Allometric body shape indices, type 2 diabetes and kidney function: A two-sample Mendelian randomization study.

Aim: To examine the association between body mass index (BMI)-independent allometric body shape indices and kidney function. Materials and

Methods: We performed a two-sample Mendelian randomization (MR) analysis, using summary statistics from UK Biobank, CKDGen and DIAGRAM. BMI-independent allometric body shape indices were: A Body Shape Index (ABSI), Waist-Hip Index (WHI) and Hip Index (HI). Kidney function outcomes were: urinary albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate and blood urea nitrogen. Furthermore, we investigated type 2 diabetes (T2D) as a potential mediator on the pathway to albuminuria. The main analysis was inverse variance-weighted random-effects MR in participants of European ancestry. We also performed several sensitivity MR analyses.

Results: A 1-standard deviation (SD) increase in genetically predicted ABSI and WHI levels was associated with higher UACR (β = 0.039 [95% confidence interval: 0.016, 0.063] log [UACR], P = 0.001 for ABSI, and β = 0.028 [0.012, 0.044] log [UACR], P = 6 x 10-4 for WHI) in women, but not in men. Meanwhile, a 1-SD increase in genetically predicted HI was associated with lower UACR in women (β = -0.021 [-0.041, 0.000] log [UACR], P = 0.05) and in men (β = -0.026 [-0.058, 0.005] log [UACR], P = 0.10). Corresponding estimates in individuals with diabetes were substantially augmented. Risk of T2D increased for genetically high ABSI and WHI in women (P < 6 x 10-19 ) only, but decreased for genetically high HI in both sexes (P < 9 x 10-3 ). No other associations were observed.

Conclusions: Genetically high HI was associated with decreased risk of albuminuria, mediated through decreased T2D risk in both sexes. Opposite associations applied to genetically high ABSI and WHI in women only.