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There are new clues that could reveal how our genes help tip the scales when it comes to body weight. As described in the April 14 issue of Science, an international team of scientists has identified a single letter change to the genetic code in humans that is associated with obesity in several sample populations. This discovery may help to clarify the biological triggers that cause body fat to be stored to excess in some people but not in others.

In the United States alone, more than half of the population is overweight and roughly a third is obese. While the excesses of modern culture — calorie-laden diets and infrequent exercise — are largely to blame for our expanding waistlines, it is clear that genes also play a role. Small genetic changes, which vary from one person to another but are shared broadly among the population as a whole, have been considered to be likely contributors to this emerging epidemic. But the problem amounts to more than adding pounds: excessive body weight carries an increased risk of serious illness, including type 2 diabetes, heart disease, high blood pressure and even cancer. Thus, efforts to identify these genetic differences carry relevance for health that goes beyond numbers on a scale.

A team of scientists including Joel Hirschhorn, an assistant professor at Children's Hospital Boston and Harvard Medical School and an associate member of the Ó³»­´«Ã½, sought to pinpoint genetic variations or "variants" that are tied to obesity. By surveying the DNA from both obese and non-obese individuals, they looked for single nucleotide polymorphisms (SNPs) that correlate with a high body mass index (BMI), a figure calculated from height and weight to measure obesity. They applied this approach to 700 people — parents and their children — enrolled in the offspring cohort of the Framingham Heart Study.

To locate the SNPs in the genome that are associated with obesity, the researchers used a two-part strategy. First, after cataloguing the SNPs in the parents' DNA, they identified the SNPs, and the likely mode of inheritance, that could best explain the BMI of their children. Then, they tested these predictions by determining the genotypes of these SNPs in the children. Importantly, these steps are statistically independent from one another and estimates in the first step do not bias the outcomes of the second.

Of the top 10 SNPs analyzed in the context of recessive inheritance, only one (rs7566605) was found to have statistical significance. Specifically, the "CC" genotype at this position correlated most strongly with obesity. The researchers replicated this finding in a larger sample from the Framingham Heart Study, noting that this SNP is a powerful predictor of BMI and that the individuals who carry it are more likely to obese. Notably, the researchers confirmed this association in four out of five additional populations drawn from diverse age groups and ethnicities, including Western Europeans, African Americans, and children. The allele was found in roughly 10% of the individuals examined, indicating that it is a common genetic variant among humans.

This variant is notable for its genomic location. It sits upstream of the INSIG2 gene, which normally slows the body's production of fatty acids and cholesterol. Fatty acids are a component of triglycerides — the chemical form in which fat is stored in cells — and their supply is regulated from both internal and dietary sources. In animal studies, the increased activity of INSIG2 within the liver results in a reduction of triglycerides in the blood. Therefore, by virtue of its proximity to INSIG2, this SNP could act indirectly to influence the amount of triglycerides present in the blood, which, if it were to rise beyond normal levels, could cause triglycerides to be stored as fat.

The SNP is also remarkable for its origins. The presence of the "CC" genotype in both Western Europeans and African Americans suggests that the allele first arose long ago, prior to human migration out of Africa, which could explain its prevalence in modern humans. This frequency also implies that the detrimental nature of the allele is a relatively recent shift, a genetic change of heart brought on by a more contemporary — and metabolically comfortable — lifestyle.