@article{1ca6f7970d9344928ac36cae6857ba43,
title = "Role of candidate gene variants in modulating the risk and severity of alcoholic hepatitis",
abstract = "Background: Alcoholic hepatitis (AH) is a severe and life-threatening alcohol-associated liver disease. Only a minority of heavy drinkers acquires AH and severity varies among affected individuals, suggesting a genetic basis for the susceptibility to and severity of AH. Methods: A cohort consisting of 211 patients with AH and 176 heavy drinking controls was genotyped for five variants in five candidate genes that have been associated with chronic liver diseases: rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3), rs72613567 in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13), rs58542926 in transmembrane 6 superfamily member 2 (TM6SF2), rs641738 in membrane bound O-acyltransferase domain containing 7 (MBOAT7), and a copy number variant in the haptoglobin (HP) gene. We tested the effects of individual variants and the combined/interacting effects of variants on AH risk and severity. Results: We found significant associations between AH risk and the risk alleles of rs738409 (p = 0.0081) and HP (p = 0.0371), but not rs72613567 (p = 0.3132), rs58542926 (p = 0.2180), or rs641738 (p = 0.7630), after adjusting for patient's age and sex. A multiple regression model indicated that PNPLA3 rs738409:G [OR = 1.59 (95% CI: 1.15–2.22), p = 0.0055] and HP*2 [OR = 1.38 (95% CI: 1.04–1.82), p = 0.0245], when combined and adjusted for age and sex also had a large influence on AH risk among heavy drinkers. In the entire cohort, variants in PNPLA3 and HP were associated with increased total bilirubin and Model for End-stage Liver Disease (MELD) score, both measures of AH severity. The HSD17B13 rs72613567:AA allele was not found to reduce risk of AH in patients carrying the G allele of PNPLA3 rs738409 (p = 0.0921). Conclusion: PNPLA3 and HP genetic variants increase AH risk and are associated with total bilirubin and MELD score, surrogates of AH severity.",
keywords = "HSD17B13, PNPLA3, alcoholic liver disease, genetic risk, haptoglobin",
author = "Beaudoin, {James J.} and Tiebing Liang and Qing Tang and Banini, {Bubu A.} and Shah, {Vijay H.} and Sanyal, {Arun J.} and Chalasani, {Naga P.} and Samer Gawrieh",
note = "Funding Information: Research reported in this publication was supported by the National Institutes of Health under Award Numbers 5U01AA021883‐04, 5U01AA021891‐04, 5U01AA021788‐04, and 5U01AA021840‐04 from the National Institute on Alcohol Abuse and Alcoholism (for the TREAT Consortium) and F31DK120196 from the National Institute of Diabetes and Digestive and Kidney Diseases (for JJB). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: Dr. Beaudoin, Dr. Liang, Ms. Tang, and Dr. Banini declare no conflicts. Dr. Shah has no conflicts relevant to this work to disclose. Dr. Sanyal: None for this project. Dr. Sanyal is President of Sanyal Biotechnology and has stock options in Genfit, Akarna, Tiziana, Indalo, Durect Inversago and Galmed. He has served as a consultant to Astra Zeneca, Nitto Denko, Conatus, Nimbus, Salix, Tobira, Takeda, Janssen, Gilead, Terns, Birdrock, Merck, Valeant, Boehringer‐Ingelheim, Bristol Myers Squibb, Lilly, Hemoshear, Zafgen, Novartis, Novo Nordisk, Pfizer, Exhalenz, and Genfit. He has been an unpaid consultant to Intercept, Echosens, Immuron, Galectin, Fractyl, Syntlogic, Affimune, Chemomab, Zydus, Nordic Bioscience, Albireo, Prosciento, and Surrozen. His institution has received grant support from Gilead, Salix, Tobira, Bristol Myers, Shire, Intercept, Merck, Astra Zeneca, Mallinckrodt, Cumberland, and Novartis. He receives royalties from Elsevier and UptoDate. Dr. Chalasani had paid consulting activities with following companies in last 12 months: AbbVie, Shire, NuSirt, Afimmune, Axovant, Allergan, Madrigal, Coherus, Siemens, and Genentech. He has received research support from Lilly, Galectin, Gilead, Exact Sciences, and Cumberland. Dr. Gawrieh: Nothing relevant to this work. Consulting: TransMedics, research grant support: Cirius, Galmed, Viking, and Zydus. Publisher Copyright: {\textcopyright} 2021 by the Research Society on Alcoholism",
year = "2021",
month = apr,
doi = "10.1111/acer.14581",
language = "English (US)",
volume = "45",
pages = "709--719",
journal = "Alcoholism: Clinical and Experimental Research",
issn = "0145-6008",
publisher = "Wiley-Blackwell",
number = "4",
}