Conventional and Genetic Evidence on the Association between Adiposity and CKD

Abstract

Significance Statement Conventional epidemiology associates increased body mass index (BMI) with higher risk of CKD. Diabetes and high BP explain half of the association. However, residual confounding factors preclude causal inferences and impede mediation assessments. A genetic approach (Mendelian randomization) may overcome these limitations. Analyses of 281,228 genotyped UK Biobank participants identified positive independent genetic associations between central and general adiposity with CKD, suggesting both are causal risk factors. Conventional approaches underestimate the role of known mediators. Diabetes and BP (and correlates) explain >80% of genetic associations between waist-to-hip ratio and CKD and two-thirds between BMI and CKD. In people without diabetes, obesity appeared to cause CKD. BP accounted for about half of the BMI-CKD associations. Background The size of any causal contribution of central and general adiposity to CKD risk and the underlying mechanism of mediation are unknown. Methods Data from 281,228 UK Biobank participants were used to estimate the relevance of waist-to-hip ratio and body mass index (BMI) to CKD prevalence. Conventional approaches used logistic regression. Genetic analyses used Mendelian randomization (MR) and data from 394 waist-to-hip ratio and 773 BMI-associated loci. Models assessed the role of known mediators (diabetes mellitus and BP) by adjusting for measured values (conventional analyses) or genetic associations of the selected loci (multivariable MR). Results Evidence of CKD was found in 18,034 (6.4%) participants. Each 0.06 higher measured waist-to-hip ratio and each 5-kg/m 2 increase in BMI were associated with 69% (odds ratio, 1.69; 95% CI, 1.64 to 1.74) and 58% (1.58; 1.55 to 1.62) higher odds of CKD, respectively. In analogous MR analyses, each 0.06–genetically-predicted higher waist-to-hip ratio was associated with a 29% (1.29; 1.20 to 1.38) increased odds of CKD, and each 5-kg/m 2 genetically-predicted higher BMI was associated with a 49% (1.49; 1.39 to 1.59) increased odds. After adjusting for diabetes and measured BP, chi-squared values for associations for waist-to-hip ratio and BMI fell by 56%. In contrast, mediator adjustment using multivariable MR found 83% and 69% reductions in chi-squared values for genetically-predicted waist-to-hip ratio and BMI models, respectively. Conclusions Genetic analyses suggest that conventional associations between central and general adiposity with CKD are largely causal. However, conventional approaches underestimate mediating roles of diabetes, BP, and their correlates. Genetic approaches suggest these mediators explain most of adiposity-CKD–associated risk.

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