Comprehending the genetic obesity basis could help in cardiometabolic disease prevention in women

Abstract Introduction Epidemiological studies suggest that the location and distribution of excess fat, rather than overall adiposity, provide better insights into the risk of cardiometabolic diseases. Fat distribution, often assessed through waist-to-hip ratio (WHR), has been shown to have a heritable component. Heritability is approximately 50% in women and only around 20% in men. However, which genetic factors influence fat distribution remains poorly understood. Aim Assess the relationship between a set of single nucleotide polymorphisms previously associated with obesity and the WHR in overweight and obese women. Methods A cohort study was conducted on 512 women (aged 56.1 ± 6.4 years) with Body Mass Index (BMI) 25 kg/m². WHR was calculated as the ratio of waist circumference (measured at the narrowest point between the lower rib and the iliac crest) to hip circumference (measured at the widest point of the hips). Two groups were composed according to WHR values: WHR 0.85 (android/central fat distribution) and WHR ≤0.85 (gynoid fat distribution). Fifteen single nucleotide polymorphisms previously linked to obesity and lipid metabolism abnormalities were genotyped using TaqMan real-time PCR. The association of these SNPs with WHR was achieved by bivariate and multivariate logistic regression analysis, and the dominant or recessive genetic model was considered for comparison. Results After bivariate analysis, PSRC1 variant rs599839 (AA+GA vs GG) showed a significant association with android-type obesity (OR=3.18; 95%CI 0.99-10.27; p=0.041), together with SLC30A8 rs1326634 (CC vs TT+TC) (OR=2.38; 95%CI 1.31-4.33; p=0.004). KIF6 rs20455 (TT vs CC+CT) was associated with gynoid-type obesity (OR=0.47; 95%CI 0.22-0.99; p=0.043) in bivariate analyses. After multivariate logistic regression with these three significant genes adjusted for the traditional risk factors, only SLC30A8 rs1326634 (CC vs TT+TC) that encodes the secretory granule-resident and largely endocrine pancreas-restricted zinc transporter ZnT8, remained in the equation as independently associated with an increased WHR (OR=2.50; 95%CI 1.37-4.57; p=0.003). Conclusion A significant association between the SLC30A8 rs1326634 gene variant and android/central fat distribution was found in overweight and obese women. Understanding the genetic basis of obesity and central fat distribution can enable lifestyle changes or pharmacologic interventions to attenuate the risk of cardiometabolic complications.