NEW YORK (GenomeWeb) – A team of European researchers has uncovered new risk loci for alcohol-related cirrhosis.
Through a genome-wide association study drawing on more than 700 cases and 1,400 controls, the Technical University Dresden's Jochen Hampe and his colleagues homed in on new risk loci in MBOAT7 and TM6SF2, as well as confirmed a locus in PNPLA3 previously linked to cirrhosis risk, as they reported today in Nature Genetics. These three genes, the researchers added, all have roles in lipid processing, suggesting a link between lipid turnover and cirrhosis pathogenesis.
"[W]e hypothesize that the genetic variants in these loci confer risk via dysfunctional lipid turnover," Hampe and his colleagues wrote in their paper. "Further research is needed to determine whether the fine-mapping studies have identified the variants underlying the functional variability in the encoded protein."
To search for variants linked to alcohol-related cirrhosis, the team of researchers performed a two-stage genome-wide association study that compared heavy drinkers with and without cirrhosis. Only 10 percent to 15 percent of heavy drinkers develop cirrhosis, the researchers noted, though they added that it is the second most common indication for liver transplants among Westerners.
In the first stage, the team drew upon 410 Germans with alcohol-related cirrhosis and 1,119 heavy drinkers without liver disease, while the second stage used a cohort of 301 cases and 346 controls from the UK. The team then used IMPUTE2 and the 1,000 Genomes Project reference panel to perform genotype imputation.
A meta-analysis of the markers indicated that the strongest signal could be traced to rs738409 in PNPLA3, which had previously been linked to cirrhosis risk through a candidate gene study.
In additional samples from Germany and Belgium, Hampe and his colleagues sought to validate the signals they uncovered, and replicated not only the rs738409 PNPLA3 signal, but also the variants rs626283 in MBOAT7 and rs10401969 in SUGP1.
Adjusting for age, sex, BMI, and type 2 diabetes didn't affect whether the loci remained significant, the researchers added.
At MBOAT7, the strongest signal came from the imputed variant rs626283, though the researchers noted that there was a cluster of variants in MBOAT7 and the nearby TMC4 that were in high linkage disequilibrium.
Through a cis-eQTL analysis that drew on publicly available human liver datasets, the researchers found that both MBOAT7 and TMC4 are expressed in the human liver. However, they noted genotype-specific differential expression for the disease-linked allele in liver tissue from patients with cirrhosis for MBOAT7, but not for TMC4.
Through fine mapping, they found that a TM6SF2 signal at rs58542926 was in complete LD with the SUGP1 variant, suggesting that was the risk loci.
These new risk variants in MBOAT7 and TM6SF2 are distinct, the researchers said, from loci that have been associated with alcohol consumption, dependence, and withdrawal symptoms.
All risk variants are linked to lipid metabolism, Hampe and his colleagues noted.
MBOAT7, they said, encodes an enzyme that has lysophosphatidylinositol acyltransferase activity, has been implicated in anti-inflammatory processes, and catalyzes the transfer of fatty acids between phospholipids and lysophospholipids in rat liver microsomes.
Meanwhile, TM6SF2 activity is needed for very-low-density lipoprotein secretion, the researchers said, adding that the risk variant they found could affect its function, leading to hepatic lipid trapping and steatosis. In addition, the TM6SF2 risk variant, they said, is a risk factor for non-alcoholic fatty liver disease.
PNPLA3 has previously been linked to increased intrahepatic fat.
These three cirrhosis risk variants, Hampe and his colleagues added, "may also help to define high-risk populations for targeted abstinence intervention and hepatic surveillance programs."