Genetics of Type 2 Diabetes

Abstract

BACKGROUND Type 2 diabetes (T2D) is a complex disorder that is affected by multiple genetic and environmental factors. Extensive efforts have been made to identify the disease-affecting genes to better understand the disease pathogenesis, find new targets for clinical therapy, and allow prediction of disease. CONTENT Our knowledge about the genes involved in disease pathogenesis has increased substantially in recent years, thanks to genomewide association studies and international collaborations joining efforts to collect the huge numbers of individuals needed to study complex diseases on a population level. We have summarized what we have learned so far about the genes that affect T2D risk and their functions. Although more than 40 loci associated with T2D or glycemic traits have been reported and reproduced, only a minor part of the genetic component of the disease has been explained, and the causative variants and affected genes are unknown for many of the loci. SUMMARY Great advances have recently occurred in our understanding of the genetics of T2D, but much remains to be learned about the disease etiology. The genetics of T2D has so far been driven by technology, and we now hope that next-generation sequencing will provide important information on rare variants with stronger effects. Even when variants are known, however, great effort will be required to discover how they affect disease risk.

Recent advances in the molecular genetics of type 2 diabetes mellitus

“…As supported by numerous studies in the literature [12,13] , both defects are the result of a complex interaction between genetic and environmental factors (Figure 1), including chemical agents (calcium and zinc ions) and polluting organic substances that are suspected to play a role in amyloid fiber formation in pancreatic β-cells, thus contributing to the pathology of T2DM [14][15][16][17] . The involvement in the pathogenesis of T2DM of multiple genes that interact with each other in an epistatic manner may explain why, despite the enormous efforts made to date, the identification of genetic determinants responsible for an increased susceptibility to T2DM still remains unsolved [18,19] . The present review aims to give an overview of the recent findings in this context.…”

“…Genotyping for genetic markers in family members with and without T2DM has allowed the identification of DNA regions containing loci associated with disease risk. Thanks to this method, the association of T2DM with the calpain-10 (CAPN10) gene [20] was initially identified and later its association with the transcription factor 7-like 2 (TCF7L2) gene [21] , whose genetic variants in affected individuals increase the risk of diabetes approximately 1.5 times [19] . Another approach used was to search for genetic variants within functional candidate genes encoding for protein(s) with important implications for glucose homeostasis and positional candidate genes that have a genetic association on the basis of a previous linkage study.…”

“…In cases in which it was possible to ascertain the precise pathogenic mechanism, for example, through the study of association with the circulating levels of insulin or through the direct analysis of the gene's protein product, it has been seen that most of the genes identified are involved in pancreatic β-cell mass and/or function, thus with implications in insulin secretion defects (Table 1). This observation suggests that most of the risk associated with T2DM in the general population relates to genetic defects in β-cells, while peripheral insulin resistance predominantly suffers from the environmental component [18,19,60] . Figure 2 depicts some of the genes whose alteration confers an elevated risk of T2DM.…”

“…The therapeutic response to sulfonylureas is compromised in patients with mutations in these genes. Other genes whose mutations were initially considered responsible for the less common forms of diabetes mellitus have subsequently been associated with an increased risk of T2DM [19] . Among these are the hepatocyte nuclear factor-1 homeobox A ( AHN-F1A) gene, whose mutations are responsible for the most common monogenic form of MODY (MODY3), a form of maturity onset diabetes of the young (also known as HNF1A-MODY), and the gene hepatocyte nuclear factor-1 homeobox B (HNF1B), which determines a less frequent but more severe monogenic form of diabetes, the MODY5.…”

“…Although defects in INSR have been reported in a large number of patients with T2DM, mutations in the INSR gene have been found only in a small percentage (3%-4%) of these patients in whom genetic defects leading to receptor protein abnormalities were identified as cause of disease. However, certain patients with apparently normal INSR genes have reduced expression of both the INSR protein and INSR mRNA levels [13,18,19] . In these patients, it is possible that there are mutations in genes encoding transacting factors which regulate the level of INSR gene expression [40] .…”