Body Mass Index and the Risk of Rheumatic Disease: Linear and Nonlinear Mendelian Randomization Analyses.

OBJECTIVE: While the association between obesity and risk of rheumatic disease is well established, the precise causal relation has not been conclusively proved. Here, we estimate the causal effect of body mass index (BMI) on the risk of developing five different rheumatic diseases.

METHODS: Linear and nonlinear mendelian randomization (MR) were used to estimate the effect of BMI on risk of rheumatic disease, and sex-specific effects were identified. Analyses were performed in 361,952 participants from the UK Biobank cohort for the five rheumatic diseases: rheumatoid arthritis (N=8,381 cases), osteoarthritis (N=87,430), psoriatic arthropathy (N=933), gout (N=13,638), and inflammatory spondylitis (N=4,328).

RESULTS: Using linear MR, we found that one standard deviation higher BMI increases the incidence rate for rheumatoid arthritis (IRR=1.52; 95% CI=1.36-1.69), osteoarthritis (IRR=1.49; 1.43-1.55), psoriatic arthropathy (IRR=1.80; 1.31-2.48), gout (IRR=1.73; 1.56-1.92), and inflammatory spondylitis (IRR=1.34; 1.14-1.57) in all individuals. BMI was found to be a stronger risk factor in women compared to men for psoriatic arthropathy (sex-interaction P=3.3×10-4 ) and gout (P=4.3×10-3 ), and the effect on osteoarthritis was stronger in premenopausal compared to postmenopausal women (P=1.8×10-3 ). Nonlinear effects of BMI were identified for osteoarthritis and gout in men, and for gout in women. The nonlinearity for gout was also more extreme in men compared to women (P=0.03).

CONCLUSION: Higher BMI causes an increased risk for rheumatic disease, an effect that is more pronounced in women for both gout and psoriatic arthropathy. The novel sex- and BMI-specific causal effects identified here, give further insight into rheumatic-disease etiology and mark an important step towards personalized medicine. This article is protected by copyright. All rights reserved.