Validating a non-invasive, ALT-based non-alcoholic fatty liver phenotype in the million veteran program.
17-Hydroxysteroid Dehydrogenases
/ genetics
Abdomen
/ diagnostic imaging
Adaptor Proteins, Signal Transducing
/ genetics
Aged
Alanine Transaminase
/ genetics
Electronic Health Records
Female
Genetic Loci
Genetic Predisposition to Disease
Genetic Variation
Humans
Lipase
/ genetics
Liver
/ pathology
Lysophospholipase
/ genetics
Male
Membrane Proteins
/ genetics
Middle Aged
Non-alcoholic Fatty Liver Disease
/ ethnology
Phenotype
Risk Factors
Veterans
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
02
11
2019
accepted:
27
07
2020
entrez:
26
8
2020
pubmed:
26
8
2020
medline:
9
10
2020
Statut:
epublish
Résumé
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. 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. 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. We validate a simple, non-invasive ALT-based NAFLD phenotype using EHR data by leveraging previously established NAFLD risk-associated genetic polymorphisms.
Sections du résumé
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.
Identifiants
pubmed: 32841307
doi: 10.1371/journal.pone.0237430
pii: PONE-D-19-30549
pmc: PMC7447043
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
GCKR protein, human
0
Membrane Proteins
0
17-Hydroxysteroid Dehydrogenases
EC 1.1.-
HSD17B13 protein, human
EC 1.1.-.-
Alanine Transaminase
EC 2.6.1.2
Lipase
EC 3.1.1.3
adiponutrin, human
EC 3.1.1.3
Lysophospholipase
EC 3.1.1.5
LYPLAL1 protein, human
EC 3.1.2.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0237430Subventions
Organisme : NIDDK NIH HHS
ID : R56 DK101478
Pays : United States
Organisme : NIDDK NIH HHS
ID : K23 DK115897
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK101478
Pays : United States
Organisme : CSRD VA
ID : IK2 CX001780
Pays : United States
Organisme : CSRD VA
ID : I01 CX001737
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK078616
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG010067
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA026302
Pays : United States
Organisme : BLRD VA
ID : I01 BX005831
Pays : United States
Organisme : NIDDK NIH HHS
ID : UM1 DK078616
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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