Browsing by Author "Morgan, Timothy R."

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    Genome-wide Association Study and Meta-analysis on Alcohol-Associated Liver Cirrhosis Identifies Genetic Risk Factors
    (Wiley, 2021-05) Schwantes-An, Tae-Hwi; Darlay, Rebecca; Mathurin, Philippe; Masson, Steven; Liangpunsakul, Suthat; Mueller, Sebastian; Aithal, Guruprasad P.; Eyer, Florian; Gleeson, Dermot; Thompson, Andrew; Muellhaupt, Beat; Stickel, Felix; Soyka, Michael; Goldman, David; Liang, Tiebing; Lumeng, Lawrence; Pirmohamed, Munir; Nalpas, Bertrand; Jacquet, Jean-Marc; Moirand, Romain; Nahon, Pierre; Naveau, Sylvie; Perney, Pascal; Botwin, Greg; Haber, Paul S.; Seitz, Helmut K.; Day, Christopher P.; Foroud, Tatiana M.; Daly, Ann K.; Cordell, Heather J.; Whitfield, John B.; Morgan, Timothy R.; Seth, Devanshi; GenomALC Consortium; Medical and Molecular Genetics, School of Medicine
    Background and Aims Only a minority of heavy drinkers progress to alcohol-associated cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. Approach and Results We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy-drinking subjects without known liver disease from Australia, the United States, the United Kingdom, and three countries in Europe. A genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, body mass index, and diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta-analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome-wide significant risk association of rs738409 in patatin-like phospholipase domain containing 3 (PNPLA3) (odds ratio [OR] = 2.19 [G allele], P = 4.93 × 10−17) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 × 10−10) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a protective association at rs374702773 in Fas-associated factor family member 2 (FAF2) (OR = 0.61 [del(T) allele], P = 2.56 × 10−8) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR = 0.79, P = 0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1 and SUGP1/TM6SF2) were also genome-wide significant in the meta-analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. Conclusions Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.
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    Standard Definitions and Common Data Elements for Clinical Trials in Patients With Alcoholic Hepatitis: Recommendation From the NIAAA Alcoholic Hepatitis Consortia
    (Elsevier, 2016-04) Crabb, David W.; Bataller, Naga P.; Chalasani, Naga P.; Kamath, Patrick S.; Lucey, Michael; Mathurin, Philippe; McClain, Craig; McCullough, Arthur; Mitchell, Mack C.; Morgan, Timothy R.; Department of Medicine, IU School of Medicine
    Heavy drinkers are at risk for a spectrum of histologic alcohol-related liver injury: steatosis, alcoholic steatohepatitis (ASH), alcohol-related fibrosis, and cirrhosis. Alcoholic hepatitis (AH), the clinical entity associated with severe ASH, has high short-term mortality. The standard-of-care therapy, prednisolone, has limited efficacy and many side effects; no other treatment has consistently shown survival benefit. The National Institute on Alcohol Abuse and Alcoholism (NIAAA)-funded Alcoholic Hepatitis Consortia carry out translational research on pathophysiologic mechanisms, genetic and environmental risk factors, phase II clinical trials, and development of biomarkers. The consortia members were convened by the National Institutes of Health to address diagnostic criteria and practical issues related to clinical AH research, and to develop a set of common data elements to harmonize ongoing and future trials. This was accomplished through 3 face-to-face meetings of the investigators and representatives of the National Institutes of Health, and subsequent electronic communications over the course of 6 months. Evidence for the recommendations was based on published trials and observational data from several of the consortia members. A draft manuscript was iteratively reviewed by members of the consortia. The goal was to reach agreements on recommendations and definitions that could facilitate trial design, and simultaneously be tested by research groups pooling their data. The recommendations made here are specifically directed to achieve better uniformity in clinical trials, rather than serving as clinical practice guidelines.