Genome-wide association study of liver enzyme elevation in rheumatoid arthritis patients starting methotrexate

Pharmacogenomics. 2021 Oct;22(15):973-982. doi: 10.2217/pgs-2021-0064. Epub 2021 Sep 15.


Aim: To identify novel genetic variants predisposing to elevation of Alanine aminotransferase (ALT) in rheumatoid arthritis (RA) patients after initiation of methotrexate (MTX) treatment. Patients & methods: We performed genome-wide association studies in 198 RA patients starting MTX. Outcomes were maximum level of ALT and ALT >1.5-times the upper level of normal within the first 6 months of treatment. Results:RAVER2 (rs72675408) was significantly associated with maximum level of ALT (p = 4.36 × 10-8). This variant is in linkage disequilibrium with rs72675451, which is associated with differential expression of JAK1 and RAVER2. Conclusion: We found an association between ALT elevation and genetic variants that may regulate the expression of JAK1 and RAVER2. JAK1 encodes a janus kinase involved in the pathogenesis of RA.

Keywords: cohort study; genome-wide association studies; hepatotoxicity; methotrexate; rheumatoid arthritis; risk 13 factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alanine Transaminase / blood
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / enzymology
  • Arthritis, Rheumatoid / genetics*
  • Chemical and Drug Induced Liver Injury / enzymology*
  • Cohort Studies
  • Female
  • Gene Expression Regulation
  • Genome-Wide Association Study*
  • Heterogeneous-Nuclear Ribonucleoproteins / genetics
  • Humans
  • Janus Kinase 1 / genetics
  • Liver / drug effects
  • Liver / enzymology*
  • Male
  • Methotrexate / therapeutic use*
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Young Adult


  • Antirheumatic Agents
  • Heterogeneous-Nuclear Ribonucleoproteins
  • RAVER2 protein, human
  • Alanine Transaminase
  • JAK1 protein, human
  • Janus Kinase 1
  • Methotrexate