Genetic risk factors in rheumatoid arthritis: A Mendelian randomization study of chronic kidney disease in European populations.

Abstract

Rheumatoid arthritis (RA) is a heritable autoimmune disease linked to chronic kidney disease (CKD) in observational studies. However, whether this association is causal and driven by shared genetic risk remains unclear, warranting genetic investigation. To investigate possible causal relationships between RA and different CKD subtypes, we used Mendelian randomization (MR) analyses with data from genome-wide association studies. The inverse variance weighted (IVW) methodology was the main method, and sensitivity analyses were added to improve the validity of the causal estimations. Our analysis predicted that RA significantly increases the risk of IgA nephropathy (IVW odds ratio [OR]&#x2005;=&#x2005;1.041, 95% confidence interval [CI]&#x2005;=&#x2005;1.018-1.065, P&#x2005;=&#x2005;4.286e-04), diabetic nephropathy (IVW OR&#x2005;=&#x2005;1.078, 95% CI&#x2005;=&#x2005;1.009-1.152, P&#x2005;=&#x2005;.027), nephrotic syndrome (IVW OR&#x2005;=&#x2005;1.164, 95% CI&#x2005;=&#x2005;1.078-1.257, P&#x2005;=&#x2005;1.012e-04), and chronic renal failure (IVW OR&#x2005;=&#x2005;1.046, 95% CI&#x2005;=&#x2005;1.018-1.075, P&#x2005;=&#x2005;1.000e-03). MR analyses confirmed RA's positive causal effect on these CKD subtypes (all P&#x2005;<&#x2005;.05). While heterogeneity was observed for IgA nephropathy and chronic renal failure, sensitivity analyses (MR-Egger intercept, all P&#x2005;>&#x2005;.05) revealed no evidence of horizontal pleiotropy, supporting the robustness of our findings. Our findings suggest that in European-ancestry populations, a genetic predisposition to RA is causally associated with a higher risk of specific types of CKD. While these results require validation in diverse ethnic groups, they highlight the potential importance of renal monitoring for genetically susceptible RA patients, which may help mitigate the public health burden of CKD.