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Researchers Detect Diabetes, Heart Risk Locus Link to Lower Body Fat

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A new Nature Genetics study suggests that a genetic locus linked to lower body fat levels also ups heart disease and type 2 diabetes risk.

"[I]t is not only overweight individuals who can be predisposed for these metabolic diseases, and lean individuals shouldn't make assumptions that they are healthy based on their appearance," senior author Ruth Loos, a researcher with the Medical Research Council Epidemiology Unit in Cambridge, UK, said in a statement.

Loos led an international research team that used a two-stage meta-analysis to search for genetic variants behind body fat percentage, first looking at more than 36,600 individuals assessed through 15 previous genome-wide association studies. When they tested potential body fat-associated sites identified in the first phase of the study in nearly 40,000 more individuals, the researchers were left with three validated risk loci in and around FTO, a gene known to influence body fat and obesity, as well SPRY2 and IRS1.

Unexpectedly though, their findings indicate that the version of IRS1 associated with decreased body fat is also associated with metabolic disruptions that correspond to elevated type 2 diabetes and coronary artery disease risk, especially in men, implying that leanness doesn't necessarily buffer against the risk of such diseases.

The team's follow-up studies suggest the variant is linked to lower IRS1 expression in fat tissue and lower levels of fat under the skin in men — a skewed fat distribution that alters the ratio of this subcutaneous fat relative to the visceral fat around internal organs.

"[W]e identified a locus near IRS1 that is associated with reduced body fat percentage and adipose tissue IRS1 expression in men but also with a combination of adverse metabolic and disease risk traits, including lower levels of subcutaneous fat, increased insulin resistance … and increased risk of diabetes and coronary artery disease," Loos and her co-authors wrote.

Although nearly three-dozen genetic loci have been tied to body mass index, which takes into account fat as well as lean tissue, the researchers explained, relatively little is known about the genetic factors that specifically influence actual fat levels in the body.

To explore this in more detail, the team did a meta-analysis involving 36,625 individuals —29,069 of European ancestry and 7,557 of Indian-Asian descent — who had been enrolled through 15 past studies and genotyped at roughly 2.5 million SNPs. They also did analyses looking at men and women separately as well as analyses using data on the European population alone.

By testing the top 14 SNPs in follow-up studies of up to 39,576 more individuals of European descent from 11 past studies, the team then narrowed in on three SNPs with verified body fat associations: SNPs in FTO and near IRS1, which were linked to body fat in both the European and Indian-Asian populations, and a third SNP near SPRY2 that was associated with body fat in the European group alone.

From their follow-up studies, the researchers found evidence that rs2943650, the SNP upstream of the insulin growth factor mediator coding gene IRS1, was associated with lower overall body fat, showing stronger effects in men. On the other hand, the variant showed no obvious ties to BMI.

Nevertheless, consistent with past studies linking the locus to type 2 diabetes and coronary artery disease, they reported, the same SNP was associated with elevated triglyceride and insulin resistance levels and lower high-density lipoprotein cholesterol levels. Again, this pattern was more pronounced in men.

Additional analyses, meanwhile, supported the researchers' theory that the IRS1 variant alters body fat distribution. In particular, their data suggests the SNP, which is tied to lower IRS1 expression in fat tissue, also corresponds to lower levels of subcutaneous fat in men, leading to lower subcutaneous fat to visceral fat ratios.

"What we've discovered is that certain genetic variants keep you lean by reducing how much fat you store under your skin," Loos said in a statement. "We don't know for sure, but we can speculate that these individuals are then more predisposed to store fat elsewhere, such as in the liver and in muscle."