A Pilot Genome‐Wide Analysis Study Identifies Loci Associated With Response to Obeticholic Acid in Patients With NASH. Issue 12 (3rd November 2019)

• Record Type: Journal Article
• Authors: Gawrieh, Samer; Guo, Xiuqing; Tan, Jingyi; Lauzon, Marie; Taylor, Kent D.; Loomba, Rohit; Cummings, Oscar W.; Pillai, Sreekumar; Bhatnagar, Pallav; Kowdley, Kris V.; Yates, Katherine; Wilson, Laura A.; Chen, Yii‐Der Ida; Rotter, Jerome I.; Chalasani, Naga
• Other Names: Allende Daniela investigator.; Dasarathy Srinivasan investigator.; McCullough Arthur J investigator.; Penumatsa Revathi investigator.; Dasarathy Jaividhya investigator.; Lavine Joel E investigator.; Abdelmalek Manal F investigator.; Bashir Mustafa investigator.; Buie Stephanie investigator.; Diehl Anna Mae investigator.; Guy Cynthia investigator.; Kigongo Christopher investigator.; Kopping Mariko investigator.; Malik David investigator.; Piercy Dawn investigator.; Ragozzino Linda investigator.; Sandrasegaran Kumar investigator.; Vuppalanchi Raj investigator.; Brunt Elizabeth M investigator.; Cattoor Theresa investigator.; Carpenter Danielle investigator.; Freebersyser Janet investigator.; King Debra investigator.; Lai Jinping investigator.; Neuschwander Brent A investigator.; Siegner Joan investigator.; Stewart Susan investigator.; Torretta Susan investigator.; Wriston Kristina investigator.; Gonzalez Maria Cardona investigator.; Davila Jodie investigator.; Jhaveri Manan investigator.; Mukhtar Nizar investigator.; Ness Erik investigator.; Poitevin Michelle investigator.; Quist Brook investigator.; Soo Sherilynn investigator.; Ang Brandon investigator.; Behling Cynthia investigator.; Bhatt Archana investigator.; Middleton Michael S investigator.; Sirlin Claude investigator.; Akhter Maheen F investigator.; Bass Nathan M investigator.; Brandman Danielle investigator.; Gill Ryan investigator.; Hameed Bilal investigator.; Maher Jacqueline investigator.; Terrault Norah investigator.; Ungermann Ashley investigator.; Yeh Matthew investigator.; Boyett Sherry investigator.; Contos Melissa J investigator.; Kirwin Sherri investigator.; Luketic Velimir A.C. investigator.; Puri Puneet investigator.; Sanyal Arun J investigator.; Schlosser Jolene investigator.; Siddiqui Mohammad S investigator.; Yost‐Schomer Leslie investigator.; Brunt Elizabeth M investigator.; Fowler Kathryn investigator.; Kleiner David E investigator.; Doo Edward C investigator.; Hall Sherry investigator.; Hoofnagle Jay H investigator.; Robuck Patricia R investigator.; Sherker Averell H investigator.; Torrance Rebecca investigator.; Belt Patricia investigator.; Clark Jeanne M investigator.; Dodge John investigator.; Donithan Michele investigator.; Isaacson Milana investigator.; Lazo Mariana investigator.; Meinert Jill investigator.; Miriel Laura investigator.; Smith Jacqueline investigator.; Smith Michael investigator.; Sternberg Alice investigator.; Tonascia James investigator.; Natta Mark L investigator.; Wagoner Annette investigator.; Yamada Goro investigator.;
• Is Part Of: Hepatology communications. Volume 3:Issue 12(2019)
• Page Start: 1571
• Page End: 1584
• Publication Date: 2019-11-03
• Subjects: Hepatology -- Periodicals; Liver -- Diseases -- Periodicals; Liver Diseases; Gastroenterology; Periodicals; Fulltext; Internet Resources; Periodicals; 616.36
• DOI: 10.1002/hep4.1439
• Languages: English
• ISSNs: 2471-254X

Abstract

Abstract : 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. Abstract : We conducted a genome wide association study (GWAS) in FLINT trial participants to identify variants associated with NASH resolution and fibrosis improvement. We identified several variants associated with histological improvement and pruritus in individuals with NASH receiving obeticholic acid (OCA). The rs75508464 variant near CELA3B had the most significant effect on NASH resolution in those receiving OCA.