Rare variant associations with waist-to-hip ratio in European-American and African-American women from the NHLBI-Exome Sequencing Project

Abstract

Waist-to-hip ratio (WHR), a relative comparison of waist and hip circumferences, is an easily accessible measurement of body fat distribution, in particular central abdominal fat. A high WHR indicates more intra-abdominal fat deposition and is an established risk factor for cardiovascular disease and type 2 diabetes. Recent genome-wide association studies have identified numerous common genetic loci influencing WHR, but the contributions of rare variants have not been previously reported. We investigated rare variant associations with WHR in 1510 European-American and 1186 African-American women from the National Heart, Lung, and Blood Institute-Exome Sequencing Project. Association analysis was performed on the gene level using several rare variant association methods. The strongest association was observed for rare variants in IKBKB (P = 4.0 × 10 − 8 ) in EuropeanAmericans, where rare variants in this gene are predicted to decrease WHRs. The activation of the IKBKB gene is involved in inflammatory processes and insulin resistance, which may affect normal food intake and body weight and shape. Meanwhile, aggregation of rare variants in COBLL1, previously found to harbor common variants associated with WHR and fasting insulin, were nominally associated (P = 2.23 × 10 − 4 ) with higher WHR in European-Americans. However, these significant results are not shared between African-Americans and European-Americans that may be due to differences in the allelic architecture of the two populations and the small sample sizes. Our study indicates that the combined effect of rare variants contribute to the interindividual variation in fat distribution through the regulation of insulin response.

Association of Genetic Variants Related to Gluteofemoral vs Abdominal Fat Distribution With Type 2 Diabetes, Coronary Disease, and Cardiovascular Risk Factors

“…Second, the discovery and characterization of genetic variants was conducted in a large data set but was limited to individuals of European ancestry. While the genetic determinants of anthropometric phenotypes may be partly shared across different ethnicities, further investigations in other populations and ethnicities will be required for a complete understanding of the genetic relationships between body shape and cardiometabolic risk. Third, this study was largely based on population-based cohorts, the participants of which are usually healthier than the general population, and used analytical approaches that deliberately minimized the influence of outliers, in this case people with extreme fat distribution.…”

Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity

“…A number of studies have connected rare genetic variation to fat distribution. An early sequencing study performed in women reported rare variants in IKBKB associating with waist-to-hip ratio (WHR) 14 . Rare variants in PDE3B and ACVR1C have been reported to associate with WHRadjBMI and related traits 9 , 10 , 13 and an exome array study of WHRadjBMI reported several novel rare variant associations 15 .…”

Long non‐coding RNA NORAD aggravates acute myocardial infarction by promoting fibrosis and apoptosis via miR‐577/COBLL1 axis

“…A previous study revealed that the genetic loci including COBLL1 that is strongly associated with body fat percentage showed distinct cross‐phenotype association signatures with a range of cardiometabolic traits 37 . Aggregation of rare variants in COBLL1 is associated with higher waist‐to‐hip ratio in European‐Americans, which is an established risk factor for cardiovascular disease 38 …”