Gene variants associated with an 'apple-shaped' body type, in which weight is deposited around the abdomen rather than in the hips and thighs, increases the risk for type 2 diabetes and coronary heart disease, as well as the incidence of several cardiovascular risk factors, a Harvard study found.
"People vary in their distribution of body fat – some put fat in their belly, which we call abdominal adiposity, and some in their hips and thighs," says Dr Sekar Kathiresan, director of theMassachusetts General Hospital Centre for Genomic Medicine, associate professor of medicine at Harvard Medical School, and senior author of the report. "Abdominal adiposity has been correlated with cardio-metabolic disease, but whether it actually has a role in causing those conditions was unknown. We tested whether genetic predisposition to abdominal adiposity was associated with the risk for type 2 diabetes and coronary heart disease and found that the answer was a firm 'yes'."
While several observational studies have reported greater incidence of type 2 diabetes and heart disease among individuals with abdominal adiposity, they could not rule out the possibility that lifestyle factors – such as diet, smoking and a lack of exercise – were the actual causes of increased disease risk. It also could have been possible that individuals in the early stages of heart disease might develop abdominal adiposity because of a limited ability to exercise. The current study was designed to determine whether body type really could increase cardiometabolic risk.
To answer that question, the research team applied a genetic approach called mendelian randomisation, which measures whether inherited gene variants actually cause outcomes such as the development of a disease. Using data from a previous study that identified 48 gene variants associated with waist-to-hip ratio adjusted for body mass index – an established measure for abdominal adiposity – they developed a genetic risk score. They then applied that score to data from six major genome-wide association studies and to individual data from the UK Biobank – a total research group of more than 400,000 individuals – to determine any association between a genetic predisposition to abdominal adiposity and cardio-metabolic disease and its risk factors.
The results clearly indicated that genetic predisposition to abdominal adiposity is associated with significant increases in the incidence of type 2 diabetes and coronary heart disease, along with increases in blood lipids, blood glucose and systolic blood pressure. No association was found between the genetic risk score and lifestyle factors, and testing confirmed that only the abdominal adiposity effects of the identified gene variants were associated with cardio-metabolic risk.
"These results illustrate the power of using genetics as a method of determining the effects of a characteristic like abdominal adiposity on cardio-metabolic outcomes," says lead author Dr Connor Emdin, of the MGH Centre for Genomic Medicine and the cardiology division. "The lack of association between the body type genetic risk score and confounding factors such as diet and smoking provides strong evidence that abdominal adiposity itself contributes to causing type 2 diabetes and heart disease."
Emdin continues, "Not only do these results allow us to use body shape as a marker for increased cardio-metabolic risk, they also suggest that developing drugs that modify fat distribution may help prevent these diseases. Future research also could identify individual genes that could be targeted to improve body fat distribution to reduce these risks."
Abstract
Importance: In observational studies, abdominal adiposity has been associated with type 2 diabetes and coronary heart disease (CHD). Whether these associations represent causal relationships remains uncertain.
Objective: To test the association of a polygenic risk score for waist-to-hip ratio (WHR) adjusted for body mass index (BMI), a measure of abdominal adiposity, with type 2 diabetes and CHD through the potential intermediates of blood lipids, blood pressure, and glycemic phenotypes.
Design, Setting, and Participants: A polygenic risk score for WHR adjusted for BMI, a measure of genetic predisposition to abdominal adiposity, was constructed with 48 single-nucleotide polymorphisms. The association of this score with cardiometabolic traits, type 2 diabetes, and CHD was tested in a mendelian randomization analysis that combined case-control and cross-sectional data sets. Estimates for cardiometabolic traits were based on a combined data set consisting of summary results from 4 genome-wide association studies conducted from 2007 to 2015, including up to 322 154 participants, as well as individual-level, cross-sectional data from the UK Biobank collected from 2007-2011, including 111 986 individuals. Estimates for type 2 diabetes and CHD were derived from summary statistics of 2 separate genome-wide association studies conducted from 2007 to 2015 and including 149 821 individuals and 184 305 individuals, respectively, combined with individual-level data from the UK Biobank.
Exposures: Genetic predisposition to increased WHR adjusted for BMI.
Main Outcomes and Measures: Type 2 diabetes and CHD.
Results: Among 111 986 individuals in the UK Biobank, the mean age was 57 (SD, 8) years, 58 845 participants (52.5%) were women, and mean WHR was 0.875. Analysis of summary-level genome-wide association study results and individual-level UK Biobank data demonstrated that a 1-SD increase in WHR adjusted for BMI mediated by the polygenic risk score was associated with 27-mg/dL higher triglyceride levels, 4.1-mg/dL higher 2-hour glucose levels, and 2.1–mm Hg higher systolic blood pressure (each P < .001). A 1-SD genetic increase in WHR adjusted for BMI was also associated with a higher risk of type 2 diabetes (odds ratio, 1.77 [95% CI, 1.57-2.00]; absolute risk increase per 1000 participant-years, 6.0 [95% CI, CI, 4.4-7.8]; number of participants with type 2 diabetes outcome, 40 530) and CHD (odds ratio, 1.46 [95% CI, 1.32-1.62]; absolute risk increase per 1000 participant-years, 1.8 [95% CI, 1.3-2.4]; number of participants with CHD outcome, 66 440).
Conclusions and Relevance: A genetic predisposition to higher waist-to-hip ratio adjusted for body mass index was associated with increased risk of type 2 diabetes and coronary heart disease. These results provide evidence supportive of a causal association between abdominal adiposity and these outcomes.
Authors
Connor A Emdin, Amit V Khera, Pradeep Natarajan, Derek Klarin, Seyedeh M Zekavat, Allan J Hsiao, Sekar Kathiresan
[link url="https://www.sciencedaily.com/releases/2017/02/170214162852.htm"]Massachusetts General Hospital material[/link]
[link url="http://jamanetwork.com/journals/jama/article-abstract/2601502"]JAMA abstract[/link]