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Randomized Controlled Trial
. 2022 Aug:55:152036.
doi: 10.1016/j.semarthrit.2022.152036. Epub 2022 May 28.

Genetics are not likely to offer clinically useful predictions for elevated liver enzyme levels in patients using low dose methotrexate

Jing Cui  1 , Daniel I Chasman  2 , Soumya Raychaudhuri  3 , Chang Xu  4 , Paul M Ridker  5 , Daniel H Solomon  4 , Elizabeth W Karlson  4
Affiliations
Randomized Controlled Trial

Genetics are not likely to offer clinically useful predictions for elevated liver enzyme levels in patients using low dose methotrexate

Jing Cui et al. Semin Arthritis Rheum. 2022 Aug.

Abstract

Objective: To examine genetic influence on the risk of elevations in liver function tests (AST and ALT) among patients using low-dose methotrexate (LD-MTX).

Methods: We examined data from the LD-MTX arm of a randomized double-blind placebo-controlled trial conducted among subjects without rheumatic disease. Genome wide association studies (GWAS) were performed in subjects of European ancestry to test the association between single nucleotide polymorphisms (SNPs) and the log transformed maximum values of AST, ALT, and dichotomized outcome with AST or ALT > 2 times upper limit of normal (ULN). The association between variants in MTX metabolism candidate genes and the outcomes was also tested. Furthermore, associations between a drug induced liver injury (DILI) weighted genetic risk score (wGRS) and the outcomes were tested, combining 10 SNPs and 11 classical HLA alleles associated with DILI.

Results: In genome-wide genetic analyses among 1,429 subjects of European ancestry who were randomized to receive LD-MTX, two SNPs reached genome wide significance for association with log transformed maximum ALT. We observed associations between established candidate genes in MTX pharmacogenetics and log transformed maximum AST and ALT, as well as in dichotomized outcome with AST or ALT > 2 x ULN. There was no association between DILI wGRS or candidate variants and AST, ALT, or DILI response.

Conclusions: Modest evidence was observed that common variants affected AST and ALT levels in subjects of European ancestry on LD-MTX, but this genetic effect is not useful as a clinical predictor of MTX toxicity.

Trial registration: ClinicalTrials.gov NCT01594333.

Keywords: Drug induced liver injury; Genetic risk score; Genome wide association study; Low dose methotrexate; Pharmacogenetics.

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Figures

Fig. 1.
Fig. 1.
Manhattan plot for primary log transformed maximum AST and ALT level, and secondary outcome of LFT>2X ULN, in LD-MTX subjects with European ancestry. 1a, GWAS MH plot for log transformed maximum AST; 1b, GWAS MH plot for log transformed maximum ALT; 1c, GWAS MH plot for LFT >2X ULN. *Solid line indicate genome wide significant cut off, 5 × 10−8
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References

    1. Farber S, Diamond LK. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med 1948;238(23):787–93. - PubMed
    1. Weinblatt ME, Coblyn JS, Fox DA, et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 1985;312(13):818–22. - PubMed
    1. Nikiphorou E, Negoescu A, Fitzpatrick JD, et al. Indispensable or intolerable? Methotrexate in patients with rheumatoid and psoriatic arthritis: a retrospective review of discontinuation rates from a large UK cohort. Clin Rheumatol 2014;33(5):609–14. - PubMed
    1. Visser K, van der Heijde DM. Risk and management of liver toxicity during methotrexate treatment in rheumatoid and psoriatic arthritis: a systematic review of the literature. Clin Exp Rheumatol 2009;27(6):1017–25. - PubMed
    1. Lewis JH. Hy’s law,’ the ‘Rezulin Rule,’ and other predictors of severe drug-induced hepatotoxicity: putting risk-benefit into perspective. Pharmacoepidemiol Drug Saf 2006;15(4):221–9. - PubMed

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