Dataset Information

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

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.

SUBMITTER: Serper M

PROVIDER: S-EPMC7447043 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Serper Marina M Vujkovic Marijana M Kaplan David E DE Carr Rotonya M RM Lee Kyung Min KM Shao Qing Q Miller Donald R DR Reaven Peter D PD Phillips Lawrence S LS O'Donnell Christopher J CJ Meigs James B JB Wilson Peter W F PWF Vickers-Smith Rachel R Kranzler Henry R HR Justice Amy C AC Gaziano John M JM Muralidhar Sumitra S Pyarajan Saiju S DuVall Scott L SL Assimes Themistocles L TL Lee Jennifer S JS Tsao Philip S PS Rader Daniel J DJ Damrauer Scott M SM Lynch Julie A JA Saleheen Danish D Voight Benjamin F BF Chang Kyong-Mi KM

PloS one 20200825 8

<h4>Background & aims</h4>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.<h4>Methods</h4>MVP participants with alanine aminotransferases (ALT) >40 units/L for men and >30 units/L for wo ...[more]

PMID: 32841307

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Project description:PurposePrimary open-angle glaucoma (POAG) is a degenerative eye disease for which early treatment is critical to mitigate visual impairment and irreversible blindness. POAG-associated loci individually confer incremental risk. Genetic risk score(s) (GRS) could enable POAG risk stratification. Despite significantly higher POAG burden among individuals of African ancestry (AFR), GRS are limited in this population. A recent large-scale, multi-ancestry meta-analysis identified 127 POAG-associated loci and calculated cross-ancestry and ancestry-specific effect estimates, including in European ancestry (EUR) and AFR individuals. We assessed the utility of the 127-variant GRS for POAG risk stratification in EUR and AFR Veterans in the Million Veteran Program (MVP). We also explored the association between GRS and documented invasive glaucoma surgery (IGS).DesignCross-sectional study.ParticipantsMVP Veterans with imputed genetic data, including 5830 POAG cases (445 with IGS documented in the electronic health record) and 64 476 controls.MethodsWe tested unweighted and weighted GRS of 127 published risk variants in EUR (3382 cases and 58 811 controls) and AFR (2448 cases and 5665 controls) Veterans in the MVP. Weighted GRS were calculated using effect estimates from the most recently published report of cross-ancestry and ancestry-specific meta-analyses. We also evaluated GRS in POAG cases with documented IGS.Main outcome measuresPerformance of 127-variant GRS in EUR and AFR Veterans for POAG risk stratification and association with documented IGS.ResultsGRS were significantly associated with POAG (P < 5 × 10-5) in both groups; a higher proportion of EUR compared with AFR were consistently categorized in the top GRS decile (21.9%-23.6% and 12.9%-14.5%, respectively). Only GRS weighted by ancestry-specific effect estimates were associated with IGS documentation in AFR cases; all GRS types were associated with IGS in EUR cases.ConclusionsVaried performance of the GRS for POAG risk stratification and documented IGS association in EUR and AFR Veterans highlights (1) the complex risk architecture of POAG, (2) the importance of diverse representation in genomics studies that inform GRS construction and evaluation, and (3) the necessity of expanding diverse POAG-related genomic data so that GRS can equitably aid in screening individuals at high risk of POAG and who may require more aggressive treatment.

Project description:BackgroundAbdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability.MethodsWe performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease.ResultsThrough a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24-1.66]; P=1.6×10-6), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97-1.15]; P=0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratioPRS, 1.26 [95% CI, 1.18-1.36]; PPRS=2.7×10-11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratioPRS+family history+smoking, 1.24 [95% CI, 1.14-1.35]; PPRS=1.27×10-6). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines.ConclusionsWe identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.

Project description:BackgroundAlthough previous studies have suggested cocoa products may promote cardiovascular health in the general population, no public data are available from patients receiving care in a national integrated health care system.ObjectivesWe tested the hypothesis that regular chocolate consumption is associated with a lower risk of coronary artery disease (CAD) events among participants of the Million Veteran Program (MVP). Secondary analysis examined if the main hypothesis was observed among participants with type 2 diabetes.MethodsWe analyzed data from MVP participants who completed the food frequency section of the MVP Lifestyle Survey and were free of CAD at the time of survey completion. CAD events during follow-up (International Statistical Classification of Diseases Ninth Revision codes 410-411 and 413-414, and Tenth Revision codes I20-I25 except I25.2) were assessed using electronic health records. We fitted a Cox proportional hazard model to estimate the RR of CAD.ResultsOf 188,447 MVP enrollees with survey data, mean ± SD age was 64 ± 12.0 y and 90% were men. For regular chocolate (28.3 g/serving) consumption of <1 serving/mo, 1-3 servings/mo, 1 serving/wk, 2-4 servings/wk, and ≥5 servings/wk, crude incidence rates (per 1000 person-years) for fatal and nonfatal CAD events or coronary procedures were 20.2, 17.5, 16.7, 17.1, and 16.9, respectively, during a mean follow-up of 3.2 y. After adjusting for age, sex, race, and lifestyle factors, the corresponding HRs (95% CIs) were 1.00 (ref), 0.92 (0.87, 0.96), 0.88 (0.83, 0.93), 0.89 (0.84, 0.95), and 0.89 (0.84, 0.96), respectively (P for linear trend < 0.0001). In a secondary analysis of 47,265 diabetics, we did not observe a decreasing trend in CAD mortality among those who consumed ≥1 serving of chocolate a month compared with those who consumed <1 serving/mo.ConclusionsRegular chocolate consumption was associated with a lower risk of CAD among veterans, but was not associated with cardiovascular disease risk in veterans with type 2 diabetes.

Dataset Information

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

Publications

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

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