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GWAS Uncovers Loci Linked to Liver Enzyme Levels

NEW YORK (GenomeWeb News) – A large, international research team has identified genetic variants corresponding to the concentrations of liver enzymes in the blood that tend to be elevated in individuals with compromised liver function.

From a GWAS involving tens of thousands of individuals for whom liver enzyme concentrations in the blood were known, the team tracked down 42 sites in the genome corresponding to liver enzymes levels. Of these, 32 of the loci had not been detected in past studies of liver function. By folding in expression quantitative trait loci and other analyses, the team narrowed in on 69 genes that appear to be promising candidates for involvement in liver function-related processes. The study appeared online yesterday in Nature Genetics.

"Our new study is a big step towards understanding the role that different genes play in keeping the liver working normally, and towards identifying targets for drugs that can help prevent the liver from functioning abnormally or becoming susceptible to disease," Imperial College London researcher John Chambers, who was first author on the study, said in a statement.

The concentration of liver enzymes in the blood tends to be bumped up in individuals with conditions or exposures that lead to liver damage and disease, including infection, adverse drug reactions, and metabolic conditions. But there is also a genetic component to liver enzyme concentrations in the blood, the study authors noted.

Because higher-than-usual liver enzyme levels can portend a range of diseases ranging from liver cirrhosis or liver cancer to diabetes or heart disease, they explained, understanding the heritability of liver function could help in determining disease risk, predicting toxicity related to new therapeutic compounds, and more.

"The liver is a central hub in the body and because it has so many diverse functions, it is linked to a large number of conditions," Chambers said.

For the current study, he and his colleagues assessed genotype data for 61,089 individuals genotyped with Affymetrix, Illumina, or Perlegen arrays as part of numerous large, published studies.

In particular, they looked for genetic factors coinciding with variability in the blood concentrations of three enzyme markers of liver damage or related disease: alanine transaminase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT).

The search uncovered more than 1,300 SNPs at 42 loci that were linked to blood levels of at least one of the liver enzymes. Variants at 35 of the loci reached genome-wide significance in the samples tested initially, the researchers reported, while SNPs at the remaining seven loci reached genome-wide significance when tested in 12,139 more individuals.

In an effort to find functionally important genes in these regions, the team folded analyses of coding variants, linkage disequilibrium patterns, eQTL patterns in related tissues, and information from studies published in the past. They also did metabonomic profiling to look at how the newly identified loci related to levels of other metabolites.

Among the 69 candidate genes at the liver enzyme level linked loci, the researchers found genes from a network of metabolic pathways, as well as genes of unknown function and genes influencing glycoprotein biology, bile transport, inflammation, and immunity.

"We are particularly excited about the genes whose precise role we don't yet know," co-corresponding author Jaspal Kooner, a researcher with Imperial College London's National Heart and Lung Institute, said in a statement. "Investigating these further should help us to fill in the gaps in our understanding about what happens when the liver ceases to function normally and how we might be able to tackle this."

Given the range of genes identified — and the fact that at least some of the candidate genes have apparent roles in disease or infection beyond the liver, in the pancreas, stomach, and intestine — those involved in the study speculated that the levels of the ALP, ALT, and GGT enzymes may be regulated by pathways both within and outside of the liver.

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