MD Conference Express EASD 2012 - (Page 30)
n sElEcTEd UpdATEs On gEnETics
Human Genetics and Type 2 Diabetes: Behind the Headlines
Written by Maria Vinall
Significant advancements in the knowledge of human genetics and type 2 diabetes (T2DM) have been made in the last 5 years. It was only in 2007 that one of the first genome-wide association studies (GWAS) for T2DM identified the first genetic polymorphism with a robust relationship to diabetes—a common variant in the fat mass and obesity associated FTO gene that predisposes individuals to diabetes through an effect on body mass index (BMI) [Frayling TM et al. Science 2007]. Researchers have now identified ~65 regions of the genome that influence diabetes [Morris AP et al. Nat Genet 2012]. Genetic studies have also become larger. The 2007 study included ~39,000 participants, while current studies of BMI include up to 350,000. These advances are virtually all tied to improvements in technology that now allow researchers to quickly sequence the genomes of thousands of individual patients and to analyze tens of millions of genetic variants. Timothy Frayling, PhD, University of Exeter, Exeter, United Kingdom, discussed the new biology being derived from genetic research and how it can impact research being conducted in nongenetic areas. Most forms of diabetes do not follow strict patterns of inheritance through families; they tend to appear in clusters. Prof. Frayling’s approach to genetic studies focuses on differences in allele frequency based on the principle that variant genes present more frequently in cases than in controls, thus variant status provides probability of disease status. However, he cautioned that it remains extremely difficult to identify a single causal risk factor to explain the huge variation in human beings and to sort out the effects of confounding factors. Geneticists have identified 32 polymorphisms that are robustly associated with normal variation in BMI, some of which overlap with the monogenic causes of severe obesity. Some of the common polymorphisms are located near genes such as POMC, BDNF, SH2B1, and MC4R— mutations known to cause severe appetite disorders and severe obesity in children [Speliotes EK et al. Nat Genet 2010]. However, the FTO genotype still stands out as the having the largest influence on BMI and related metabolic traits, and dual-energy X-ray absorptiometry measures in
children participating in the 2007 study [Frayling TM et al. Science 2007] show that the FTO effect is associated entirely with adiposity, as opposed to skeletal or lean tissue mass (Figure 1). Figure 1. FTO: The Association is with Fat Mass Rather Than Lean Mass.
120 % Increase Compared with TT p=6 x 10 -10 p=0.03
TT AT AA
110
100
90 Fat mass Lean mass
DEXA Measures in ALSPAC Age 9 Years (n=5243)
ALSPAC=Avon Longitudinal Study of Parents and Children; DEXA=dual-energy X-ray absorptiometry. Reproduced with permission from TM Frayling, PhD.
Longitudinal studies have also informed today’s knowledge of how the FTO gene functions. Sovio et al. [PloS Genet 2011] have shown that the minor (fat) allele in FTO is associated with children emerging from their adiposity trough earlier than the major (thin) allele by the age of 7 years. Thus, after the age of 7 it is difficult to assess the effects of FTO gene variants in humans because fatter individuals eat, behave, and metabolize differently than thinner individuals as a consequence of being more overweight. This association has also been documented in an animal study in which enhanced expression of FTO led to increased food intake and obesity [Church C et al. Nat Genet 2010]. Interactions between the FTO gene and the environment have been the subject of several studies. It was recently shown that the FTO genotype influences individual variation in BMI as well as mean BMI [Yang J et al. Nature 2012]. This concept, which indicates a possible increase in the strength of genetics in today’s environment, was also seen in the results of a twin study that showed strong evidence
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November 2012
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Table of Contents for the Digital Edition of MD Conference Express EASD 2012
MD Conference Express EASD 2012
Contents
Understanding Incretin Hormone Action and the Treatment of Diabetes
New ADA/EASD Guidelines Focus on Patient-Centered Care
ORIGIN Trial: Insulin Glargine and n-3 Fatty Acids Fail to Reduce CV Events in Diabetic Patients
Exenatide Once Weekly Sustained Improvement in Glycemic Control with Weight Loss Through 4 Years
DiaPep277® Shows Promise as a Therapeutic Strategy for T1DM
Linagliptin Proves Safe and Effective as Add-on Therapy to Basal Insulin
12-Week Treatment with LY2409021 Significantly Lowers HbA1C and Is Well Tolerated in Patients with T2DM
Insulin Degludec Is Superior to Sitagliptin in Improving Glycemic Control in Uncontrolled Patients with Type 2 Diabetes on Oral Agents
Dapagliflozin Does Not Impact Renal Function in Patients with T2DM
Population-Based Screening for T2DM:The ADDITION-Cambridge Trial
The Challenges of Pharmaceutical Management of Painful Diabetic Peripheral Neuropathy
Enterovirus Infection
Novel Oral Agents
GLP-1
Genetics
Renal Denervation
Hypertension and Renal Function Are Risk Factors for CAD in T1DM
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