review article genetics of sub-saharan african human...

Review ArticleGenetics of Sub-Saharan African Human PopulationImplications for HIVAIDS Tuberculosis and Malaria

Gerald Mboowa12

1 Department of Medical Microbiology College of Health Sciences Makerere University PO Box 7072 Kampala Uganda2 School of Allied Health Sciences International Health Sciences University PO Box 7782 Kampala Uganda

Correspondence should be addressed to Gerald Mboowa gmboowayahoocom

Received 28 April 2014 Revised 9 July 2014 Accepted 1 August 2014 Published 18 August 2014

Academic Editor Yoko Satta

Copyright copy 2014 Gerald Mboowa This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Sub-Saharan Africa has continued leading in prevalence and incidence of major infectious disease killers such as HIVAIDStuberculosis and malaria Epidemiological triad of infectious diseases includes susceptible host pathogen and environment Itis imperative that all aspects of vertices of the infectious disease triad are analysed to better understand why this is so Studies doneto address this intriguing reality though have mainly addressed pathogen and environmental components of the triad Africa isthe most genetically diverse region of the world as well as being the origin of modern humans Malaria is relatively an ancientinfection in this region as compared to TB and HIVAIDS from the evolutionary perspective we would draw lessons that thisancestrally unique population now under three important infectious diseases both ancient and exotic will be skewed into increasedgenetic diversity moreover other evolutionary forces are also still at play Host genetic diversity resulting from many years ofmalaria infection has been well documented in this population we are yet to account for genetic diversity from the trio of theseinfections Effect of host genetics on treatment outcome has been documented Host genetics of sub-Saharan African populationand its implication to infectious diseases are an important aspect that this review seeks to address

1 Introduction

HIVAIDS TB and malaria are three important killerdiseases globally however these continue to devastatemore of sub-Saharan African populations with a totalof 27 countries Sub-Saharan Africa alone accounted foran estimated 70 percent of all people living with HIV[1] and 70 percent of all AIDS deaths in 2011 [2] Datapublished by the World Health Organization (WHO 2014httpwwwwhointmediacentrefactsheetsfs104en) indi-cate that sub-Saharan Africa carried the greatest propor-tion of new tuberculosis cases per population with over255 cases per 100 000 population in 2012 (WHO 2013httpwwwwhointmediacentrefactsheetsfs094en) indi-cate most malaria cases and deaths occur in sub-SaharanAfrica

Sub-Saharan Africa is important regarding origin ofhuman species and the way in which genetic variation affectshuman phenotypes Africa is thought to be the ancestralhomeland of all modern humans and is the most recent

homeland of millions of individuals whose ancestors werebrought to Europe and to the Americas as slaves [3] There ismuch to be learned from the genetics of sub-Saharan Africanpopulations about human origins and evolution and aboutthe origin and nature of human complex disease At presentwe have little understanding of the genetic structure of sub-Saharan populations and the genetic basis of complex diseasein African populations because very few genetic studies havebeen conducted in African ethnic groups Research activityhas traditionally been biased towards the study of non-African populations and our knowledge of even the mostfundamental information about the genetic basis of disease inAfrica is quite limited [3] yet these three infectious diseasesaccount for the highest morbidity and mortality Increasedfunding and resources for studying genetic diversity in Africaare needed to reconstruct human evolutionary history todissect the genetic basis of resistance and susceptibilityto disease and to design better drugs for all people [3]I suggest that this will require collaborative efforts withAfrican institutions and ensure that the capacity is sustained

Hindawi Publishing CorporationInternational Journal of Evolutionary BiologyVolume 2014 Article ID 108291 8 pageshttpdxdoiorg1011552014108291

2 International Journal of Evolutionary Biology

A shared set of DNA resources and the establishment of anAfrican genetic database would help to provide researcherswith common information and would facilitate studies ofseveral loci in the same set of African populations Studiesalso need to meet strict ethical standards and to involve bothlocal researchers and study participants [3] I am compelledto propose that modern humans who migrated away fromsub-SaharanAfrica encounterednew environment and exoticpathogens in their new geographical niches Those exoticpathogens and other evolutionary forces which they metin the different areas where they settled would account forunique genetics Infectious diseases have continued and willcontinue shaping the course of human evolution

The hypothesis whereby infectious diseases have beenacting as a powerful selective pressure was formulated longago but it was not until the availability of large-scale geneticdata and the development of novel methods to studymolecu-lar evolution that we could assess how pervasively infectiousagents have shaped human genetic diversity [4] Diseaseoutcome ismultifactorial process requiring interplay of host-environment-microbial factors which ultimately determinedisease resistance and progression Genetic structures of theexposed human populations will determine the susceptibilitypatterns that are always observed in the host Recent genome-wide analysis indicates that among the diverse environmentalfactors that most likely acted as selective pressures duringthe evolution of human species (climate diet regimes andinfections) pathogen load had the strongest influence onthe shaping of human genetic variability [5] Possibly theindigenous pathogens in sub-Saharan Africa coevolved withtheir hosts creating unique genetic profiles in these humanpopulations I propose that a form of Newtonrsquos third lawof motion happens during an interaction between host andpathogen action and reaction are equal and opposite Thisimplies that the selective pressure exerted by these pathogensonto selected host genes in response to specific pathogengenes received similar pressure from the host driving host-pathogen diversity observed as unique genetic profiles inboth host and pathogen accounting for coevolution Studiesshow certain host-pathogens specificities probably due tocoevolution I further propose that these unique geneticprofiles created over time affect vaccine efficacy and of latewe know that treatment outcome is also affected by the hostgenetic structures The unique genetic profiles created inthese human populations can act as risk genetic factors foremerging pathogens Penicillin was a wonder drug at thebirth of the antibiotic era but after half a century of its clinicaluse we observe emergence of penicillin resistant bacteriastrains these have acquired genetic variations that theirancestors never had In the antibioticantiviral era drugs arealso likely to act as selective pressure creating genetic diversityin pathogen genomes as well as hostsrsquo

2 Human Host Genetic Diversity andInfectious Diseases

The high levels of genetic diversity in African populationsand their demographic history make these populations

particularly informative for the fine mapping of com-plex genetic diseases [6] as well as infectious diseasesStudies using mitochondrial (mt) DNA and nuclear DNAmarkers consistently indicate that Africa is the most genet-ically diverse region of the world [7] Historically humanpopulation genetic studies have relied on one or two Africanpopulations as being representative of African diversity butrecent studies show extensive genetic variation among evengeographically close African populations which indicatesthat there is not a single ldquorepresentativerdquo African population[3]

The immunological responses to MTB are due to theinteraction between the immune system human host andbacterial and environmental factors [8] Genetic as well asacquired defects in host immune response pathways greatlyincrease the risk of progressive disease [9] Results fromgenome-wide linkage studies suggest that TB disease suscep-tibility is highly likely to be polygenic with contributionsfrom many minor loci [10] and a large number of TBsusceptibility markers have been identified from candidategene studies as ldquodisease-causingrdquo genes which include TIRAPHLA DQB1 VDR IL-12120573 IL12R1205731 IFN-120574 SLC11A1 andMCP-1 However to date the greatest evidence to support anunderlying genetic basis for TB has come from the discoveryof single gene defects predisposing to disseminated and oftenlethal mycobacterial disease [11]

To better understand why HIVAIDS tuberculosis andmalaria aremore common infectious diseases in sub-SaharanAfrica we must appreciate the regionrsquos human genetic diver-sity and this will provide data that may help understandwhy there is a mixed population of both resistant andsusceptible populations coexisting We can assert that theindigenous infections like malaria and tuberculosis havecreated unique genetic structures in these mixed ethnicpopulations which can be risk factors for exotic infec-tious diseases like HIVAIDS and vice versa A notionthat exposure to indigenous pathogensparasites in theseareas shaped the genetic structures of these native humanpopulations resulting in interethnic variation in suscep-tibility to modern infectious agents is undisputable Thegreat human genetic diversity and the continued presenceof infectious agents in sub-Saharan Africa will continuecontributing to the observed susceptibilities to infectiousdiseases

3 HIVAIDS

Host genetic polymorphisms contribute to interindividualvariation in susceptibility to acquiring HIV-1 infection thedegree of infectiousness to others (as reflected by the viralload) and rates of disease progression [12] Such polymor-phisms might also contribute to significant interpopula-tion differences in HIV-1 prevalence [12ndash16] Duffy antigenreceptor for chemokines (DARC) expressed on red bloodcells (RBCs) influences plasma levels of HIV-1-suppressiveand proinflammatory chemokines such as CCL5RANTES[17] DARC is also the RBC receptor for Plasmodiumvivax Africans with DARC-46CC genotype which confers

International Journal of Evolutionary Biology 3

a DARC- negative phenotype are resistant to vivax malariaHIV-1 attaches to RBCs via DARC effecting transinfectionof target cells [17] In African Americans DARC-46CC isassociated with 40 increase in the odds of acquiring HIV-1 [17] If extrapolated to Africans about 11 of the HIV-1 burden in Africa may be linked to this genotype Afterinfection occurs however DARC-negative RBC status isassociated with slower disease progression [17]

Host genetic influence on HIVAIDS susceptibility bya polymorphism that is differentially distributed betweenpopulations is best illustrated by the effects of the European-specific 32 bp deletion (D32) in the gene for CC chemokinereceptor 5 (CCR5) which is the major coreceptor for R5strains of HIV-1 that represent the majority of transmissi-ble viruses [18] CCR5-Δ32 exhibit variable frequencies indistinct populations [19ndash22] and possibly their phenotypesdepend on the host ethnicity analyzed [12 20ndash24] Distri-bution of the protective Δ32 allele is however restricted toNorthern Europe where it occurs at a frequency of (10ndash16)and its frequency decreases in a Southeast cline towards theMediterranean and gradually disappears in the African andAsian populations [25] The Δ32 mutation is most commonin individuals of European descent but is absent or rare inthe black African population [25] A recent study in SouthAfrica detected Δ32 mutation only in the Caucasian groupand it also reported greater genetic diversity in CCR5 genein the black South African population showing 39 mutationsbeing exclusive [26] This extensive variation in CCR5 genein a small studied African population is in agreement withthe concept that Africans have the greatest ethnic geneticdiversity in the world

The genes CCL3L1CCL4L1 encode the chemokinesMIP-1120572 and MIP-1120573 which are both ligands for the chemokinereceptor CCR5 used as a coreceptor by R5 strains of HIV[27] CCL3L1 gene dose has been associated with inter-subject differences in susceptibility to HIV acquisition inEuropean African and Hispanic-American adults intra-venous drug users from Estonia and hemophiliacs fromJapan [13 28 29] The average copy number of CCL3L1varies among populations [13] A study in Central AfricanPygmies indicated that there might be a CCL3L1-CCR5-dependent biological basis for interpopulation differencesin HIV prevalence and concluded that the copy numberof CCL3L1 genes is determinant of HIV-AIDS susceptibility[30]

The CCR5-Δ32 mutation along with single nucleotidepolymorphisms (SNPs) in the CCR5 promoter and theCCR2-V64I mutation have been included in sevenhuman haplogroups (HH) previously associated withresistancesusceptibility to HIV-1 infection and differentrates of AIDS progression [31] In vitro studies havedemonstrated that HIV-1 can use alternative coreceptorssuch as CCR2 [32] A genetic variant of CCR2 (CCR2-V64I)leads to variations in the CCR2 transmembrane region andhas been associated with slow progression to AIDS howeverits effect on susceptibility to acquire HIV-1 infection hasnot been defined to date [33] This would be a study worthcarrying out in sub-SaharanAfrican population Recently theimmunoregulatory cytokine IL-10 was identified as playing

a key role in suppressing antiviral immune responsesleading to viral persistence [34 35] A study in South Africapopulations indicated that individuals carrying the IL-10-592AA genotype were more likely to become HIV-1 infectedfurther these results generally suggested that IL-10 promoterpolymorphisms were linked to low IL-10 production andassociated with increased HIV-1 susceptibility [36]

A study in Kenya revealed pathological interactionsbetween HIV and malaria in dually infected patients but thepublic health implications of the interplay have remainedunclear [37] A transient almost one-log elevation in HIVviral load occurred during febrile malaria episodes inaddition susceptibility to malaria was enhanced in HIV-infected patients [37] Coinfection might also have facilitatedthe geographic expansion of malaria in areas where HIVprevalence is high therefore transient and repeated increasesin HIV viral load resulting from recurrent coinfection withmalaria may be an important factor in promoting the spreadof HIV in sub-Saharan Africa [37]

4 Tuberculosis

A lot of attention has been given to study the importanceof the Mycobacterium tuberculosis pathogen and the geneticconstitution of the host largely ignored especially in the mostaffected regions like sub-Saharan Africa It is estimated thatonly 10 of those who become infected withMycobacteriumtuberculosis will ever develop clinical disease [38] A growingbody of evidence suggests that host genetics play a role inthe predisposition to tuberculosis (TB) disease in additionto pathogen environmental and socioeconomic factors [3940] Genetic factors contributing to TB susceptibility includevariants of the human leukocyte antigen (HLA) class IIcomplex [41ndash44] and the vitaminD receptor gene (VDR) [45ndash48] HLA alleles are found to be associated with susceptibilityand resistance to infectious diseases including HIVAIDStuberculosis and malaria that impose huge public healthburdens in sub-Saharan Africa [49 50] HLA studies havealso yielded important insights into the role of pathogensin driving HLA polymorphism For example a study thatanalyzed 61 human populations across the world showed thatpopulations that have a greater burden of pathogens showhigher HLA diversity and those populations farther fromAfrica (geographic distance measured through landmassesfrom Ethiopia) are characterized by lower HLA diversity [51]

Tuberculosis was a major selective force in the evolutionof Western European populations whereas malaria served asimilar role in Africa [52 53] Genes involved in protectiveimmunity are under greater selective pressure showinggreater variability than other genes [52 53] For a disease to bea selective pressure in the evolution of a human populationthe gene would have to have a significant impact for longperiods of time influencing morbidity and mortality beforereproductive age [52 53] TB is currently a world-widepathogen and archeologic evidence indicates a great prehis-toric prevalence for the disease in crowded cities of Europeand North Africa [54 55] It appears however that thisorganism was once completely absent from several isolated


areas [56 57] the largest of which was Africa [58] Recentobservations strongly suggest a significant role for geneticfactors in innate resistance to infection by Mycobacteriumtuberculosis [58] This relation was discovered in a study oftuberculosis in Arkansas nursing homes and was supportedby data from three outbreaks of tuberculosis in two prisons[58] A personrsquos resistance level was found to correlate withthe region of his or her ancestry [58] Ancestors of personsin the more resistant group tended to derive from denselypopulated areas and cities rife with tuberculosis whereas theancestors of persons in the more susceptible group tended toderive from areas once free of tuberculosis [58]

With the completion of Human Genome Projectand advances in genotyping technology Genome-WideAssociation (GWA) Study has been one powerful toolfor the study of genetic susceptibility in human complexdiseases [59] Recently a study conducted in Ghana and TheGambia using Genome-Wide Association Study (GWAS)identified a susceptibility locus of rs4331426 on chromosome18q112 for tuberculosis in the African population [60]In a case-control study in The Gambia two candidategenes natural resistance associated macrophage protein(NRAMP1) and VDR were found to be associated withtuberculosis [46 61] Another study in The Gambia andSouth Africa reported using a genome-wide search on alarge number of families with an infectious disease resultsfrom linkage analysis alone provided suggestive evidence fortuberculosis-susceptibility genes on chromosomes 15q andXq and these results were supported by the results ofcommon ancestry using microsatellite (CAM) mapping [62]

Macrophage migration inhibitory factor (MIF) is aninnate cytokine encoded in a functionally polymorphicgenetic locus [63] The number of CATT tetranucleotiderepeats at minus794 is associated with differentialMIF expressionthe minus794 CATT5 variant is a low-expression allele [63]Globally the CATT5 allele is more frequently identifiedamong African-Americans and Africans compared withtheir Caucasian American or Western European counter-parts [64] The proposed MIF-TB susceptibility allele (minus794CATT5) is found commonly in Caucasians (sim45) and ismore prevalent in African-Americans and in Africans (60ndash80) indicating that MIF genotype may make a clinicallymeaningful contribution to TB disease risk [64 65]The results from a recent study in Uganda found thatmycobacteremic subjects were more likely to be genotypiclow expressers of MIF (minus794 CATT55 33 versus 18odds ratio (OR) 22 119875 = 0009) This association remainedsignificant in multivariate analysis adjusting for age sexCD4 count and use of highly active antiretroviral therapy(HAART) [63]

Studies by Khor et al looking at variant alleles of CISHgene polymorphisms and susceptibility to infectious diseasesfound that the minor alleles of three SNPs (minus292 +1320and +3415) were associated with increased susceptibility toTB in Malawian population and further reported that TBsusceptibility in the Gambia was accounted for by more thanone SNP implying a highly genetically diverse population[66]

5 Malaria

During the course of human evolution in regions wheremalaria is prevalent naturally occurring genetic defensemechanisms have evolved for resisting infection by plas-modium [67] Most of the human genes that are thought toprovide reduced risk from malarial infection are expressedin red blood cells or play a role in the immune system andthey include human leukocyte antigen (HLA) 120572- and 120573-globin Duffy factor (FY) tumor necrosis factor (TNF) 120572 andglucose-6-phosphate dehydrogenase (G6PD) [67] Perhapsno disease in history has exerted as strong a selective pressureon the human genome as falciparum malaria [67] Evidencesuggests thatPlasmodium falciparum has infected humans forat least 5000ndash10000 years and human haplotype studies haveshown that alleles that may offer protection against malariahave undergone selection during that same time frame [6869] The selection pressure from malaria has led to manyvariants of erythrocytes other than hemoglobin S (HbS) [70]

Anatomically modern humans appeared in East Africaabout 200000 years ago spread out from sub-Saharan Africaapproximately 100000 years ago and subsequently colonizedthe rest of the world in a series of migratory events [71]This implies that ethnic populations that remained in sub-Saharan Africa have been exposed to malaria for periodslong enough to shape their genetic structures by plasmodiumunlike those that left this region around that time Geo-graphical epidemiological and in vitro evidence support thehypothesis that G6PD enzyme deficiency confers protectionfrom disease caused by the Plasmodium falciparum parasite[72] G6PD is encoded by a 162 kb gene found on the Xchromosome and approximately 160 genetic variants causingclinical deficiency of G6PD have been characterized [73]The geographical distribution of these deficiency allelesclosely reflects human populations exposed historically toendemic malaria [74] Relatively little attention has beengiven to the associations between genetic polymorphismsand uncomplicated malaria which accounts for over 99 ofmalarial illnesses in countries where malaria is endemic [75]The 202A376G G6PD A-allele is considered to be the mostcommon G6PD deficiency allele in sub-Saharan Africa [76]though incidence and prevalence of malaria have continuedto be high in this region yet known to confer protectionagainst malaria We suggest that protection may be conferredby more than one gene concept remains to be elucidated

In western and central Africa 95ndash99 of humans havethe Duffy negative phenotype a condition that is thoughtto confer complete protection against the Plasmodium vivaxduring the blood stages of its life cycle [77 78] howeverPlasmodium falciparum is known to be the commonest causeof malaria in Africa making this phenotype less useful insub-Saharan African population A study on human geneticpolymorphisms and asymptomatic Plasmodium falciparummalaria in Gabonese school children did not find sta-tistically significant association between mannose bindinglectin (MBL) tumor necrosis factor-120572 (TNF-120572) and nitricoxide synthase 2(NOS2) polymorphisms and asymptomaticmalaria [79] Reports associating several genetic disorderswith malaria susceptibility or resistance are on the rise and


studies of heritability indicate that approximately 25 of therisk for severe malaria progression is determined throughhuman genetic factors [80] The genetic background of theaffected individual might also influence cytokine expressionand disease outcomes [81 82] Notably the frequency ofgenetic alterations differs depending on the population originand structure and some mutations might differentially influ-ence the disease outcome in different patterns [80] Howeverheritability studies have suggested that although about 25 oftotal variation in malaria incidence and hospitalization canbe accounted for by host genetic variation sickle cell statusaccounts for only 2 of this variation [83] Thus many othergenetic factors likely affect the outcome studied by Cromptonet al [83] Moreover specific genetic factors will likely affectdifferent populations differently and certain polymorphisms(eg absence of the Duffy antigen which protects againstPlasmodium vivax infection primarily in Africans and theband 3 mutation that causes ovalocytosis primarily in Asianpopulations) have strong geographic determinants [68]

6 Concluding Remarks

Infectious diseases continue to present a major threat forhuman populations and consequently shape genetic diver-sity of human populations In the western world applicationof genetic and genomic technologies to study human geneticbasis of diseases has been widely performed however insub-Saharan Africa where infectious diseases remain animportant component of human survival these studies arelimited in sub-SaharanAfrica A lot of research has been doneto describe pathogen and environment factors associatedwith the high prevalence and incidence of these diseasesin sub-Saharan Africa however less attention has beengiven to human host genetic factors in sub-Saharan Africapopulation largely due to limited expertise in Africa scholarsand the technologies This has been further complicated bythe fact that more than 40 of African scientists live inOrganization for Economic Cooperation and Development(OECD) countries predominately in Europe the UnitedStates and Canada [83] In some OECD countries like theUnited States sub-Saharan Africans are the most educatedimmigrant group [84]Therefore African institutions shouldembrace genetic and genomic studies so that they can providemeaningful data on the genetic basis of infectious diseasesin sub-Saharan Africa human population This will guidenew drug and vaccine development This will increase ourunderstanding of the human genetic markers responsiblefor the observed variations in susceptibilities to infectiousdiseases in human populations in sub-Saharan Africa

Genetics can affect treatment outcomes as wasdemonstrated in a recent study that showed sulfadoxine-pyrimethamine treatment to be approximately half as likelyto fail in children with sickle cell trait compared withchildren who had normal hemoglobin [85] This further mayrequire that regions embrace individualized medicines sinceeven in the proantibioticproantiviral and vaccine era nomuch significant success has been registered to eliminatethese infectious diseases Host genetic diversity in this region

may need to be matched with customized medicines Thiswill need collaborations and commitment from Africans atvarious levels We are optimistic that genetic and genomicstudies on large sub-Saharan African population willprovide a great deal of insight into why the three importantglobal infectious diseases are more prevalent in this regionirrespective of available interventions and further guide newtreatment interventions and vaccine development

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

References

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[4] R Cagliani and M Sironi ldquoPathogen-driven selection in thehuman genomerdquo International Journal of Evolutionary Biologyvol 10 pp 1155ndash1161 2013

[5] M Fumagalli M Sironi U Pozzoli A Ferrer-Admettla LPattini and R Nielsen ldquoSignatures of environmental geneticadaptation pinpoint pathogens as the main selective pressurethrough human evolutionrdquo PLoS Genetics vol 7 no 11 ArticleID e1002355 2011

[6] L B Jorde W S Watkins and M J Bamshad ldquoPopula-tion genomics a bridge from evolutionary history to geneticmedicinerdquoHumanMolecular Genetics vol 10 no 20 pp 2199ndash2207 2001

[7] L B JordeW SWatkinsM J Bamshad et al ldquoThe distributionof human genetic diversity a comparison of mitochondrialautosomal and Y-chromosome datardquo The American Journal ofHuman Genetics vol 66 no 3 pp 979ndash988 2000

[8] D B Meya and K P W J McAdam ldquoThe TB pandemic an oldproblem seeking new solutionsrdquo Journal of Internal Medicinevol 261 no 4 pp 309ndash329 2007

[9] B Kampmann C Hemingway A Stephens et al ldquoAcquiredpredisposition to mycobacterial disease due to autoantibodiesto IFN-120574rdquo Journal of Clinical Investigation vol 115 no 9 pp2480ndash2488 2005

[10] P C Hill R H Brookes I M O Adetifa et al ldquoComparisonof enzyme-linked immunospot assay and tuberculin skin testin healthy children exposed to Mycobacterium tuberculosisrdquoPediatrics vol 117 no 5 pp 1542ndash1548 2006

[11] S M Newton A J Brent S Anderson E Whittaker andB Kampmann ldquoPaediatric tuberculosisrdquo The Lancet InfectiousDiseases vol 8 no 8 pp 498ndash510 2008

[12] E Gonzalez M Bamshad NM Sato et al ldquoRace-specific HIV-1 disease-modifying effects associated with CCR5 haplotypesrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 96 no 21 pp 12004ndash12009 1999

[13] E Gonzalez H Kulkarni H Bolivar et al ldquoThe influenceof CCL3L1 gene-containing segmental duplications on HIV-1AIDS susceptibilityrdquo Science vol 307 no 5714 pp 1434ndash14402005


[14] P Schliekelman C Garner and M Slatkin ldquoNatural selectionand resistance to HIVrdquo Nature vol 411 no 6837 pp 545ndash5462001

[15] A D Sullivan J Wigginton and D Kirschner ldquoThe coreceptormutation CCR512057532 influences the dynamics of hiv epidemicsand is selected for by HIVrdquo Proceedings of the National Academyof Sciences of the United States of America vol 98 no 18 pp10214ndash10219 2001

[16] CWinkler P An and S J OrsquoBrien ldquoPatterns of ethnic diversityamong the genes that influence AIDSrdquo Human MolecularGenetics vol 13 no 1 pp 9ndash19 2004

[17] W He S Neil H Kulkarni et al ldquoDuffy Antigen Receptor forChemokinesMediates trans-Infection ofHIV-1 fromRedBloodCells to Target Cells and Affects HIV-AIDS Susceptibilityrdquo CellHost and Microbe vol 4 no 1 pp 52ndash62 2008

[18] J Lama andV Planelles ldquoHost factors influencing susceptibilityto HIV infection and AIDS progressionrdquo Retrovirology vol 4article 52 2007

[19] A H Salem E Farid R Fadel et al ldquoDistribution of four HIVtype 1-resistance polymorphisms (CCR5-Δ32 CCR5-m303CCR2-64I and SDF1-31015840A) in the Bahraini populationrdquo AIDSResearch and Human Retroviruses vol 25 no 10 pp 973ndash9772009

[20] E Gonzalez R Dhanda M Bamshad et al ldquoGlobal survey ofgenetic variation in CCR5 RANTES and MIP-1120572 impact onthe epidemiology of the HIV-1 pandemicrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 98 no 9 pp 5199ndash5204 2001

[21] B Su G Sun D Lu et al ldquoDistribution of three HIV-1resistance-conferring polymorphisms (SDF1-31015840A CCR2-641and CCR5-Δ32) in global populationsrdquo European Journal ofHuman Genetics vol 8 no 12 pp 975ndash979 2000

[22] M W Smith M Dean M Carrington et al ldquoContrastinggenetic influence of CCR2 and CCR5 variants on HIV-1infection and disease progression Hemophilia growth anddevelopment study (HGDS) multicenter AIDS cohort study(MACS) multicenter hemophilia cohort study (MHCS) SanFrancisco City Cohort (SFCC) ALIVE studyrdquo Science vol 277pp 959ndash965 1997

[23] S Mummidi S S Ahuja E Gonzalez et al ldquoGenealogy ofthe CCR5 locus and chemokine system gene variants associ-ated with altered rates of HIV-1 disease progressionrdquo NatureMedicine vol 4 no 7 pp 786ndash793 1998

[24] P AnM PMartin GWNelson et al ldquoInfluence of CCR5 pro-moter haplotypes on AIDS progression in African-AmericansrdquoAIDS vol 14 no 14 pp 2117ndash2122 2000

[25] J J Martinson N H Chapman D C Rees Y T Liu and JB Clegg ldquoGlobal distribution of the CCR5 gene 32-basepairdeletionrdquo Nature Genetics vol 16 no 1 pp 100ndash103 1997

[26] F Barmania M Potgieter and M S Pepper ldquoMutations inC-C chemokine receptor type 5 (CCR5) in South Africanindividualsrdquo International Journal of Infectious Diseases vol 17no 12 pp e1148ndashe1153 2013

[27] E Aklillu L Odenthal-Hesse J Bowdrey et al ldquoCCL3L1 copynumber HIV load and immune reconstitution in sub-SaharanAfricansrdquo BMC Infectious Diseases vol 13 article 536 2013

[28] M Sadam T Karki K Huik et al ldquoCCL3L1 variable genecopy number influence on the susceptibility to HIV-1AIDSamong estonian intravenous drug userrdquo in Proceedings of the15th Conference on Retroviruses and Opportunistic Infections(CROI rsquo08) Abstract 296 2008

[29] T Nakajima H Ohtani T Naruse et al ldquoCopy numbervariations of CCL3L1 and long-term prognosis of HIV-1 infec-tion in asymptomatic HIV-infected Japanese with hemophiliardquoImmunogenetics vol 59 no 10 pp 793ndash798 2007

[30] H Kulkarni V C Marconi B K Agan et al ldquoRole ofCCL3L1-CCR5 genotypes in the epidemic spread of HIV-1 andevaluation of vaccine efficacyrdquo PLoS ONE vol 3 no 11 ArticleID e3671 2008

[31] W Zapata W Aguilar-Jimenez N Pineda-Trujillo W RojasH Estrada and M T Rugeles ldquoInfluence of CCR5 and CCR2genetic variants in the resistancesusceptibility to HIV in sero-discordant couples fromColombiardquoAIDS Research andHumanRetroviruses vol 29 no 12 pp 1594ndash1603 2013

[32] B Lee B J Doranz S Rana et al ldquoInfluence of the CCR2-V64I polymorphism on human immunodeficiency virus type1 coreceptor activity and on chemokine receptor function ofCCR2b CCR3 CCR5 and CXCR4rdquo Journal of Virology vol 72no 9 pp 7450ndash7458 1998

[33] S Mummidi M Bamshad S S Ahuja et al ldquoEvolution ofhuman and non-human primate CC chemokine receptor 5 geneand mRNA Potential roles for haplotype and mRNA diver-sity differential haplotype-specific transcriptional activity andaltered transcription factor binding to polymorphic nucleotidesin the pathogenesis of HIV-1 and simian immunodeficiencyvirusrdquo Journal of Biological Chemistry vol 275 no 25 pp18946ndash18961 2000

[34] D G Brooks M J Trifilo K H Edelmann L Teyton D BMcGavern and M B A Oldstone ldquoInterleukin-10 determinesviral clearance or persistence in vivordquo Nature Medicine vol 12no 11 pp 1301ndash1309 2006

[35] M Ejrnaes C M Filippi M M Martinic et al ldquoResolution ofa chronic viral infection after interleukin-10 receptor blockaderdquoThe Journal of Experimental Medicine vol 203 no 11 pp 2461ndash2472 2006

[36] D D Naicker L Werner E Kormuth et al ldquoInterleukin-10promoter polymorphisms influence HIV-1 susceptibility andprimary HIV-1 pathogenesisrdquo Journal of Infectious Diseases vol200 no 3 pp 448ndash452 2009

[37] L J Abu-Raddad P Patnaik and J G Kublin ldquoDual infectionwith HIV and malaria fuels the spread of both diseases in Sub-Saharan Africardquo Science vol 314 no 5805 pp 1603ndash1606 2006

[38] C J L Murray K Styblo and A Rouillon ldquoTuberculosis indeveloping countries Burden intervention and costrdquoBulletin ofthe International Union Against Tuberculosis and Lung Diseasevol 65 no 1 pp 6ndash24 1990

[39] G S Cooke and M R Siddiqui ldquoHost genetics and the dis-section of mycobacterial immunityrdquo Clinical and ExperimentalImmunology vol 135 no 1 pp 9ndash11 2004

[40] H McShane ldquoSusceptibility to tuberculosismdashthe importanceof the pathogen as well as the hostrdquo Clinical and ExperimentalImmunology vol 133 no 1 pp 20ndash21 2003

[41] P Selvaraj H Uma A M Reetha et al ldquoHLA antigen profilein pulmonary tuberculosis patients and their spousesrdquo IndianJournal of Medical Research vol 107 pp 155ndash158 1998

[42] M Ravikumar V Dheenadhayalan K Rajaram et al ldquoAssoci-ations of HLA-DRB1 DQB1 and DPB1 alleles with pulmonarytuberculosis in south Indiardquo Tubercle and Lung Disease vol 79no 5 pp 309ndash317 1999

[43] A Dubaniewicz B Lewko G Moszkowska B Zamorskaand J Stepinski ldquoMolecular subtypes of the HLA-DR antigensin pulmonary tuberculosisrdquo International Journal of InfectiousDiseases vol 4 no 3 pp 129ndash133 2000


[44] A E Goldfeld J C Delgado S Thim et al ldquoAssociation ofan HLA-DQ allele with clinical tuberculosisrdquo Journal of theAmericanMedical Association vol 279 no 3 pp 226ndash228 1998

[45] L Bornman S J Campbell K Fielding et al ldquoVitaminD receptor polymorphisms and susceptibility to tuberculosisin West Africa a case-control and family studyrdquo Journal ofInfectious Diseases vol 190 no 9 pp 1631ndash1641 2004

[46] R Bellamy C Ruwende T Corrah et al ldquoTuberculosis andchronic hepatitis B virus infection in Africans and variation inthe vitamin D receptor generdquo Journal of Infectious Diseases vol179 no 3 pp 721ndash724 1999

[47] R J Wilkinson M Llewelyn Z Toossi et al ldquoInfluence ofvitamin D deficiency and vitamin D receptor polymorphismson tuberculosis among Gujarati Asians in west London a case-control studyrdquoThe Lancet vol 355 no 9204 pp 618ndash621 2000

[48] P Selvaraj P R Narayanan and A M Reetha ldquoAssociationof vitamin D receptor genotypes with the susceptibility topulmonary tuberculosis in female patients and resistance infemale contactsrdquo Indian Journal of Medical Research vol 111 pp172ndash179 2000

[49] J M Blackwell S E Jamieson and D Burgner ldquoHLA andinfectious diseasesrdquo Clinical Microbiology Reviews vol 22 no2 pp 370ndash385 2009

[50] The Global Burden of Disease 2004 Update WorldHealth Organization Geneva Switzerland 2008httpwwwwhointhealthinfoglobal burden diseaseGBDreport 2004update AnnexApdf

[51] F Prugnolle A Manica M Charpentier J F Guegan VGuernier and F Balloux ldquoPathogen-driven selection andworldwide HLA class I diversityrdquo Current Biology vol 15 no11 pp 1022ndash1027 2005

[52] L H Miller ldquoImpact of malaria on genetic polymorphismand genetic diseases in Africans and African AmericansrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 91 no 7 pp 2415ndash2419 1994

[53] G S Cooke and A V S Hill ldquoGenetics of susceptibility tohuman infectious diseaserdquo Nature Reviews Genetics vol 2 no12 pp 967ndash977 2001

[54] M D Grmek Diseases in the Ancient Greek World JohnsHopkins Press Baltimore Md USA 1989

[55] D Brothweii and A T SandisonDiseases in Antiquity-A Surveyof theDiseases Injuries and Surgery of Early Populations CharlesThomas Springfield Ill USA 1967

[56] G E BushnellA Study of the Epidemiology of Tuberculosis withEspecial Reference to Tuberculosis of the Tropics and of the NegroRace WilliamWood amp Co New York NY USA 1920

[57] N Nuteis Medical Problems of Newly Contacted Indian Groupvol 165 Pan American Health Organization Scientific Publica-tions Washington DC USA 1968

[58] W W Stead ldquoGenetics and resistance to tuberculosis couldresistance be enhanced by genetic engineering rdquo Annals ofInternal Medicine vol 116 no 11 pp 937ndash941 1992

[59] T Wang and H Wang ldquoA genome-wide association studyprimer for cliniciansrdquo Taiwanese Journal of Obstetrics andGynecology vol 48 no 2 pp 89ndash95 2009

[60] R Bellamy C Ruwende T Corrah K P W J McAdam HC Whittle and A V S Hill ldquoVariations in the NRAMP1 geneand susceptibility to tuberculosis in West Africansrdquo The NewEngland Journal of Medicine vol 338 no 10 pp 640ndash644 1998

[61] R Bellamy N Beyers K P W J McAdam et al ldquoGeneticsusceptibility to tuberculosis in Africans a genome-wide scanrdquo

Proceedings of the National Academy of Sciences of the UnitedStates of America vol 97 no 14 pp 8005ndash8009 2000

[62] R Das M S Koo B H Kim et al ldquoMacrophage migrationinhibitory factor (MIF) is a critical mediator of the innateimmune response to Mycobacterium tuberculosisrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 110 no 32 pp e2997ndashe3006 2013

[63] W W Stead J W Senner W T Reddick and J P LofgrenldquoRacial differences in susceptibility to infection by Mycobac-terium tuberculosisrdquoThe New England Journal of Medicine vol322 no 7 pp 422ndash427 1990

[64] X Zhong L Leng A Beitin et al ldquoSimultaneous detection ofmicrosatellite repeats and SNPs in the macrophage migrationinhibitory factor (MIF) gene by thin-film biosensor chips andapplication to rural field studiesrdquo Nucleic Acids Research vol33 no 13 pp e121ndashe137 2005

[65] S A Tishkoff R Varkonyi N Cahinhinan et al ldquoHaplotypediversity and linkage disequilibrium at human G6PD recentorigin of alleles that confermalarial resistancerdquo Science vol 293no 5529 pp 455ndash462 2001

[66] C C Khor F O Vannberg S J Chapman et al ldquoCISH andsusceptibility to infectious diseasesrdquo The New England Journalof Medicine vol 362 pp 22ndash32 2010

[67] S Parikh and P J Rosenthal ldquoHuman genetics and malariarelevance for the design of clinical trialsrdquo Journal of InfectiousDiseases vol 198 no 9 pp 1255ndash1257 2008

[68] P C Sabeti D E Reich J M Higgins et al ldquoDetectingrecent positive selection in the human genome from haplotypestructurerdquo Nature vol 419 no 6909 pp 832ndash837 2002

[69] D LHartl ldquoTheorigin ofmalariamixedmessages fromgeneticdiversityrdquo Nature Reviews Microbiology vol 2 no 1 pp 15ndash222004

[70] J Ohashi I Naka J Patarapotikul et al ldquoExtended linkagedisequilibrium surrounding the hemoglobin E variant due tomalarial selectionrdquo The American Journal of Human Geneticsvol 74 no 6 pp 1198ndash1208 2004

[71] T D White B Asfaw D DeGusta et al ldquoPleistocene Homosapiens from Middle Awash Ethiopiardquo Nature vol 423 no6941 pp 742ndash747 2003

[72] C Ruwende and A Hill ldquoGlucose-6-phosphate dehydrogenasedeficiency and malariardquo Journal of Molecular Medicine vol 76no 8 pp 581ndash588 1998

[73] P J Mason J M Bautista and F Gilsanz ldquoG6PD deficiency thegenotype-phenotype associationrdquo Blood Reviews vol 21 no 5pp 267ndash283 2007

[74] A C Allison and D F Clyde ldquoMalaria in African childrenwith deficient erythrocyte glucose-6-phosphate dehydroge-naserdquo British Medical Journal vol 1 no 5236 pp 1346ndash13491961

[75] RW Snow C A Guerra AMNoor H YMyint and S I HayldquoThe global distribution of clinical episodes of Plasmodiumfalciparum malariardquo Nature vol 434 no 7030 pp 214ndash2172005

[76] T G Clark A E Fry S Auburn et al ldquoAllelic heterogeneity ofG6PD deficiency in West Africa and severe malaria suscepti-bilityrdquo European Journal of Human Genetics vol 17 no 8 pp1080ndash1085 2009

[77] L H Miller S J Mason D F Clyde and M H McGinnissldquoThe resistance factor to Plasmodium vivax in blacks TheDuffy blood group genotype FyFyrdquo The New England Journalof Medicine vol 295 no 6 pp 302ndash304 1976


[78] R L Culleton T Mita M Ndounga et al ldquoFailure to detectPlasmodium vivax in West and Central Africa by PCR speciestypingrdquoMalaria Journal vol 7 pp 174ndash175 2008

[79] L EMombo F Ntoumi C Bisseye et al ldquoHuman genetic poly-morphisms and asymptomatic Plasmodium falciparummalariain Gabonese schoolchildrenrdquo The American Journal of TropicalMedicine and Hygiene vol 68 no 2 pp 186ndash190 2003

[80] M J Mackinnon T W Mwangi R W Snow K Marsh and TN Williams ldquoHeritability of malaria in Africardquo PLoS Medicinevol 2 no 12 article e340 pp 1253ndash1259 2005

[81] L Schofield J Villaquiran A Ferreira H Schellekens RNussenzweig and V Nussenzweig ldquo120574 Interferon CD8+ T cellsand antibodies required for immunity to malaria sporozoitesrdquoNature vol 330 no 6149 pp 664ndash666 1987

[82] S G S Vreden M F van den Broek M C Oettinger J PVerhave J H E TMeuwissen andRW Sauerwein ldquoCytokinesinhibit the development of liver schizonts of themalaria parasiteplasmodium berghei in vivordquo European Journal of Immunologyvol 22 no 9 pp 2271ndash2275 1992

[83] P D Crompton B Traore K Kayentao et al ldquoSickle cell traitis associated with a delayed onset of malaria implications fortime-to-event analysis in clinical studies of malariardquo Journal ofInfectious Diseases vol 198 no 9 pp 1265ndash1275 2008

[84] N Gabara ldquoDeveloped nations should invest in African univer-sitiesrdquo BuaNews 2009

[85] D J Terlouw M A Aidoo V Udhayakumar et al ldquoIncreasedefficacy of sulfadoxine-pyrimethamine in the treatment ofuncomplicated falciparum malaria among children with sicklecell trait in Western Kenyardquo Journal of Infectious Diseases vol186 no 11 pp 1661ndash1668 2002

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

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Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



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ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

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Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


A shared set of DNA resources and the establishment of anAfrican genetic database would help to provide researcherswith common information and would facilitate studies ofseveral loci in the same set of African populations Studiesalso need to meet strict ethical standards and to involve bothlocal researchers and study participants [3] I am compelledto propose that modern humans who migrated away fromsub-SaharanAfrica encounterednew environment and exoticpathogens in their new geographical niches Those exoticpathogens and other evolutionary forces which they metin the different areas where they settled would account forunique genetics Infectious diseases have continued and willcontinue shaping the course of human evolution

The hypothesis whereby infectious diseases have beenacting as a powerful selective pressure was formulated longago but it was not until the availability of large-scale geneticdata and the development of novel methods to studymolecu-lar evolution that we could assess how pervasively infectiousagents have shaped human genetic diversity [4] Diseaseoutcome ismultifactorial process requiring interplay of host-environment-microbial factors which ultimately determinedisease resistance and progression Genetic structures of theexposed human populations will determine the susceptibilitypatterns that are always observed in the host Recent genome-wide analysis indicates that among the diverse environmentalfactors that most likely acted as selective pressures duringthe evolution of human species (climate diet regimes andinfections) pathogen load had the strongest influence onthe shaping of human genetic variability [5] Possibly theindigenous pathogens in sub-Saharan Africa coevolved withtheir hosts creating unique genetic profiles in these humanpopulations I propose that a form of Newtonrsquos third lawof motion happens during an interaction between host andpathogen action and reaction are equal and opposite Thisimplies that the selective pressure exerted by these pathogensonto selected host genes in response to specific pathogengenes received similar pressure from the host driving host-pathogen diversity observed as unique genetic profiles inboth host and pathogen accounting for coevolution Studiesshow certain host-pathogens specificities probably due tocoevolution I further propose that these unique geneticprofiles created over time affect vaccine efficacy and of latewe know that treatment outcome is also affected by the hostgenetic structures The unique genetic profiles created inthese human populations can act as risk genetic factors foremerging pathogens Penicillin was a wonder drug at thebirth of the antibiotic era but after half a century of its clinicaluse we observe emergence of penicillin resistant bacteriastrains these have acquired genetic variations that theirancestors never had In the antibioticantiviral era drugs arealso likely to act as selective pressure creating genetic diversityin pathogen genomes as well as hostsrsquo

2 Human Host Genetic Diversity andInfectious Diseases

The high levels of genetic diversity in African populationsand their demographic history make these populations

particularly informative for the fine mapping of com-plex genetic diseases [6] as well as infectious diseasesStudies using mitochondrial (mt) DNA and nuclear DNAmarkers consistently indicate that Africa is the most genet-ically diverse region of the world [7] Historically humanpopulation genetic studies have relied on one or two Africanpopulations as being representative of African diversity butrecent studies show extensive genetic variation among evengeographically close African populations which indicatesthat there is not a single ldquorepresentativerdquo African population[3]

The immunological responses to MTB are due to theinteraction between the immune system human host andbacterial and environmental factors [8] Genetic as well asacquired defects in host immune response pathways greatlyincrease the risk of progressive disease [9] Results fromgenome-wide linkage studies suggest that TB disease suscep-tibility is highly likely to be polygenic with contributionsfrom many minor loci [10] and a large number of TBsusceptibility markers have been identified from candidategene studies as ldquodisease-causingrdquo genes which include TIRAPHLA DQB1 VDR IL-12120573 IL12R1205731 IFN-120574 SLC11A1 andMCP-1 However to date the greatest evidence to support anunderlying genetic basis for TB has come from the discoveryof single gene defects predisposing to disseminated and oftenlethal mycobacterial disease [11]

To better understand why HIVAIDS tuberculosis andmalaria aremore common infectious diseases in sub-SaharanAfrica we must appreciate the regionrsquos human genetic diver-sity and this will provide data that may help understandwhy there is a mixed population of both resistant andsusceptible populations coexisting We can assert that theindigenous infections like malaria and tuberculosis havecreated unique genetic structures in these mixed ethnicpopulations which can be risk factors for exotic infec-tious diseases like HIVAIDS and vice versa A notionthat exposure to indigenous pathogensparasites in theseareas shaped the genetic structures of these native humanpopulations resulting in interethnic variation in suscep-tibility to modern infectious agents is undisputable Thegreat human genetic diversity and the continued presenceof infectious agents in sub-Saharan Africa will continuecontributing to the observed susceptibilities to infectiousdiseases

3 HIVAIDS

Host genetic polymorphisms contribute to interindividualvariation in susceptibility to acquiring HIV-1 infection thedegree of infectiousness to others (as reflected by the viralload) and rates of disease progression [12] Such polymor-phisms might also contribute to significant interpopula-tion differences in HIV-1 prevalence [12ndash16] Duffy antigenreceptor for chemokines (DARC) expressed on red bloodcells (RBCs) influences plasma levels of HIV-1-suppressiveand proinflammatory chemokines such as CCL5RANTES[17] DARC is also the RBC receptor for Plasmodiumvivax Africans with DARC-46CC genotype which confers








4 Tuberculosis








5 Malaria












References

































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology








4 Tuberculosis








5 Malaria












References

































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






5 Malaria












References

































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology









References

































































































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 sub-saharan african human...

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