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

Johanna Karlsson Sundbaum; Eva Baecklund; Niclas Eriksson; Hugo Kohnke; Matilda Wallenberg; Marco Cavalli; Claes Wadelius; Mia Wadelius; Pär Hallberg

doi:10.2217/pgs-2021-0064

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.

Authors

Johanna Karlsson Sundbaum^{1

2}, Eva Baecklund¹, Niclas Eriksson^{3

4}, Hugo Kohnke⁴, Matilda Wallenberg^{4

5}, Marco Cavalli⁶, Claes Wadelius⁶, Mia Wadelius⁴, Pär Hallberg⁴

Affiliations

¹ Department of Medical Sciences, Rheumatology, Uppsala University, SE-751 85, Uppsala, Sweden.
² Department of Health Sciences, Luleå University of Technology, SE-971 87, Luleå, Sweden.
³ Uppsala Clinical Research center, SE-751 85, Uppsala, Sweden.
⁴ Department of Medical Sciences, Clinical Pharmacogenomics & Science for Life Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden.
⁵ Svensk Dos AB, Box 2, SE-751 03, Uppsala, Sweden.
⁶ Department of Immunology, Genetics & Pathology, & Science for Life Laboratory, Uppsala University, SE-751 22, Uppsala, Sweden.

PMID: 34521259
DOI: 10.2217/pgs-2021-0064

Abstract

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

Substances

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