiansrdquo Diabetes vol59 no 5 pp 1276ndash1282 2010

[107] R Rong R L Hanson D Ortiz et al ldquoAssociation analysisof variation innear FTO CDKAL1 SLC30A8 HHEX EXT2IGF2BP2 LOC387761 and CDKN2B with type 2 diabetes andrelated quantitative traits in Pima IndiansrdquoDiabetes vol 58 no2 pp 478ndash488 2009

[108] M G Hayes A Pluzhnikov K Miyake et al ldquoIdentification oftype 2 diabetes genes in Mexican Americans through genome-wide association studiesrdquo Diabetes vol 56 no 12 pp 3033ndash3044 2007

[109] J E Below E R Gamazon J V Morrison et al ldquoGenome-wide association and meta-analysis in populations from StarrCounty Texas andMexico City identify type 2 diabetes suscep-tibility loci and enrichment for expression quantitative trait lociin top signalsrdquo Diabetologia vol 54 no 8 pp 2047ndash2055 2011

[110] ldquoSequence variants in SLC16A11 are a common risk factor fortype 2 diabetes in Mexicordquo Nature vol 506 pp 97ndash101 2013

[111] V Lyssenko C L F Nagorny M R Erdos et al ldquoCommonvariant in MTNR1B associated with increased risk of type 2diabetes and impaired early insulin secretionrdquo Nature Geneticsvol 41 no 1 pp 82ndash88 2009

[112] T W Boesgaard N Grarup T Joslashrgensen K Borch-JohnsenT Hansen and O Pedersen ldquoVariants at DGKBTMEM195ADRA2A GLIS3 and C2CD4B loci are associated with reducedglucose-stimulated beta cell function in middle-aged Danishpeoplerdquo Diabetologia vol 53 no 8 pp 1647ndash1655 2010

[113] TNielsen T Sparsoslash NGrarup et al ldquoType 2 diabetes risk allelenear CENTD2 is associated with decreased glucose-stimulatedinsulin releaserdquo Diabetologia vol 54 no 5 pp 1052ndash1056 2011

[114] SD ReesM Z IHydrie J POrsquoHare et al ldquoEffects of 16 geneticvariants on fasting glucose and type 2 diabetes in South AsiansADCY5 and GLIS3 variants may predispose to type 2 diabetesrdquoPLoS ONE vol 6 no 9 Article ID e24710 2011

[115] T W Boesgaard A P Gjesing N Grarup et al ldquoVariant nearADAMTS9 known to associate with type 2 diabetes is relatedto insulin resistance in offspring of type 2 diabetes patientsmdashEUGENE2 studyrdquo PLoS ONE vol 4 no 9 Article ID e72362009


[116] A Anand and K Chada ldquoIn vivo modulation ofHmgic reducesobesityrdquo Nature Genetics vol 24 no 4 pp 377ndash380 2000

[117] T Q Binh P T Phuong B T Nhung et al ldquoAssociationof the common FTO-rs9939609 polymorphism with type 2diabetes independent of obesity-related traits in a Vietnamesepopulationrdquo Gene vol 513 no 1 pp 31ndash35 2013

[118] B Xi F Takeuchi G R Chandak et al ldquoCommon polymor-phism near the MC4R gene is associated with type 2 diabetesdata from a meta-analysis of 123 373 individualsrdquoDiabetologiavol 55 no 10 pp 2660ndash2666 2012

[119] V Lyssenko R Lupi P Marchetti et al ldquoMechanisms by whichcommon variants in the TCF7L2 gene increase risk of type 2diabetesrdquoThe Journal of Clinical Investigation vol 117 no 8 pp2155ndash2163 2007

[120] D T Villareal H Robertson G I Bell et al ldquoTCF7L2 variantrs7903146 affects the risk of type 2 diabetes by modulatingincretin actionrdquo Diabetes vol 59 no 2 pp 479ndash485 2010

[121] O le Bacquer J Kerr-Conte S Gargani et al ldquoTCF7L2rs7903146 impairs islet function and morphology in non-diabetic individualsrdquoDiabetologia vol 55 no 10 pp 2677ndash26812012

[122] Y Takeda Y Fujita J Honjo et al ldquoReduction of both 120573 celldeath and alpha cell proliferation by dipeptidyl peptidase-4inhibition in a streptozotocin-induced model of diabetes inmicerdquo Diabetologia vol 55 no 2 pp 404ndash412 2012

[123] K H Yoon S H Ko J H Cho et al ldquoSelective 120573-cell loss and120572-cell expansion in patients with type 2 diabetes mellitus inKoreardquoThe Journal of Clinical Endocrinology ampMetabolism vol88 no 5 pp 2300ndash2308 2003

[124] C L Kirkpatrick PMarchetti F Purrello et al ldquoType 2 diabetessusceptibility gene expression in normal or diabetic sortedhuman alpha and beta cells correlations with age or BMI of isletdonorsrdquo PLoS ONE vol 5 no 6 Article ID e11053 2010

[125] V Korinek N Barker P Moerer et al ldquoDepletion of epithelialstem-cell compartments in the small intestine of mice lackingTcf-4rdquo Nature Genetics vol 19 no 4 pp 379ndash383 1998

[126] W Ip Y T Chiang and T Jin ldquoThe involvement of the Wntsignaling pathway and TCF7L2 in diabetes mellitus the currentunderstanding dispute and perspectiverdquoCell amp Bioscience vol2 no 1 article 28 2012

[127] J Dessimoz C Bonnard J Huelsken and A Grapin-BottonldquoPancreas-specific deletion of120573-catenin revealsWnt-dependentand Wnt-independent functions during developmentrdquo CurrentBiology vol 15 no 18 pp 1677ndash1683 2005

[128] L CMurtaugh A C Law Y Dor andD AMelton ldquo120573-cateninis essential for pancreatic acinar but not islet developmentrdquoDevelopment vol 132 no 21 pp 4663ndash4674 2005

[129] S Papadopoulou and H Edlund ldquoAttenuated Wnt signalingperturbs pancreatic growth but not pancreatic functionrdquo Dia-betes vol 54 no 10 pp 2844ndash2851 2005

[130] P W Heiser J Lau M M Taketo P L Herrera and MHebrok ldquoStabilization of 120573-catenin impacts pancreas growthrdquoDevelopment vol 133 no 10 pp 2023ndash2032 2006

[131] R S Heller D S Dichmann J Jensen et al ldquoExpression pat-terns ofWnts Frizzleds sFRPs andmisexpression in transgenicmice suggesting a role for Wnts in pancreas and foregut patternformationrdquo Developmental Dynamics vol 225 no 3 pp 260ndash270 2002

[132] I C Rulifson S K Karnik P W Heiser et al ldquoWnt signalingregulates pancreatic 120573 cell proliferationrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 104 no 15 pp 6247ndash6252 2007

[133] S F Boj JH vanEsMHuch et al ldquoDiabetes risk gene andWnteffector TCF7L2TCF4 controls hepatic response to perinataland adult metabolic demandrdquo Cell vol 151 no 7 pp 1595ndash16072012

[134] F Chimienti A Favier andM Seve ldquoZnT-8 a pancreatic120573-cell-specific zinc transporterrdquo Biometals vol 18 no 4 pp 313ndash3172005

[135] M Tamaki Y Fujitani T Uchida T Hirose R Kawamori andH Watada ldquoDownregulation of ZnT8 expression in pancreatic120573-cells of diabetic micerdquo Islets vol 1 no 2 pp 124ndash128 2009

[136] L D Pound S A Sarkar R K P Benninger et al ldquoDeletion ofthe mouse Slc30a8 gene encoding zinc transporter-8 results inimpaired insulin secretionrdquo Biochemical Journal vol 421 no 3pp 371ndash376 2009

[137] M Tamaki Y Fujitani A Hara et al ldquoThe diabetes-susceptiblegene SLC30A8ZnT8 regulates hepatic insulin clearancerdquo TheJournal of Clinical Investigation vol 123 no 10 pp 4513ndash45242013

[138] F Chimienti S Devergnas F Pattou et al ldquoIn vivo expressionand functional characterization of the zinc transporter ZnT8 inglucose-induced insulin secretionrdquo Journal of Cell Science vol119 no 20 pp 4199ndash4206 2006

[139] L D Pound Y Hang S A Sarkar et al ldquoThe pancreatic islet120573-cell-enriched transcription factor Pdx-1 regulates Slc30a8gene transcription through an intronic enhancerrdquo BiochemicalJournal vol 433 no 1 pp 95ndash105 2011

[140] Q Qi and F B Hu ldquoGenetics of type 2 diabetes in Europeanpopulationsrdquo Journal of Diabetes vol 4 no 3 pp 203ndash212 2012

[141] M Imamura D Shigemizu T Tsunoda et al ldquoAssessing theclinical utility of a genetic risk score constructed using 49 sus-ceptibility alleles for type 2 diabetes in a Japanese populationrdquoThe Journal of Clinical Endocrinology ampMetabolism vol 98 no10 pp 1667ndash1673 2013

[142] J N Cooke M C Y Ng N D Palmer et al ldquoGenetic riskassessment of type 2 diabetes-associated polymorphisms inAfrican Americansrdquo Diabetes Care vol 35 no 2 pp 287ndash2922012

[143] M Iwata S Maeda Y Kamura et al ldquoGenetic risk scoreconstructed using 14 susceptibility alleles for type 2 diabetesis associated with the early onset of diabetes and may predictthe future requirement of insulin injections among Japaneseindividualsrdquo Diabetes Care vol 35 no 8 pp 1763ndash1770 2012

[144] P J Talmud A D Hingorani J A Cooper et al ldquoUtility ofgenetic and non-genetic risk factors in prediction of type 2diabetes Whitehall II prospective cohort studyrdquo BritishMedicalJournal vol 340 Article ID b4838 2010

[145] J M de Miguel-Yanes P Shrader M J Pencina et al ldquoGeneticrisk reclassification for type 2 diabetes by age below or above 50years using 40 type 2 diabetes risk single nucleotide polymor-phismsrdquo Diabetes Care vol 34 no 1 pp 121ndash125 2011

[146] M C Cornelis and F B Hu ldquoGene-environment interactionsin the development of type 2 diabetes recent progress andcontinuing challengesrdquo Annual Review of Nutrition vol 32 pp245ndash259 2012

[147] L Wang H L McLeod and R M Weinshilboum ldquoGenomicsand drug responserdquo The New England Journal of Medicine vol364 no 12 pp 1144ndash1153 2011

[148] G C Mannino and G Sesti ldquoIndividualized therapy for type2 diabetes clinical implications of pharmacogenetic datardquoMolecular Diagnosis ampTherapy vol 16 no 5 pp 285ndash302 2012


[149] H Xu M Murray and A J McLachlan ldquoInfluence of geneticpolymorphisms on the pharmacokinetics and pharmacody-namics of sulfonylurea drugsrdquo Current Drug Metabolism vol10 no 6 pp 643ndash658 2009

[150] A Surendiran S C Pradhan A Agrawal et al ldquoInfluence ofCYP2C9 gene polymorphisms on response to glibenclamide intype 2 diabetes mellitus patientsrdquo European Journal of ClinicalPharmacology vol 67 no 8 pp 797ndash801 2011

[151] M Rafiq S E Flanagan A-M Patch et al ldquoEffective treatmentwith oral sulfonylureas in patients with diabetes due to sulfony-lurea receptor 1 (SUR1) mutationsrdquo Diabetes Care vol 31 no 2pp 204ndash209 2008

[152] Y Feng G Mao X Ren et al ldquoSer1369Ala variant in sul-fonylurea receptor gene ABCC8 is associated with antidiabeticefficacy of gliclazide in Chinese type 2 diabetic patientsrdquoDiabetes Care vol 31 no 10 pp 1939ndash1944 2008

[153] E R Pearson L A Donnelly C Kimber et al ldquoVariationin TCF7L2 influences therapeutic response to sulfonylureas aGoDARTs studyrdquo Diabetes vol 56 no 8 pp 2178ndash2182 2007

[154] M G Garcıa-Escalante V M Suarez-Solıs M T D J Lopez-Avila D D C Pinto-Escalante and H Laviada-Molina ldquoEffectof the Gly972Arg SNP43 and Pro12Ala polymorphisms ofthe genes IRS1 CAPN10 and PPARG2 on secondary failure tosulphonylurea and metformin in patients with type 2 diabetesin Yucatan Mexicordquo Investigacion Clinica vol 50 no 1 pp 65ndash76 2009

[155] M L Becker A-J Aarnoudse C Newton-Cheh et al ldquoCom-mon variation in the NOS1AP gene is associated with reducedglucose-lowering effect and with increased mortality in users ofsulfonylureardquo Pharmacogenetics and Genomics vol 18 no 7 pp591ndash597 2008

[156] A Seeringer S Parmar A Fischer et al ldquoGenetic variants ofthe insulin receptor substrate-1 are influencing the therapeuticefficacy of oral antidiabeticsrdquoDiabetes Obesity andMetabolismvol 12 no 12 pp 1106ndash1112 2010

[157] G Sesti M A Marini M Cardellini et al ldquoThe Arg972 variantin insulin receptor substrate-1 is associated with an increasedrisk of secondary failure to sulfonylurea in patients with type 2diabetesrdquo Diabetes Care vol 27 no 6 pp 1394ndash1398 2004

[158] E R Pearson I Flechtner P R Njoslashlstad et al ldquoSwitching frominsulin to oral sulfonylureas in patients with diabetes due toKir62 mutationsrdquo The New England Journal of Medicine vol355 no 5 pp 467ndash477 2006

[159] Y Shu S A Sheardown C Brown et al ldquoEffect of genetic vari-ation in the organic cation transporter 1 (OCT1) on metforminactionrdquo The Journal of Clinical Investigation vol 117 no 5 pp1422ndash1431 2007

[160] M V Tzvetkov S V Vormfelde D Balen et al ldquoThe effectsof genetic polymorphisms in the organic cation transportersOCT1 OCT2 and OCT3 on the renal clearance of metforminrdquoClinical Pharmacology amp Therapeutics vol 86 no 3 pp 299ndash306 2009

[161] M L Becker L E Visser R H N van Schaik A HofmanA G Uitterlinden and B H C Stricker ldquoGenetic variation inthe organic cation transporter 1 is associated with metforminresponse in patients with diabetes mellitusrdquo PharmacogenomicsJournal vol 9 no 4 pp 242ndash247 2009

[162] M M H Christensen C Brasch-Andersen H Green et alldquoThe pharmacogenetics of metformin and its impact on plasmametformin steady-state levels and glycosylated hemoglobinA1crdquo Pharmacogenetics and Genomics vol 21 no 12 pp 837ndash850 2011

[163] I S Song H J Shin E J Shim et al ldquoGenetic variants ofthe organic cation transporter 2 influence the disposition ofmetforminrdquo Clinical Pharmacology amp Therapeutics vol 84 no5 pp 559ndash562 2008

[164] M L Becker L E Visser R H N van Schaik A HofmanA G Uitterlinden and B H C Stricker ldquoGenetic variationin the multidrug and toxin extrusion 1 transporter proteininfluences the glucose-lowering effect of metformin in patientswith diabetes a preliminary studyrdquo Diabetes vol 58 no 3 pp745ndash749 2009

[165] K A Jablonski J B McAteer P I W de Bakker et alldquoCommon variants in 40 genes assessed for diabetes incidenceand response to metformin and lifestyle intervention in thediabetes prevention programrdquoDiabetes vol 59 no 10 pp 2672ndash2681 2010

[166] J H Choi S W Yee A H Ramirez et al ldquoA common 51015840-UTR variant in MATE2-K is associated with poor response tometforminrdquo Clinical Pharmacology amp Therapeutics vol 90 no5 pp 674ndash684 2011

[167] K Zhou C Bellenguez C C A Spencer et al ldquoCommonvariants near ATM are associated with glycemic response tometformin in type 2 diabetesrdquo Nature Genetics vol 43 no 2pp 117ndash120 2011

[168] J Kirchheiner I Roots M Goldammer B Rosenkranz and JBrockmoller ldquoEffect of genetic polymorphisms in cytochromeP450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oralantidiabetic drugs clinical relevancerdquo Clinical Pharmacokinet-ics vol 44 no 12 pp 1209ndash1225 2005

[169] Y Cheng G Wang W Zhang et al ldquoEffect of CYP2C9and SLCO1B1 polymorphisms on the pharmacokinetics andpharmacodynamics of nateglinide in healthy Chinese malevolunteersrdquo European Journal of Clinical Pharmacology vol 69no 3 pp 407ndash413 2013

[170] W Zhang Y-J He C-T Han et al ldquoEffect of SLCO1B1 geneticpolymorphism on the pharmacokinetics of nategliniderdquo BritishJournal of Clinical Pharmacology vol 62 no 5 pp 567ndash5722006

[171] Q Huang J-Y Yin X-P Dai et al ldquoAssociation analysisof SLC30A8 rs13266634 and rs16889462 polymorphisms withtype 2 diabetes mellitus and repaglinide response in ChinesepatientsrdquoEuropean Journal of Clinical Pharmacology vol 66 no12 pp 1207ndash1215 2010

[172] Q Xiang Y M Cui X Zhao L Yan and Y Zhou ldquoTheinfluence of MDR1G2677TA genetic polymorphisms on thepharmacokinetics of repaglinide in healthyChinese volunteersrdquoPharmacology vol 89 no 1-2 pp 105ndash110 2012

[173] X-P Dai Q Huang J-Y Yin et al ldquoKCNQ1 gene poly-morphisms are associated with the therapeutic efficacy ofrepaglinide in Chinese type 2 diabetic patientsrdquo Clinical andExperimental Pharmacology and Physiology vol 39 no 5 pp462ndash468 2012

[174] F-F Sheng X-P Dai J Qu et al ldquoNAMPT-3186CT polymor-phismaffects repaglinide response inChinese patientswith type2 diabetes mellitusrdquo Clinical and Experimental Pharmacologyand Physiology vol 38 no 8 pp 550ndash554 2011

[175] H Takane ldquoGenetic polymorphisms of SLCO1B1 for drug phar-macokinetics and its clinical implicationsrdquo Yakugaku Zasshivol 131 no 11 pp 1589ndash1594 2011

[176] J He Z Qiu N Li et al ldquoEffects of SLCO1B1 polymorphisms onthe pharmacokinetics and pharmacodynamics of repaglinidein healthy Chinese volunteersrdquo European Journal of ClinicalPharmacology vol 67 no 7 pp 701ndash707 2011


[177] KMizushige T Tsuji andTNoma ldquoPioglitazone cardiovascu-lar effects in prediabetic patientsrdquoCardiovascular Drug Reviewsvol 20 no 4 pp 329ndash340 2002

[178] E S Kang S Y Park H J Kim et al ldquoEffects of Pro12Alapolymorphism of peroxisome proliferator-activated receptor1205742 gene on rosiglitazone response in type 2 diabetesrdquo ClinicalPharmacology ampTherapeutics vol 78 no 2 pp 202ndash208 2005

[179] K-H Zhang Q Huang X-P Dai et al ldquoEffects of the per-oxisome proliferator activated receptor-120574 coactivator-1120572 (PGC-1120572) Thr394Thr and Gly482Ser polymorphisms on rosiglitazoneresponse in Chinese patients with type 2 diabetes mellitusrdquoTheJournal of Clinical Pharmacology vol 50 no 9 pp 1022ndash10302010

[180] H Makino I Shimizu S Murao et al ldquoA pilot study suggeststhat the GG genotype of resistin single nucleotide polymor-phism at minus420 may be an independent predictor of a reductionin fasting plasma glucose and insulin resistance by pioglitazonein type 2 diabetesrdquo Endocrine Journal vol 56 no 9 pp 1049ndash1058 2009

[181] H Sun Z-C Gong J-Y Yin et al ldquoThe association ofadiponectin allele 45TG and minus11377CG polymorphisms withtype 2 diabetes and rosiglitazone response in Chinese patientsrdquoBritish Journal of Clinical Pharmacology vol 65 no 6 pp 917ndash926 2008

[182] H-L Liu Y-G Lin J Wu et al ldquoImpact of genetic poly-morphisms of leptin and TNF-120572 on rosiglitazone response inChinese patients with type 2 diabetesrdquo European Journal ofClinical Pharmacology vol 64 no 7 pp 663ndash671 2008

[183] J Kirchheiner S Thomas S Bauer et al ldquoPharmacokineticsand pharmacodynamics of rosiglitazone in relation to CYP2C8genotyperdquo Clinical Pharmacology ampTherapeutics vol 80 no 6pp 657ndash667 2006

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


Table 1 European-derived susceptibility loci for type 2 diabetes


mechanism

2000 PPAR120574 [8] rs1801282 3 12368125 CG 092 114 Insulin actionCandidate andlarge-scale

association study

2003 KCNJ11 [9] rs5219 11 17366148 TC 05 114 120573-Cell functionCandidate andlarge-scale

association study

2006 TCF7L2 [10] rs7903146 10 114748339 TC 025 137 120573-Cell functionCandidate andlarge-scale

association study

2007 WFS1 [11] rs10010131 4 6343816 GA 06 111 120573-Cell functionCandidate andlarge-scale

association study

2007 HNF1B [12] rs4430796 17 rs4430796 AG 047 11 120573-Cell functionCandidate andlarge-scale

association study2007 IGF2BP2 [13ndash15] rs4402960 3 186994381 TG 029 114 120573-Cell function GWAS2007 CDKN2A-CDKN2B [13ndash15] rs10811661 9 rs10811661 TC 079 12 120573-Cell function GWAS2007 CDKAL1 [13ndash16] rs10946398 6 20769013 CA 031 112 120573-Cell function GWAS2007 SLC30A8 [17] rs13266634 8 118253964 CT 075 112 120573-Cell function GWAS2007 HHEXIDE [17] rs1111875 10 94452862 CT 056 113 120573-Cell function GWAS2007 FTO [13 15 18] rs8050136 16 rs8050136 AC 045 117 Obesity GWAS2008 NOTCH2 [19] rs10923931 1 120230001 TG 0106 113 Unknown GWAS2008 ADAMTS9 [19] rs4607103 3 64686944 CT 0761 109 Insulin action GWAS2008 THADA [19] rs7578597 2 43644474 TC 0902 115 120573-Cell function GWAS2008 TSPAN8LGR5 [19] rs7961581 12 69949369 CT 0269 109 120573-Cell function GWAS2008 CDC123CAMK1D [19] rs12779790 10 12368016 GA 0183 111 120573-Cell function GWAS2008 JAZF1 [19] rs864745 7 28147081 TC 0501 11 120573-Cell function GWAS2009 MTNR1B [20] rs1387153 11 92313476 TC 0283 115 120573-Cell function GWAS2009 IRS1 [21] rs2943641 2 226801989 CT 0633 119 Insulin action GWAS2010 DGKBTMEM195 [22] rs2191349 7 15030834 TG 0333 106 120573-Cell function GWAS2010 GCKR [22] rs780094 2 27594741 CT 0394 106 Insulin action GWAS2010 GCK [22] rs4607517 7 44202193 AG 0195 107 120573-Cell function GWAS2010 PROX1 [22] rs340874 1 212225879 CT 0492 107 120573-Cell function GWAS2010 ADCY5 [22] rs11708067 3 124548468 AG 0226 112 120573-Cell function GWAS2010 RBMS1ITGB6 [23] rs7593730 2 160879700 CT 023 09 Insulin action GWAS2010 KCNQ1 [24] rs231362 11 2648047 GA 052 108 120573-Cell function GWAS2010 DUSP9 [24] rs5945326 X 152553116 AG 079 127 Insulin action GWAS2010 PRC1 [24] rs8042680 15 89322341 AC 022 107 Unknown GWAS2010 ZFAND6 [24] rs11634397 15 78219277 GA 06 106 Unknown GWAS2010 HNF1A [24] rs7957197 12 119945069 TA 085 107 Unknown GWAS2010 HMGA2 [24] rs1531343 12 64461161 CG 01 11 Insulin action GWAS2010 CENTD2 [24] rs1552224 11 72110746 AC 088 114 120573-Cell function GWAS2010 CHCHD9 [24] rs13292136 9 81141948 CT 093 111 Unknown GWAS2010 TP53INP1 [24] rs896854 8 96029687 TC 048 106 Unknown GWAS2010 KLF14 [24] rs972283 7 130117394 GA 055 107 Insulin action GWAS2010 ZBED3 [24] rs4457053 5 76460705 GA 026 108 Unknown GWAS2010 BCL11A [24] rs243021 2 60438323 AG 046 108 Unknown GWAS


Table 1 Continued































































6 Conclusion







Acknowledgments


References










119860119879119875



























































3


















1119862























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


Table 1 Continued































































6 Conclusion







Acknowledgments


References










119860119879119875



























































3


















1119862























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology























































6 Conclusion







Acknowledgments


References










119860119879119875



























































3


















1119862























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






Acknowledgments


References










119860119879119875



























































3


















1119862























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology









































3


















1119862























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology















































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

review article genetics of type 2 diabetes: insights into...

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