Two genetic studies expand list of genes connected to major Western health problems

The Children's Hospital of PhiladelphiaMar 5 2014

Two recent genetic studies expand the list of genes involved with body fat and body mass index, and their connection to major Western health problems: heart disease, high blood pressure and diabetes. One study showed that higher body mass index (BMI) caused harmful effects on the risk of type 2 diabetes, high blood pressure and inflammation, while another study found gene signals linked to higher levels of body fat metrics, without showing causality.

"These findings are highly relevant to the obesity pandemic in the United States and many other countries," said geneticist Brendan J. Keating, D. Phil., of the Center for Applied Genomics at The Children's Hospital of Philadelphia. "Of course, much research remains to be performed to discover further genes involved in these complex metabolic diseases, and to better understand how to improve treatments."

Keating, who previously helped create a large gene-discovery tool called the Cardio Chip, was a co-leader of both studies, which drew on large international teams of scientists using DNA, laboratory and disease data from tens of thousands of people.

In the BMI research, published in the Feb. 6 issue of the American Journal of Human Genetics, Keating collaborated with clinical epidemiologist Michael V. Holmes, M.D., Ph.D., of the Perelman School of Medicine at the University of Pennsylvania. That study used a recently developed epidemiology tool called Mendelian randomization (MR) that rules out confounding factors such as behavioral and environmental influences to construct genetic risk scores for specific traits of interest.

The study team analyzed eight population cohorts including over 34,000 individuals of European descent, of whom over 4,400 had type 2 diabetes, over 6,000 had coronary heart disease and over 3,800 had a previous stroke.

Their analysis, concluded the authors, supports the importance of BMI in regulating cardiometabolic traits and the risk of type 2 diabetes. "Our findings suggest that lowering BMI is likely to result in multiple reductions of cardiovascular traits: in blood pressure, inflammation, fasting glucose and insulin, and in the risk of type 2 diabetes," said Keating.

"This study is the first to use this emerging MR technique with a combination of genetic markers known to impact BMI, to assess the causal relationship of BMI and a comprehensive repertoire of traits," said Holmes. He added that, although the study showed that increasing BMI has an undesirable effect on cardiometabolic factors, interestingly, it did not show that higher BMI increased the risk of coronary heart disease.

Keating also co-led a second study, published Jan. 6 in Human Molecular Genetics, analyzing genes associated with central adiposity. Measures of central adiposity, or body fat, can be derived using waist circumference and waist-to-hip ratio. "For assessing the influence of weight-related genes, central adiposity is preferable to BMI, because BMI also reflects the influence of genes affecting height," said Keating.

Keating's co-senior author was Kira C. Taylor, Ph.D., M.S., of the University of Louisville. The study team performed a meta-analysis in over 57,000 subjects of European ancestry, then validated their results in even larger numbers from independent studies.

This study discovered three novel genetic signals associated with central adiposity, in the genes TMCC1, HOXC10, and PEMT. In addition, the team found two more novel genetic signals, in the SHC1 and ATBDB4 genes, which were only observed in women. "Previous research has reported different gene variants operating between men and women related to adiposity," said Keating. "This gives us initial clues of the genes involved with sex-specific body shapes. Future research using these findings may yield insight into the actual biological mechanisms that dictate why males and females have different body distributions of fat deposits."

The adiposity study showed an association, not a causal role, for the genetic signals, with other signals yet to be discovered using even larger sample sizes. Several of the genes, added Keating, are in regulatory regions. He added that additional work is needed to tease out the biology of these signals, but the first steps of identifying genes underpinning these traits has been accomplished.