Alcoholic liver cirrhosis (ALC) causes a significant mortality worldwide. World Health Organization 2014 Report on ?alcohol and health? reports 50% of liver cirrhosis mortality worldwide is due to alcohol, reaching as high as ~60% in north America and Europe. In principle, all alcoholic liver diseases are preventable with appropriate behavioral and lifestyle change, including pharmaceutical approaches. However, progress in developing specific pharmaceutical interventions has been hampered by poor understanding of both genetic and non-genetic factors contributing towards the pathogenesis of this disease. The OVERALL GOAL is to identify loci, genes and polymorphisms underlying genetic risk for the development of ALC in heavy drinkers. To do this the multinational GenomALC Consortium has successfully collected extensive phenotype data and blood/DNAs from >5000 heavy drinkers with and without cirrhosis which will be subjected to genotyping via genome-wide SNP association approach in 2016-2017 (UO1-AA018389). Through other significant collaborations, the consortium has access to additional ~2000 genotype- phenotype data making it the largest discovery cohort for ALC genetics. The consortium has also done the groundwork in identifying and accessing ?mega-cohort? Genomics Biobanks (e.g UK Biobank) as independent validation cohorts.
The specific aims of the current application are, aim 1: To identify genetic risk factors for ALC through case-control GWAS in GenomALC discovery cohort (n=~7411);
aim 2 : To confirm allelic associations in independent validation cohorts available from established ?mega-cohort? genomic databases;
aim 3 : To perform meta-analysis with results from other GWAS on alcoholic cirrhosis;
aim 4 : To examine overlap in genetic risk between alcoholic cirrhosis and potentially related diseases and biomarkers of cirrhosis. The GenomALC team (geneticists, genetic statisticians, clinicians) has the right expertise, skills and established infrastructure to perform these analyses. This large case-control GWAS has the power to identify novel SNPs, create new knowledge and infer pathways/mechanisms leading to alcoholic cirrhosis, thus identifying potential targets for new or repurposed drug treatments.
The significance of this project is enormous given the worldwide problem of ALC and its lack of treatment. Genetic risk factors combined with clinical and phenotype risks, offers the potential to improved disease prediction, patient care, and the realization of the promise of personalized medicine.
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