Validating a non-invasive, ALT-based non-alcoholic fatty liver phenotype in the million veteran program

• Type of Material: Article
• Authors: Marina Serper, Corporal Michael J. Crescenz VA Medical Center; Marijana Vujkovic, Corporal Michael J. Crescenz VA Medical Center; David E. Kaplan, Corporal Michael J. Crescenz VA Medical Center; Rotonya M. Carr, Corporal Michael J. Crescenz VA Medical Center; Kyung Min Lee, Boston University; Qing Shao, Edith Nourse Rogers Memorial Veterans Affairs Hospital; Donald R. Miller, Edith Nourse Rogers Memorial Veterans Affairs Hospital; Peter D. Reaven, Phoenix VA Health Care System; Lawrence Phillips, Emory University; Christopher J. O'Donnell, VA Boston Healthcare System; James B. Meigs, Harvard University; Peter Wilson, Emory University; Rachel Vickers-Smith, University of Louisville; Henry R. Kranzler, University of Louisville; Amy C. Justice, Yale University; John M. Gaziano, VA Boston Healthcare System; Sumitra Muralidhar, Veterans Health Administration; Saiju Pyarajan, VA Boston Healthcare System; Scott L. DuVall, VA Salt Lake City Health Care System; Themistocles L. Assimes, Stanford University; Jennifer S. Lee, Stanford University; Philip S. Tsao, Stanford University; Daniel J. Rader, University of Pennsylvania; Scott M. Damrauer, Corporal Michael J. Crescenz VA Medical Center; Julie A. Lynch, VA Salt Lake City Health Care System; Danish Saleheen, Corporal Michael J. Crescenz VA Medical Center; Benjamin F. Voight, Corporal Michael J. Crescenz VA Medical Center; Kyong-Mi Chang, Corporal Michael J. Crescenz VA Medical Center
• Language: English
• Date: 2020-08-25
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: : This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
• License: Creative Commons Universal : Public Domain Dedication
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0237430
• Title of Journal or Parent Work: PLoS ONE
• Volume: 15
• Issue: 8
• Start Page: e0237430
• End Page: e0237430
• Grant/Funding Information: SMD is supported by the Veterans Administration [IK2-CX001780].; BFV acknowledges support from DK101478, HG010067 and a Linda Pechenik Montague Investigator award. KMC, SMD, JMG, CJO, LSP, JSL, and PST are supported by the VA Cooperative Studies Program.; This work was supported by funding from the VA award I01-BX003362 (KMC and PST) and the VA Informatics and Computing Infrastructure (VINCI) VA HSR RES 130457 (SLD).; MS acknowledges support from K23-DK115897. RMC acknowledges support from RO1 AA026302.
• Keywords: Science & Technology; TM6SF2; Health; PNPLA3; Multidisciplinary Sciences; AUDIT-C; Variant; NAFLD; Science & Technology - Other Topics; Confers susceptibility; Genome-wide association; Disease; Fibrosis
• Research Categories: Health Sciences, Health Care Management; Health Sciences, Medicine and Surgery; Biology, Genetics; Health Sciences, Epidemiology

Abstract

Background & aims Given ongoing challenges in non-invasive non-alcoholic liver disease (NAFLD) diagnosis, we sought to validate an ALT-based NAFLD phenotype using measures readily available in electronic health records (EHRs) and population-based studies by leveraging the clinical and genetic data in the Million Veteran Program (MVP), a multi-ethnic mega-biobank of US Veterans. Methods MVP participants with alanine aminotransferases (ALT) >40 units/L for men and >30 units/L for women without other causes of liver disease were compared to controls with normal ALT. Genetic variants spanning eight NAFLD risk or ALT-associated loci (LYPLAL1, GCKR, HSD17B13, TRIB1, PPP1R3B, ERLIN1, TM6SF2, PNPLA3) were tested for NAFLD associations with sensitivity analyses adjusting for metabolic risk factors and alcohol consumption. A manual EHR review assessed performance characteristics of the NAFLD phenotype with imaging and biopsy data as gold standards. Genetic associations with advanced fibrosis were explored using FIB4, NAFLD Fibrosis Score and platelet counts. Results Among 322,259 MVP participants, 19% met non-invasive criteria for NAFLD. Trans-ethnic meta-analysis replicated associations with previously reported genetic variants in all but LYPLAL1 and GCKR loci (P<6x10-3), without attenuation when adjusted for metabolic risk factors and alcohol consumption. At the previously reported LYPLAL1 locus, the established genetic variant did not appear to be associated with NAFLD, however the regional association plot showed a significant association with NAFLD 279kb downstream. In the EHR validation, the ALT-based NAFLD phenotype yielded a positive predictive value 0.89 and 0.84 for liver biopsy and abdominal imaging, respectively (inter-rater reliability (Cohen’s kappa = 0.98)). HSD17B13 and PNPLA3 loci were associated with advanced fibrosis. Conclusions We validate a simple, non-invasive ALT-based NAFLD phenotype using EHR data by leveraging previously established NAFLD risk-associated genetic polymorphisms.