Full text

Turn on search term navigation

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. The work is made available under the Creative Commons CC0 public domain dedication: https://creativecommons.org/publicdomain/zero/1.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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.

Details

Title
Validating a non-invasive, ALT-based non-alcoholic fatty liver phenotype in the million veteran program
Author
Serper, Marina; Vujkovic, Marijana; Kaplan, David E; Carr, Rotonya M; Lee, Kyung Min; Shao, Qing; Miller, Donald R; Reaven, Peter D; Phillips, Lawrence S; Christopher J O’Donnell; Meigs, James B; Wilson, Peter W F; Vickers-Smith, Rachel; Kranzler, Henry R; Justice, Amy C; Gaziano, John M; Muralidhar, Sumitra; Pyarajan, Saiju; DuVall, Scott L; Assimes, Themistocles L; Lee, Jennifer S; Tsao, Philip S; Rader, Daniel J; Damrauer, Scott M; Lynch, Julie A; Saleheen, Danish; Voight, Benjamin F; Chang, Kyong-Mi; on behalf of the VA Million Veteran Program
First page
e0237430
Section
Research Article
Publication year
2020
Publication date
Aug 2020
Publisher
Public Library of Science
e-ISSN
19326203
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2437106817
Copyright
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. The work is made available under the Creative Commons CC0 public domain dedication: https://creativecommons.org/publicdomain/zero/1.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.