title: Variants in the LGALS9 Gene Are Associated With Development of Liver Disease in Heavy Consumers of Alcohol.
abstract: OBJECTIVE
  Alcohol consumption is a major cause of chronic liver disease and contributes to a large proportion of cirrhosis-related deaths worldwide. However, only a fraction of heavy consumers of alcohol develop advanced alcoholic liver disease (ALD), so there are likely to be other risk factors. We investigated whether polymorphisms in the gene encoding galectin-9 (LGALS9), previously shown to mediate liver injury, were associated with the development of ALD.
  
  
  METHODS
  We isolated DNA from peripheral blood mononuclear cells (PBMCs) of 575 individuals with at-risk alcohol consumption but no other risk factors for chronic liver disease; all subjects were white Europeans who had consumed more than 80 grams ethanol per day. Of the subjects, 388 had ALD (including, 268 with cirrhosis and 74 with alcoholic hepatitis; mean age, 49 y; 72% male) and 187 had normal liver function with no biochemical or clinical evidence of liver disease (controls; mean age, 42 y; 73% male). Select LGALS9 polymorphisms were genotyped using allelic discrimination. We also genotyped and measured expression of LGALS9 messenger RNA in PBMCs from individuals who were not heavy consumers of alcohol.
  
  
  RESULTS
  We used data from the HapMap project to identify 5 single-nucleotide polymorphisms (SNPs) that tag all the common haplotypes. When we looked for these SNPs in individuals with vs without liver disease, 4 (rs3751093, rs4239242, rs732222, and rs4794976) were associated with an increased risk of developing ALD. We found that levels of LGALS9 messenger RNA and protein expressed were associated with an allele carried by PBMCs. Multivariate analysis confirmed that rs4239242 and rs4794976 were associated with an increased risk of ALD.
  
  
  CONCLUSIONS
  In a genetic analysis of heavy consumers of alcohol, we associated 2 SNPS in LGALS9 with the development of ALD. Although larger studies are required, this information could be used to determine the risk of individuals developing ALD or to develop therapeutic agents.
authors.affiliation: Division of Gastroenterology/Hepatology, University of Colorado, Aurora, Colorado. Electronic address: Hugo.Rosen@ucdenver.edu.
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Rosen
authors.affiliation: Division of Gastroenterology/Hepatology, University of Colorado, Aurora, Colorado.
authors.forename: Lucy
authors.initials: L
authors.lastname: Golden-Mason
authors.affiliation: Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, United Kingdom.
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
authors.affiliation: Division of Pulmonary Medicine, University of Colorado, Aurora, Colorado.
authors.forename: Ivana
authors.initials: I
authors.lastname: Yang
authors.affiliation: Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, United Kingdom.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Day
mesh_terms: D000437:Alcoholism / Q000150:complications*; D037161:Galectins / Q000096:biosynthesis / Q000235:genetics*; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D005838:Genotype; D008104:Liver Cirrhosis, Alcoholic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D037161:Galectins; C105032:LGALS9 protein, human; D012333:RNA, Messenger
keywords: Fibrosis; Genetic; Human; Susceptibility