Separating the effects of life course adiposity on diabetic nephropathy: a comprehensive multivariable Mendelian randomization study.

Abstract

Previous Mendelian randomization (MR) of obesity and diabetic nephropathy (DN) risk used small sample sizes or focused on a single adiposity metric. We explored the independent causal connection between obesity-related factors and DN risk using the most extensive GWAS summary data available, considering the distribution of adiposity across childhood and adulthood. To evaluate the overall effect of each obesity-related exposure on DN (Ncase = 3,676, Ncontrol = 283,456), a two-sample univariate MR (UVMR) analysis was performed. The independent causal influence of each obesity-related feature on DN was estimated using multivariable MR (MVMR) when accounting for confounding variables. It was also used to examine the independent effects of adult and pediatric obesity, adjusting for their interrelationships. We used data from genome-wide association studies, including overall general (body mass index, BMI) and abdominal obesity (waist-to-hip ratio with and without adjustment for BMI, i.e., WHR and WHRadjBMI), along with childhood obesity (childhood BMI). UVMR revealed a significant association between adult BMI (OR=1.24, 95%CI=1.03-1.49, P=2.06×10-2) and pediatric BMI (OR=1.97, 95%CI=1.59-2.45, P=8.55×10-10) with DN risk. At the same time, adult WHR showed a marginally significant increase in DN (OR =1.27, 95%CI = 1.01-1.60, P=3.80×10-2). However, the outcomes were adverse when the influence of BMI was taken out of the WHR (WHRadjBMI). After adjusting for childhood BMI, the causal effects of adult BMI and adult abdominal obesity (WHR) on DN were significantly attenuated and became nonsignificant in MVMR models. In contrast, childhood BMI had a constant and robust independent effect on DN risk(adjusted for adult BMI: IVW, OR=1.90, 95% CI=1.60-2.25, P=2.03×10-13; LASSO, OR=1.91, 95% CI=1.65-2.21, P=3.80×10-18; adjusted for adult WHR: IVW, OR=1.80, 95% CI=1.40-2.31, P=4.20×10-6; LASSO, OR=1.90, 95% CI=1.56-2.32, P=2.76×10-10). Our comprehensive analysis illustrated the hazard effect of obesity-related exposures for DN. In addition, we showed that childhood obesity plays a separate function in influencing the risk of DN and that the adverse effects of adult obesity (adult BMI and adult WHR) can be substantially attributed to it. Thus, several obesity-related traits deserve more attention and may become a new target for the prevention and treatment of DN and warrant further clinical investigation, especially in childhood obesity.