The fact that more than half of obese insulin-resistant subjects will never develop diabetes points to susceptibility for the disease in some humans, while protective factors against the disease are present in others. Indeed, a positive family history confers a two- to threefold increased risk for the disease with a 15% to 30% risk to develop type 2 diabetes or IGT in first- degree relatives of type 2 diabetes subjects.

The risk is even higher (around 60% by the age of 60 years) if both parents have diabetes. Similarly, if one twin has type 2 diabetes, the risk for type 2 diabetes mellitus in the other twin is higher in monozygotic (identical) twins (35% to 58%) as compared with dizygotic twins (around 20%). A caveat is the presence of low birth weight in many twins, since low birth weight per se associates with increased risk of type 2 diabetes later in life.

Genetic Factors

The polygenic nature of the disease has it made difficult to dissect individual genes conferring increased risk for diabetes. In general, two methods, the so-called candidate gene approach and the genome-wide scan approach have been used.

The candidate gene approach examines specific genes with a plausible role in the disease process. The genome-wide scan locates genes through their chromosomal (genomic) position. In genetic studies the population-attributable risk is often given; this is the percentage of a disease that would be eliminated if the genetic factor were removed from the population.

Candidate Genes

PPAR-Gamma
Currently,  the most robust single candidate variant is the highly prevalent Pro12Ala polymorphism in PPAR-γ gene. PPARγ is a transcription factor; the isoform PPAR_γ2 is specific for adipose tissue,  where it plays a key role in regulating adipogenic differentiation.

The proline allele of the P12A polymorphism in PPAR_γ2 has a prevalence of 75% in Caucasian, and leads to a relative risk of 1.25 for diabetes, which leads to a population-attributable risk of 16%.

PGC1α
The Gly483Ser polymorphism in PPARγ coactivator (PGC1α), a transcriptional cofactor of PPARγ, is highly prevalent (around 38%).

PGC1a is a regulator of oxidative phosphorylation in mitochondria, which has been shown to be diminished early in the disease and even in nondiabetic first-degree relatives of type 2 diabetes patients. A meta-analysis concludes to only a very modest relative risk of around 1.07 leading to a population-attributable risk of 2.5%.

HNF4Alpha
The discovery of MODY genes has rendered them candidate genes for type 2 diabetes. Genetic variation near or in the P2-promoter of the MODY-1 gene HNF4A (chromosome 20q) may relate to type 2 diabetes.

KCNJ11
Clearly,  beta-cell potassium channels are candidates for genetic predisposition for type 2 diabetes.  The E23K variant in the KCNJ11 gene (Potassium Inward Rectifier 6.2 (KIR6.2) channel)  has been found in meta-analyses to confer a relative increased risk of 1.23 for heterozygotes and around 1.65 for homozygous carriers, presumably due to decreased insulin secretion. Since this variant is highly prevalent (15% to 20%), the population-attributable risk is around 7%.

 

Michael Stumvoll
Department of Medicine, University of Leipzig, Leipzig, Germany

Barry J. Goldstein
Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Jefferson Medical
College of Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.

Timon W. van Haeften
Department of Internal Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands

REFERENCES