TY - JOUR
T1 - A Pilot Genome-Wide Analysis Study Identifies Loci Associated With Response to Obeticholic Acid in Patients With NASH
AU - NASH CLINICAL RESEARCH NETWORK
AU - Gawrieh, Samer
AU - Guo, Xiuqing
AU - Tan, Jingyi
AU - Lauzon, Marie
AU - Taylor, Kent D.
AU - Loomba, Rohit
AU - Cummings, Oscar W.
AU - Pillai, Sreekumar
AU - Bhatnagar, Pallav
AU - Kowdley, Kris V.
AU - Yates, Katherine
AU - Wilson, Laura A.
AU - Chen, Yii Der Ida
AU - Rotter, Jerome I.
AU - Chalasani, Naga
AU - Allende, Daniela
AU - Dasarathy, Srinivasan
AU - McCullough, Arthur J.
AU - Penumatsa, Revathi
AU - Dasarathy, Jaividhya
AU - Lavine, Joel E.
AU - Abdelmalek, Manal F.
AU - Bashir, Mustafa
AU - Buie, Stephanie
AU - Diehl, Anna Mae
AU - Guy, Cynthia
AU - Kigongo, Christopher
AU - Kopping, Mariko
AU - Malik, David
AU - Piercy, Dawn
AU - Ragozzino, Linda
AU - Sandrasegaran, Kumar
AU - Vuppalanchi, Raj
AU - Brunt, Elizabeth M.
AU - Cattoor, Theresa
AU - Carpenter, Danielle
AU - Freebersyser, Janet
AU - King, Debra
AU - Lai, Jinping
AU - Neuschwander, Brent A.
AU - Siegner, Joan
AU - Stewart, Susan
AU - Torretta, Susan
AU - Wriston, Kristina
AU - Gonzalez, Maria Cardona
AU - Davila, Jodie
AU - Jhaveri, Manan
AU - Mukhtar, Nizar
AU - Ness, Erik
AU - Poitevin, Michelle
AU - Quist, Brook
AU - Soo, Sherilynn
AU - Ang, Brandon
AU - Behling, Cynthia
AU - Bhatt, Archana
AU - Middleton, Michael S.
AU - Sirlin, Claude
AU - Akhter, Maheen F.
AU - Bass, Nathan M.
AU - Brandman, Danielle
AU - Gill, Ryan
AU - Hameed, Bilal
AU - Maher, Jacqueline
AU - Terrault, Norah
AU - Ungermann, Ashley
AU - Yeh, Matthew
AU - Boyett, Sherry
AU - Contos, Melissa J.
AU - Kirwin, Sherri
AU - Luketic, Velimir A.C.
AU - Puri, Puneet
AU - Sanyal, Arun J.
AU - Schlosser, Jolene
AU - Siddiqui, Mohammad S.
AU - Yost-Schomer, Leslie
AU - Fowler, Kathryn
AU - Kleiner, David E.
AU - Doo, Edward C.
AU - Hall, Sherry
AU - Hoofnagle, Jay H.
AU - Robuck, Patricia R.
AU - Sherker, Averell H.
AU - Torrance, Rebecca
AU - Belt, Patricia
AU - Clark, Jeanne M.
AU - Dodge, John
AU - Donithan, Michele
AU - Isaacson, Milana
AU - Lazo, Mariana
AU - Meinert, Jill
AU - Miriel, Laura
AU - Smith, Jacqueline
AU - Smith, Michael
AU - Sternberg, Alice
AU - Tonascia, James
AU - Natta, Mark L.
AU - Wagoner, Annette
AU - Yamada, Goro
N1 - Funding Information:
Cleveland Clinic Foundation, Cleveland, OH (Daniela Allende, M.D., Srinivasan Dasarathy, M.D., Arthur J. McCullough, M.D., Revathi Penumatsa, M.P.H., and Jaividhya Dasarathy, M.D.); Columbia University, New York, NY (Joel E. Lavine, M.D., Ph.D.); Duke University Medical Center, Durham, NC (Manal F. Abdelmalek, M.D., M.P.H., Mustafa Bashir, M.D., Stephanie Buie, Anna Mae Diehl, M.D., Cynthia Guy, M.D., Christopher Kigongo, M.B., Ch.B., Mariko Kopping, M.S., R.D., David Malik, and Dawn Piercy, M.S., F.N.P.); Indiana University School of Medicine, Indianapolis, IN (Linda Ragozzino, R.N., Kumar Sandrasegaran, M.D., and Raj Vuppalanchi, M.D.); Saint Louis University, St Louis, MO (Elizabeth M. Brunt, M.D. [2002-2008], Theresa Cattoor, R.N., Danielle Carpenter, M.D., Janet Freebersyser, R.N., Debra King, R.N. [2004-2015], Jinping Lai, M.D. [2015-2016], Brent A. Neuschwander-Tetri, M.D., Joan Siegner, R.N. [2004-2015], Susan Stewart, R.N. [2004-2015], Susan Torretta, and Kristina Wriston, R.N. [2015]); Swedish Medical Center, Seattle, WA (Maria Cardona Gonzalez, Jodie Davila, Manan Jhaveri, M.D., Nizar Mukhtar, M.D., Erik Ness, M.D., Michelle Poitevin, Brook Quist, and Sherilynn Soo); University of California San Diego, San Diego, CA (Brandon Ang, Cynthia Behling, M.D., Ph.D., Archana Bhatt, Michael S. Middleton, M.D., Ph.D., and Claude Sirlin, M.D.); University of California San Francisco, San Francisco, CA: Maheen F. Akhter, BS; Nathan M. Bass, M.D., Ph.D. [2002-2011], Danielle Brandman, M.D., M.A.S., Ryan Gill, M.D., Ph.D., Bilal Hameed, M.D., Jacqueline Maher, M.D., Norah Terrault, M.D., M.P.H., and Ashley Ungermann, M.S.); University of Washington Medical Center, Seattle, WA (Matthew Yeh, M.D., Ph.D.); Virginia Commonwealth University, Richmond, VA (Sherry Boyett, R.N., B.S.N., Melissa J. Contos, M.D., Sherri Kirwin, Velimir A.C. Luketic, M.D., Puneet Puri, M.D. [2009-2017], Arun J. Sanyal, M.D., Jolene Schlosser, R.N., B.S.N., Mohammad S. Siddiqui, M.D., and Leslie Yost-Schomer, R.N.); Washington University, St. Louis, MO (Elizabeth M. Brunt, M.D. [2008-2015], and Kathryn Fowler, M.D. [2012-2015]); National Cancer Institute, Bethesda, MD (David E. Kleiner, M.D., Ph.D.); National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (Edward C. Doo, M.D., Sherry Hall, M.S., Jay H. Hoofnagle, M.D., Patricia R. Robuck, Ph.D., M.P.H. [2002-2011], Averell H. Sherker, M.D., and Rebecca Torrance, R.N., M.S.); and Data Coordinating Center, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD (Patricia Belt, B.S., Jeanne M. Clark, M.D., M.P.H., John Dodge, Michele Donithan, M.H.S. [2002-2017], Milana Isaacson, B.S., Mariana Lazo, M.D., Ph.D., Sc.M., Jill Meinert, Laura Miriel, B.S., Jacqueline Smith, A.A., Michael Smith, B.S., Alice Sternberg, Sc.M., James Tonascia, Ph.D., Mark L. Van Natta, M.H.S., Annette Wagoner, and Goro Yamada, Ph.D., M.H.S., M.H.S., M.M.S.).
Publisher Copyright:
© 2019 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85085030443&partnerID=8YFLogxK
U2 - 10.1002/hep4.1439
DO - 10.1002/hep4.1439
M3 - Article
C2 - 31832568
AN - SCOPUS:85085030443
VL - 3
SP - 1571
EP - 1584
JO - Hepatology Communications
JF - Hepatology Communications
SN - 2471-254X
IS - 12
ER -