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A Pilot Genome-Wide Analysis Study Identifies Loci Associated With Response to Obeticholic Acid in Patients With NASH
Journal article   Open access

A Pilot Genome-Wide Analysis Study Identifies Loci Associated With Response to Obeticholic Acid in Patients With NASH

Samer Gawrieh, Xiuqing Guo, Jingyi Tan, Marie Lauzon, Kent D Taylor, Rohit Loomba, Oscar W Cummings, Sreekumar Pillai, Pallav Bhatnagar, Kris V Kowdley, …
Hepatology Communications, v 3(12), 1571
03 Nov 2019
DOI: https://doi.org/10.1002/hep4.1439
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1002/hep4.1439View
Published, Version of Record (VoR)CC BY-NC-ND V4.0,  Open

Abstract

Analysis Care and treatment Chromosomes Genetic aspects Genomes Liver Single nucleotide polymorphisms Type 2 diabetes Genomics Liver Diseases
A significantly higher proportion of patients with nonalcoholic steatohepatitis (NASH) who received obeticholic acid (OCA) had histological improvement relative to placebo in the FLINT (farnesoid X nuclear receptor ligand obeticholic acid for noncirrhotic, NASH treatment) trial. However, genetic predictors of response to OCA are unknown. We conducted a genome‐wide association study (GWAS) in FLINT participants to identify variants associated with NASH resolution and fibrosis improvement. Genotyping was performed using the Omni2.5 content GWAS chip. To avoid false positives introduced by population stratification, we focused our GWAS on white participants. Six regions on chromosomes 1, 4, 6, 7, 15, and 17 had multiple single nucleotide polymorphisms (SNPs) with suggestive association (P < 1 × 10-4) with NASH resolution. A sentinel SNP, rs75508464, near CELA3B on chromosome 1 was associated with NASH resolution, improvement in the nonalcoholic fatty liver disease activity score, portal inflammation, and fibrosis. Among individuals carrying this allele, 83% achieved NASH resolution with OCA compared with only 33% with placebo. Eight regions on chromosomes 1, 2, 3, 11, 13, and 18 had multiple SNPs associated with fibrosis improvement; of these, rs12130403 near TDRD10 on chromosome 1 was also associated with improvement in NASH and portal inflammation, and rs4073431 near ANO3 on chromosome 11 was associated with NASH resolution and improvement in steatosis. Multiple SNPs on chromosome 11 had suggestive association with pruritus, with rs1379650 near ANO5 being the top SNP. Conclusion: We identified several variants that may be associated with histological improvement and pruritus in individuals with NASH receiving OCA. The rs75508464 variant near CELA3B may have the most significant effect on NASH resolution in those receiving OCA.

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17 citations in Web of Science
16 citations in Scopus

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Collaboration types
Industry collaboration
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Web of Science research areas
Gastroenterology & Hepatology
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