A large number of genome-wide scans has been performed. Since initial positive findings have been replicated for over 20 genomic regions, the search for the genes responsible for the association with diabetes has proven to be difficult. However, three genes have now been found in this manner, calpain-10, ENPP1, and TCF7L2.

Calpain-10
The calpain-10 gene encodes for a cysteine protease reported to be responsible for the association of a region in chromosome 2 with diabetes. A recent meta-analysis indicates that several single-nucleotide polymorphisms (SNPs) are responsible for the association, each with only a modest effect with relative risks between 1.10 and 1.5. Genetic variation in calpain-10 may affect sensitivity (83) or insulin secretion. It has also been shown to inhibit a protease involved in mitochondrial function,  which might relate to mitochondrial dysfunction as is often observed in type 2 diabetes.

ENPP1
Genome-wide scans often lead to regions that are so wide that research is often directed also by candidate genes in that specific region. The 6q16-q24 region harbors the ectonucleotide pyrophosphate/phosphodiesterase 1 (ENPP1 or PC-1) gene, which is a candidate for insulin resistance since the gene product can interact with the insulin - insulin receptor complex, thereby diminishing receptor activation. One haplotype conferred a relative risk of roughly 1.50 for type 2 diabetes and for obesity. The highly prevalent K121Q polymorphism has been found in vitro to worsening inhibition of insulin - insulin receptor autophosphorylation by the ENPP protein.

The prevalence of the ENPP1 K121Q polymorphism has been found to vary widely; for example in one study, it was found in 39% of type 2 diabetes versus 26% in nondiabetic Caucasian subjects, which would lead to a population-attributable risk of around 13%. Others have found a predominant effect of the polymorphism on (over-)weight with on average an increase in BMI of 1.3 kg/m² (or 4 kg for an adult) for homozygotes.

The mechanism of its obesity and diabetes promoting action is uncertain; although it might be that it acts by virtue of diminished insulin-induced satiety in the brain and/or by inducing insulin resistance in muscle leading to “overflow” of nutrients to adipocytes thereby leading to obesity.

TCF7L2
The genome region 10q25 harbors the transcription factor 7-like 2 (TCF7L2) gene. In studies in three cohorts, it was shown that heterozygous (38%) and homozygous (7%) carriers of a prevalent intron microsatellite have relative risks of 1.4 and 2.4 for type 2 diabetes, respectively.

Due to the high prevalence of this microsatellite the population-attributable risk for diabetes is around 18%. TCF7L2 is a transcription factor influencing the proglucagone gene; it is has been proposed to influence glucagon-like peptide 1 (GLP-1) levels. GLP-1 is one of the peptides encoded by this gene; it has stimulating effects both on insulin secretion per se, and on beta-cell growth. The importance of this gene can also be appreciated from studies showing that progression from IGT to diabetes was around 50% higher in homozygous carriers of each one of two polymorphisms in this gene.

ADIPOR2

The adiponectin receptor has also been considered a candidate gene for various reasons, including its presumed insulin sensitivity enhancing effect of adiponectin acting via IRS1.

The adiponectin receptor 2 (ADIPOR2)  presumably has major effects on the liver.  In a meta-analysis of three case-control studies, the SNP rs767870 (ADIPOR2-SNP1) was estimated to confer a relative risk of 1.25 for type 2 diabetes.  Its frequency of 19%  would lead to a population-attributable risk of 5%.

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

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