With hundreds of genes thought to be linked to obesity, the challenge is sifting through them all to determine which ones increase the risk of downstream complications like heart disease and diabetes.
In a study published Thursday in Nature Genetics, researchers took the first steps in finding a potential candidate specifically in women.
Comparing the genetic data of hundreds of individuals, they looked for genes associated with the accumulation of fat in the abdomen as measured by the waist-to-hip ratio, which has been found to be a better predictor of cardiovascular risk than body mass. They identified 91 genes linked to the waist-to-hip ratio for women, much more than the 42 genes they found for men.
They then homed in on one gene called SNX10, which had the strongest association with a high waist-to-hip ratio in women. Men and women store fat in different areas of the body, and even though SNX10 is expressed in both sexes, they found that it’s associated with abdominal fat buildup only in women.
In lab studies of human cells that are precursors to fat cells, the researchers knocked out the SNX10 gene and found that those precursor cells were not able to accumulate fat and become mature fat cells.
They then turned from lab dishes to mammals. The researchers looked at mice with the SNX10 gene deleted in fat cells and fed them a high-fat diet. The female mice didn’t develop excess fat and obesity, but the male mice did, as did a group of control mice that still had the gene.
The researchers also searched the U.K. Biobank and found that a genetic variant that increases the expression of SNX10 in fat cells was associated with high waist-to-hip ratios in women, as well as higher cholesterol and triglyceride levels – both further indicators of cardiovascular risk.
Since not all people with obesity go on to develop further health complications, as some are more susceptible to others, the findings from the study could help in eventually developing genetic markers for determining which patients are most susceptible, said Marcelo Nobrega, senior author of the study and professor of human genetics at the University of Chicago.
Especially as new, in-demand drugs for obesity come to market, but the health system has limited resources to pay for them, some doctors have said there needs to be a better way of stratifying which patients are most at risk of complications and would most need treatments.
If further studied, the findings could also help in identifying a potential target for new drug development, Nobrega said.
More broadly, the authors found that among the 91 genes linked to the waist-to-hip ratio in women, most variants of those genes are in a category of DNA elements called retrotransposons, so-called jumping genes that are remnants of ancient viral infections that have been integrated into the genome.
Years ago, these elements were thought to not contribute anything biologically in humans, but more recent research suggests that they do have effects, and these findings provide fodder for further studies on these elements, Nobrega said.
Clay Semenkovich, chief of the division of endocrinology, metabolism and lipid research at Washington University in St. Louis, said more research is needed to look at the potential effects of blocking the SNX10 gene, since that action may not necessarily be linked to better metabolic health.
For example, there are conditions that affect the ability of fat cells to store fat, leading the fat to go elsewhere in the body and causing issues such as fatty liver disease or heart disease, Semenkovich said.
But in general, “this is an important potential target gene for further study,” he said. The paper “generated some really provocative information that points to differences between the sexes in terms of body fat distribution and potentially risk of disease.”
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