UGT1A1 genetic variants are associated with increases in bilirubin levels in rheumatoid arthritis patients treated with sarilumab

Nan Lin,Anita Boyapati,Goncalo Abecasis,Alexander Lopez,Nils Ternes,Amy Damask,Jeffrey G Reid,Charles Paulding,Michael C Nivens,Alan R Shuldiner,John Overton,Aris Baras,Sara Hamon,Jennifer D Hamilton,John Penn

doi:10.1038/s41397-022-00269-5

Nan Lin, Anita Boyapati + Show 13 more

Open Access

https://doi.org/10.1038/s41397-022-00269-5

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Abstract

Sarilumab is a human monoclonal antibody against interleukin (IL)-6Rα that has been approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) and an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). Mild liver function test abnormalities have been observed in patients treated with sarilumab. We describe a genome-wide association study of bilirubin elevations in RA patients treated with sarilumab. Array genotyping and exome sequencing were performed on DNA samples from 1075 patients. Variants in the UGT1A1 gene were strongly associated with maximum bilirubin elevations in sarilumab-treated patients (rs4148325; p = 2.88 × 10−41) but were not associated with aminotransferase elevations. No other independent loci showed evidence of association with bilirubin elevations after sarilumab treatment. These findings suggest that most bilirubin increases during sarilumab treatment are related to genetic variation in UGT1A1 rather than underlying liver injury.

Highlights

Drug-induced liver injury (DILI) is the most frequent cause of safetyrelated postmarketing drug withdrawals [1, 2] and is the most common reason for acute liver failure in the United States [3, 4]
We Statistical analysis retrospectively tested if UGT1A1 variants were associated with bilirubin elevations in sarilumab-treated patients, and performed a genome-wide association study (GWAS) to explore if any genetic variants outside of the UGT1A1 locus were associated with bilirubin elevations
uridine diphosphate (UDP)-glucuronosyltransferase 1-1, the enzyme encoded by the UGT1A1 gene, is the only known enzyme responsible for bilirubin metabolism [23]

Summary

INTRODUCTION

Drug-induced liver injury (DILI) is the most frequent cause of safetyrelated postmarketing drug withdrawals [1, 2] and is the most common reason for acute liver failure in the United States [3, 4]. We Statistical analysis retrospectively tested if UGT1A1 variants were associated with bilirubin elevations in sarilumab-treated patients, and performed a genome-wide association study (GWAS) to explore if any genetic variants outside of the UGT1A1 locus were associated with bilirubin elevations. The mathematical and computational details of FCCA have been described previously [19] In this analysis, the variant is treated as the Genotype and whole-exome sequencing data Patient DNA samples underwent microarray genotyping and whole-exome sequencing. Firth logistic regression, assuming a recessive genetic model, was used to test the association between the candidate variants in UGT1A1 and ULNdichotomized total bilirubin level in sarilumab-treated patients; covariate adjustment followed the approach outlined above. Hardy–Weinberg equilibrium (HWE) tests were calculated in the major

RESULTS

Findings

DISCUSSION