(VP069) INVESTIGATING THE ASSOCIATION BETWEEN WAIST HIP RATIO AND CARDIOMETABOLIC DISEASES USING MENDELIAN RANDOMIZATION ANALYSIS

Background: Obesity and specifically increased Waist-Hip-Ratio (WHR) is a causal contributor to cardiometabolic diseases including type 2 diabetes (T2D), with some evidence of sex-differential effects. Increased lipid flux with ectopic lipid deposition in the liver, skeletal muscle and pancreas is postulated to contribute to insulin resistance and T2D. Mendelian randomization (MR) can be used to infer causal association between an exposure and outcome. Previous MR analyses indicate that increased WHR increases total free fatty acid and the ratio of monounsaturated fatty acids to total free fatty acids. We, therefore, investigated to what extent total free fatty acids and the ratio of monounsaturated fatty acids to total free fatty acids contribute to T2D with increased WHR. We also investigated whether these associations differ by sex.

METHODS AND RESULTS: Mendelian randomization (MR) was utilized to investigate causal associations between WHR and T2D and its mediation by total free fatty acids and the ratio of monounsaturated fatty acids to total free fatty acids. We used summary statistics from the largest published genome-wide association studies of people of European ancestry.

Univariable MR indicates increased WHR causally associates with T2D (beta: 1.099, SE: 0.069, OR:3 and p-value: 1.23E-56). Multivariable MR adjusting for total free fatty acid (beta:0.981, SE: 0.078, OR: 2.6 and p-value: 2.05E-29) and the ratio of monounsaturated fatty acids to total free fatty acids (beta: 0.892, SE: 0.084, OR: 2.4 and p-value: 2.01E-22) indicates that this effect of WHR is largely independent.

Sex-stratified analyses yielded concordant results. In males UVMR showed WHR causally associated with T2D (beta: 0.736, SE: 0.110, OR:2 p-value: 2.16E-11). In females, UVMR also suggests a positive causal association between WHR and T2D (beta: 0.927, SE: 0.065, OR:2.5 p-value: 3.08E-46). MVMR results in both males (WHR adjusted for total free fatty Acids (beta: 0.796, SE: 0.127, OR:2.2 and p-value: 6.57E-09) and ratio monounsaturated fatty acids to total free fatty acids (beta: 0.747, SE: 0.132, OR: 2.2 and p-value: 1.05E-07)) and in females (WHR adjusted for total free fatty Acids (beta: 0.890, SE: 0.069, OR:2.4 and p-value: 6.54E-29) and the ratio of monounsaturated fatty acids to total free fatty acids (beta: 0.877, SE: 0.074, OR:2.4 and p-value: 2.94E-25)) suggest WHR has an independent effect on T2D.

Conclusion: WHR likely increases the risk for T2D independent of circulating free fatty acid and the ratio of monounsaturated fatty acids to total free fatty acids This suggests other mediators likely contribute to increased T2D risk with increased WHR.