PLoS ONE (Jan 2020)

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

  • Marina Serper,
  • Marijana Vujkovic,
  • David E Kaplan,
  • Rotonya M Carr,
  • Kyung Min Lee,
  • Qing Shao,
  • Donald R Miller,
  • Peter D Reaven,
  • Lawrence S Phillips,
  • Christopher J O'Donnell,
  • James B Meigs,
  • Peter W F Wilson,
  • Rachel Vickers-Smith,
  • Henry R Kranzler,
  • Amy C Justice,
  • John M Gaziano,
  • Sumitra Muralidhar,
  • Saiju Pyarajan,
  • Scott L DuVall,
  • Themistocles L Assimes,
  • Jennifer S Lee,
  • Philip S Tsao,
  • Daniel J Rader,
  • Scott M Damrauer,
  • Julie A Lynch,
  • Danish Saleheen,
  • Benjamin F Voight,
  • Kyong-Mi Chang,
  • VA Million Veteran Program

DOI
https://doi.org/10.1371/journal.pone.0237430
Journal volume & issue
Vol. 15, no. 8
p. e0237430

Abstract

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Background & aimsGiven 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.MethodsMVP 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.ResultsAmong 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 (PConclusionsWe validate a simple, non-invasive ALT-based NAFLD phenotype using EHR data by leveraging previously established NAFLD risk-associated genetic polymorphisms.