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Causal effects of rheumatoid arthritis or ankylosing spondylitis on membranous nephropathy: a two-sample Mendelian
Xiu-Fen Wang1, Shao-Bin Duan1, Jian He2
1Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China.
Background:
Membranous nephropathy (MN) is the leading cause of adult-onset nephrotic syndrome, with primary MN of unclear cause accounting for 80% of cases. Retrospective clinical research reported that MN occurring in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients was triggered by nephrotoxic drugs or of unknown cause. However, whether RA or AS itself increases the risk of developing MN is unknown.
Methods:
We conducted mendelian randomization (MR) analysis to evaluate the causal effects of RA or AS on MN using genome-wide association study (GWAS) statistics. The inverse variance weighted (IVW) method was the primary analysis, and several supplementary analyses and sensitivity analyses were performed to test the causal estimates.
Results:
We obtained 30 valid instrumental variables (IVs) of RA and 16 valid IVs of AS from large-scale open-access GWASs. The genetically predicted RA significantly increased the risk of MN [IVW odds ratios (OR) = 1.327, 95% confidence interval (CI) = (1.124, 1.565), P = 8.051 × 10-4]. Three supplementary MR analyses provided the consistent positive causal effect of RA on MN (all P < 0.05). No horizontal pleiotropy was detected by MR Egger intercept analysis (P = 0.411). However, the genetically predicted AS had no causal effect on MN by IVW and supplementary analysis (all P > 0.05).
Conclusions:
Genetically predicted RA could increase the risk of MN, but genetically predicted AS was not associated with MN. Screening for kidney involvement in RA patients should be noted, and active treatment of RA will reduce the public health burden of MN.
Insights
Rheumatoid arthritis (RA) significantly increases the risk of developing membranous nephropathy (MN), a leading cause of adult nephrotic syndrome. Ankylosing spondylitis (AS) showed no causal link to MN. Early kidney screening in RA patients is crucial.
Area of Science:
- Nephrology
- Rheumatology
- Genetics
Background:
- Membranous nephropathy (MN) is the primary cause of adult nephrotic syndrome, often idiopathic.
- Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are linked to MN, but causality is unclear.
- Previous studies suggest drug toxicity or unknown factors trigger MN in RA/AS patients.
Purpose of the Study:
- To investigate the causal relationship between rheumatoid arthritis (RA) and ankylosing spondylitis (AS) and the risk of developing membranous nephropathy (MN).
- Utilize Mendelian randomization (MR) analysis with genome-wide association study (GWAS) data to assess genetic predisposition.
- Determine if RA or AS directly increases the risk of MN.
Main Methods:
- Mendelian randomization (MR) analysis employed using large-scale genome-wide association study (GWAS) summary statistics.
- Inverse variance weighted (IVW) method served as the primary analytical approach.
- Sensitivity and supplementary analyses, including MR Egger intercept, were performed to ensure robustness and detect pleiotropy.
Main Results:
- Thirty validated genetic instrumental variables for RA and 16 for AS were identified.
- Genetically predicted RA demonstrated a significant causal effect, increasing MN risk (OR=1.327, P=8.051×10⁻⁴).
- Genetically predicted AS showed no significant causal association with MN across all analyses.
Conclusions:
- Rheumatoid arthritis (RA) is a genetically predicted risk factor for developing membranous nephropathy (MN).
- Ankylosing spondylitis (AS) does not appear to causally influence the risk of MN.
- Clinical vigilance for kidney involvement in RA patients is recommended; effective RA management may mitigate MN burden.
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