Common variants associated with obesity identified

14 May 2008

An international collaborative genome wide association study looking at insulin resistance and related phenotypes has identified a gene sequence linked to an expanding waist line (central adiposity), weight gain and insulin resistance, which can lead to type 2 diabetes (see BBC news). The results of the study published in Nature Genetics identified four single nucleotide polymorphisms (SNPs) associated with waist circumference; of these the rc12970134 sequence was found to have a strongest association with waist circumference [Chambers et al. (2008) Nat. Genet. doi: 10.1038/ng.156]. The sequence was also shown to be associated with insulin resistance, in a manner that is partially independent of adiposity.

Individuals who are homozygous for the risk allele rc12970134 had a ~2cm greater waist circumference and ~10% higher homeostasis model assessment of insulin resistance (HOMA-IR) results. The study also shows that there is a higher frequency of this risk allele in individuals of Indian Asian ancestry in comparison with those of European ancestry. This finding suggests a genetic mechanism contributing to the higher incidence of obesity and insulin resistance among Indian Asians.    

All four SNPs identified in the study were found to be located near the MC4R gene, which is thought to be involved in regulating energy levels in the body. Mutations in this gene leading to a loss of function are associated with severe childhood obesity and hyperinsulinaema. Another study published in the same journal has identified other common variants near the MC4R gene that appear to influence fat mass, weight and obesity risk [Loos et al. (2008) Nat. Genet. doi: 10.1038/ng.140]; these variants have an additive effect to those of the FTO gene (see previous news). How these common variants influence the MCR4 gene is not known and a greater understanding of these factors may give an insight into the pathogenesis of both rare monogenic subgroups and the common multi-factorial forms of obesity.

Comment: The pathophysiology of obesity and related conditions that may contribute to metabolic syndrome, such as hypertension (high blood pressure), insulin resistance, central adiposity, raised levels of triglycerides and reduced levels of high-density lipoprotein (HDL) cholesterol in the blood, is known to be highly complex, and to involve multiple genetic and environmental factors. However these conditions, which are increasingly prevalent in countries such as the UK and US, significantly increase the risk of cardiovascular disease and type II diabetes, and represent a major public health problem. These recent papers represent another piece in the jigsaw puzzle in trying to understand the genetic and molecular basis of the disease, with a view to providing new ways in which to combat it. Many major reserach programs are also focused in this area. For example, pharmaceutical company Pfizer recently formed a consortium with four US universities and another company to use a systems biology approach to improve understanding of diabetes and obesity. The three-year Insulin Resistance Pathway (IRP) Project will look at insulin signalling in fat cells (see press release).

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