Reevaluating the obesity paradox across diverse disease outcomes: A Mendelian randomization study.

The "obesity paradox" suggests a protective effect of obesity on certain diseases including cardiovascular and respiratory illnesses, but results remain inconsistent, largely due to reliance on body mass index (BMI) alone. To clarify this, we used Mendelian randomization (MR) to assess causal effects of multiple obesity-related anthropometric traits on key clinical outcomes. We conducted MR analyses using summary statistics from genome-wide association study to investigate the causal effects of 13 obesity-related anthropometric indicators-including BMI, basal metabolic rate (BMR), hip circumference, waist circumference (WC), body fat percentage (BFP), arm fat mass (AFM), leg fat mass (LFM), trunk fat mass (TFM), trunk fat free mass (TFFM), whole body fat mass, whole body fat free mass (WBFFM), whole body water mass (WBWM), trunk predicted mass (TPM)-on 5 major clinical outcomes: diffuse large B cell lymphoma, pancreatic cancer, pathological fracture in patient with osteoporosis, sepsis, and 28-day mortality due to sepsis. We selected these outcomes because they represent distinct but obesity-relevant disease categories, encompassing cancer, metabolic-skeletal complications, infection, and mortality risk. Sensitivity analyses, included tests for heterogeneity and horizontal pleiotropy, were performed to assess the stability of MR results. MR analyses revealed no evidence supporting the obesity paradox but demonstrated causal associations between obesity-related traits and clinical outcomes. After excluding traits with horizontal pleiotropy, results showed: BMR, TFFM, and TPM increased diffuse large B cell lymphoma risk; BMI, BMR, AFM, LFM, TFFM, WBFFM, and TPM increased pancreatic cancer risk; BMR, TFFM, WBFFM, WBWM, and TPM increased pathological fracture risk in osteoporosis; BMI, BMR, WC, BFP, AFM, LFM, TFM, whole body fat mass and WBWM increased sepsis risk; and BMI, hip circumference, WC, BFP, AFM, LFM, and TFM increased 28-day sepsis mortality risk (all P < .05). This MR study found no evidence of an "obesity paradox" for the specific outcomes evaluated. Instead, our findings demonstrated that elevated levels of obesity-related anthropometric traits are causally associated with increased risks of diffuse large B-cell lymphoma, pancreatic cancer, pathological fractures in osteoporosis, sepsis, and sepsis-related 28-day mortality. These results provide important insights into the pathogenic role of obesity and may inform future strategies for obesity-related disease prevention and risk assessment.