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. 2020 Aug 25;15(8):e0237430.
doi: 10.1371/journal.pone.0237430. eCollection 2020.

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

Marina Serper  1   2   3 , Marijana Vujkovic  1 , David E Kaplan  1   2 , Rotonya M Carr  1   2 , Kyung Min Lee  4   5   6 , Qing Shao  4 , Donald R Miller  4 , Peter D Reaven  7 , Lawrence S Phillips  8   9 , Christopher J O'Donnell  10   11 , James B Meigs  12 , Peter W F Wilson  8   9 , Rachel Vickers-Smith  13 , Henry R Kranzler  13   14 , Amy C Justice  15   16   17 , John M Gaziano  10   18 , Sumitra Muralidhar  19 , Saiju Pyarajan  10   11 , Scott L DuVall  6   20 , Themistocles L Assimes  21   22 , Jennifer S Lee  21   22 , Philip S Tsao  21   22 , Daniel J Rader  2   23   24   25 , Scott M Damrauer  1   26 , Julie A Lynch  6   27 , Danish Saleheen  1   28 , Benjamin F Voight  1   23   29 , Kyong-Mi Chang  1   2 ; VA Million Veteran Program
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Validating a non-invasive, ALT-based non-alcoholic fatty liver phenotype in the million veteran program

Marina Serper et al. PLoS One. .

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

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