Validating a Non-invasive, ALT-based Non-alcoholic Fatty Liver Phenotype in the Million Veteran Program

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2020 Aug 26

PMID 32841307

Citations 11

Authors

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 ODonnell

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

Affiliations

Soon will be listed here.

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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