Genetics of Diabetes: An Overview

Murugu Manickam, MDClinical Assistant ProfessorDivision of Human Genetics

Murugu Manickam, MD discloses no significant financial interests or other relationships with commercial interests. Presentation will not include discussion of commercial products or services and will not include unapproved or off-label usage of a commercial product or device.

The following planning committee members have no significant financial interests or relationships with commercial interests to disclose, their educational unit does not have a financial interest or affiliation with an organization that may receive direct benefit from the subject of the proposed CME activity, and they will not be personally compensated for their role in the planning or execution of this proposed CME activity by an organization other than The Ohio State University: Amy Ehrlich, MA and Henry Zheng, PhD, MBA

Diabetes Mellitus• Increasingly common disease consisting for

multiple forms– Type 1: insulin deficiency– Type 2: insulin resistance– Gestational diabetes: only pregnancy-

associated

• Overlap is considerable– Insulin resistance to insulin deficiency over time– Gestational diabetes to insulin resistance

Diabetes

• Well recognized risk factors– Obesity– Metabolic syndrome– Chronic pancreatitis/pancreatic injury– Autoimmune disease

Genetic Risk Factors

• Rare diseases associated with development of diabetes– Cystic fibrosis– Hemochromatosis– Pheochromocytoma– Insulin receptor defects– Proinsulin cleavage enzyme defect

Autosomal recessive

Genetic Risk Factors

• Rarer disease associated with development of diabetes– MODY: maturity onset diabetes of the

young• Appears acutely like insulin dependent at

older age• Multiple genes involved (but all appear to

transmit autosomal dominant manner)

Autosomal dominant

Genetic Risk Factors• Very rare diseases associated with

development of diabetes– Mitochondrial disorders: both

autosomal recessive inheritance and mitochondrial inheritance (maternal transmission to all children)

– MELAS: mitochondrial encephalopathy, lactic acidosis, stroke like symptoms

– MNGIE, Kearns-Sayre also associated

Mitochondrial

Genomics and DiabetesThere is clear evidence that diabetes as a strong genetic component

Type II

1 parent affected: 1 in 10

2 parents affected: 1 in 2

monozygotic twin studies: 2 in 3– Last is important that it is independent of diet

Type I

smaller risk with an affected relative

• Diabetes has been one of the most investigated areas in genome wide association studies by single nucleotide polymorphisms– Over 40 to this point have been identified– Most have small relative risk and replication studies

are variable– Individually likely small effect but combination of risks

is not well defined– Some have identified previously unrealized genes

associated with diabetes including regulatory genes and enzyme controls

• Still some the findings have been very revealing– On chromosome 9,several SNPs have been

independently associated with obesity, diabetes, heart disease

– variant in PPARG and a variant in KCNJ11 are located in genes that encode drug targets (thiazolidinediones and sulfonylureas, respectively)

• But to date no difference in dosing

Pharmacogenomics

• Patients with maturity onset diabetes of the young type 3 (due to mutations in HNF1A) seem to respond better to sulfonylureas than to metformin

Summary

• There are some rare causes to diabetes that are inherited in an autosomal dominant manner- MODY most significantly

• Most SNP associated risks for diabetes only confer a small risk to the individual

• Diabetes SNPs have proven valuable for insight into disease mechanism but not for prediction of disease