HLA DRB1*01 and *04 Predisposition to Rheumatoid Arthritis and Polymorphisms of the SLCO1B1, MTHFR and PNPLA3 Genes Are Not Associated with Fatty Liver and Hepatotoxicity

Background: Nonalcoholic fatty liver disease (NAFLD) is common in rheumatoid arthritis (RA), and methotrexate (MTX) use raises concern about hepatotoxicity. We evaluated whether HLA-DRB1, PNPLA3, SLCO1B1, and MTHFR variants are associated with NAFLD, liver fibrosis, or MTX toxicity/pharmacokinetics in RA, after accounting for clinical covariates. Methods: In a cross-sectional cohort of 159 patients with RA, NAFLD, and fibrosis were assessed by FibroScan (CAP ≥ 275 dB/m; LSM > 8 kPa). We compared baseline characteristics by NAFLD status and fitted multivariable models for NAFLD, fibrosis, ALT elevation, and MTX toxicity; MTX pharmacokinetics were analyzed in 111 MTX-treated patients. Multiple testing was controlled using the Benjamini–Hochberg method. Results: The prevalence of NAFLD was 36%, and that of fibrosis was 11%. NAFLD patients had higher CAP and LSM, and markedly greater adiposity indices (body weight, BMI, waist and hip circumference, WC). BMI and WC were independently associated with NAFLD (BMI OR 1.27 per kg/m2, 95% CI 1.16–1.40; WC OR 1.06 per cm, 95% CI 1.01–1.12). No HLA-DRB1, PNPLA3, SLCO1B1, or MTHFR variant showed an association that survived multiple-comparison correction. Among MTX users, 21/111 (19%) experienced toxicity. SLCO1B1 and MTHFR variants did not influence MTX pharmacokinetics; age was associated with lower dose-normalized MTX exposure, and cumulative dose was positively associated with exposure. Conclusions: In RA, adiposity—not the tested candidate pharmacogenes—drives NAFLD risk, and SLCO1B1/MTHFR variants do not support MTX dose adjustment. The findings emphasize routine clinical risk factors over single-gene testing for NAFLD and MTX hepatotoxicity in this setting.