Endocrine Abstracts (2009) 20 PL4

New insight in the genetics of type 2 diabetes and obesity from genome wide associations studies

Philippe Froguel1,2

1Genomic Medicine, Hammersmith Hospital, Imperial College, London, UK; 2CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France.

Recent large twin studies have definitively shown that more than 70% of the variance of the BMI and waist is genetically determined in both adults and children, suggesting that the epidemics of obesity and subsequent T2D are mainly due to the environmental pressure targeting individuals who are particularly vulnerable to metabolic diseases. The dissection of monogenic early onset severe obesity and T2D cases have identified a variety of causative genes that are involved in two fundamental pathways: pancreatic beta-cell function and the control of appetite.

Genome Wide Association approaches using high-density frequent Single Nucleotide Polymorphism micro-arrays have been developed to elucidate common forms of metabolic diseases. Since the report of the first GWA in T2D in early 2007 (Sladek et al, nature), several T2D case/control GWA studies have provided more than a dozen of loci that are consistently associated with increased risk for diabetes. Meta-analyses of GWA data from several populations should bring soon additional genes but their effect is likely to be modest. Most of the new T2D associated genes are expressed in the pancreas and are guessed to control insulin secretion. Their effect is additive which makes interesting their use to predict T2D incidence.

However, these loci only explain a small fraction of T2D heritability. Other form of polymorphisms, such as gene Copy Number Variations and rare variants may also greatly contribute to T2D risk. In addition other genes may also modulate phenotypes related to glucose control in the general (non diabetic) population, and in interaction with environmental factors might play an important role in the early development of glucose intolerance and in the mortality and morbidity associated with slightly elevated glucose levels. GWA analyses of general populations for quantitative traits related to glucose homeostasis identified glucose-6-phosphatase catalytic subunit-related protein 2 (G6PC2) and the melatonin receptor 2 gene (MTNR1B) has major regulators of fasting glucose. Both genes are expressed in the pancreatic beta-cells although the melatonin receptor is also acting in the retina as a mediator of the biological clock. Impairment of the circadian clock or of sleep quality is known to impair insulin secretion.

GWAs on BMI in general populations and in severe obesity cases and normal weight controls studies have identified the brain expressed FTO and Melanocortin 4 receptor as common obesity associated genes. Recent, GWA meta-analyses for BMI and in childhood obesity also found new genes contributing to obesity risk most of them expressed in the brain and potentially involved in the regulation of food behavior.

In conclusion, GWA conducted in both large well phenotyped general population and in well-defined cases and controls are equally useful to identify fundamental pathways involved in glucose and energy homeostasis. These studies should contribute to elucidate human metabolic physiology and to understand better the natural history of T2D and associated obesity.

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