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Researchers Find Gene Variant That Protects Against Chronic Liver Disease

NEW YORK (GenomeWeb) – A team led by researchers at Regeneron Pharmaceuticals has uncovered a gene variant that appears to protect against chronic liver disease.

Chronic liver disease and cirrhosis affect about 3.9 million adults in the US and caused the deaths of 40,326 people in 2015, according to the Centers for Disease Control and Prevention.

Using data from nearly 47,000 participants in the Geisinger Health System's DiscovEHR study — which links patients' exomes to their electronic health records — researchers led by Regeneron scientists Jesper Gromada and Frederick Dewey homed in on genetic variants associated with serum levels of two proteins linked to liver injury. As they reported in the New England Journal of Medicine, the researchers found that a loss-of-function variant in HSD17B13 was linked to lower levels of those injury markers as well as to a decreased risk of alcoholic liver disease, nonalcoholic liver disease, alcoholic cirrhosis, and nonalcoholic cirrhosis.

The researchers tested for genetic associations between more than half a million genetic variants and serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), both markers of hepatocyte injury, in 46,544 people of European descent from the DiscovEHR study. In this discovery cohort, some 35 variants in 19 genes were significantly associated with ALT or AST levels.

After replication in three additional cohorts — 2,644 other individuals from the DiscovEHR population, 1,357 people from the Dallas Heart Study, and 8,526 samples from the Penn Medicine Biobank — and a combined meta-analysis, the researchers tied 13 variants in nine genes to either ALT or AST levels, both in genes previously linked to liver disease and in novel ones. This included a reproducible association between a variant in HSD17B13, which encodes hydroxysteroid 17-beta dehydrogenase 13, and both ALT and AST levels. This variant, rs72613567, is a splice variant.

The researchers tested whether the 13 variants in nine genes they found were also associated with chronic liver diseases and found six variants in five genes that were, including the rs72613567 variant.

In the discovery cohort, the HSD17B13 rs72613567:TA variant was associated with lower risk of liver disease in an allele dose-dependent manner. For instance, among heterozygotes, it was linked to a 42 percent reduced risk of alcoholic liver disease, while among homozygotes it was linked to a 53 percent reduced risk. It was likewise linked to a reduced risk of liver disease in the Dallas Liver Study cohort and to lower odds of pediatric liver disease in the Dallas Pediatric Liver Study cohort, both of which are multi-ethnic cohorts.

A previous study linked a variant in the PNPLA3 gene to increased hepatic triglyceride levels and an increased risk of nonalcoholic steatohepatitis and cirrhosis. In this study, the researchers found that the HSD17B13 allele they uncovered could counteract, in a dose-dependent manner, the effect of the PNPLA3 148M allele on ALT or AST levels. Each HSD17B13 rs72613567:TA allele was also linked to lower PNPLA3 mRNA levels. This suggested to the researchers that the HSD17B13 variant could mitigate the risk of liver injury among people genetically predisposed to liver disease.

Additionally, they reported that the HSD17B13 rs72613567:TA allele leads to the expression of truncated transcripts that encode proteins with decreased enzymatic activity.

"This genetic 'experiment of nature' has pinpointed a new target for the discovery of novel medicines that mimic the action of this variant and similarly reduce the risk of chronic liver diseases," author Aris Baras, the head of the Regeneron Genetics Center and a vice president at Regeneron, said in a statement.

The company further announced it is now teaming up with Alnylam Pharmaceuticals to develop an RNAi-based therapeutic that mimics the effect of this HSD17B13 allele. Under the terms of their agreement, Regeneron will contribute its research on HSD17B13, while Alnylam will provide its RNAi therapeutics platform to find compounds that target HSD17B13.