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Wellcome Trust GWAS Yields Liver Cirrhosis Risk Loci

By Andrea Anderson

NEW YORK (GenomeWeb News) – In a paper appearing online yesterday in Nature Genetics, members of the Wellcome Trust Case Control Consortium 3 outlined their findings from the largest genome-wide association study of primary biliary cirrhosis to date — a study that yielded numerous new risk loci for the chronic liver condition.

The GWAS, which involved more than 10,000 individuals of British and Irish descent, turned up a dozen risk loci for PBC. A meta-analysis that incorporated published data from past research, meanwhile, uncovered three more loci that had not previously reached genome-wide significance. While the findings don't immediately point to new treatments for the liver condition, they do highlight key genes and pathways that seem to contribute to the disease — particularly genes from a trio of pathways related to immune function.

Such genetic studies are a "first step" en route to developing new treatments, co-senior author Carl Anderson, a statistical genetics researcher at the Wellcome Trust Sanger Institute, told GenomeWeb Daily News. "It allows people insights into the underlying biology [of PBC] and really focuses attention on these pathways."

Primary biliary cirrhosis is an autoimmune condition that's especially common in women over 40 years old. It's characterized by inflammation and swelling of the liver's bile ducts, which interferes with the normal flow of bile. Over time, this can lead to liver damage and scarring. There are currently no effective treatments save for liver transplantation.

Moreover, prior studies had identified only about one half-dozen non-human leukocyte antigen risk loci, leaving much to be learned about the disease's heritability. "It's an autoimmune disease, we know that much," Anderson said. "But we don't really know what underpins the disease."

For the first phase of the GWAS, researchers used the Illumina 660W-Quad array to genotype 1,840 individuals with primary biliary cirrhosis and the Illumina Human1M-Duo array to genotype 5,163 unaffected controls. All of the participants were of British or Irish ancestry and had been recruited by the UK PBC Consortium.

From there, researchers took the top 28 previously unreported candidate loci from the discovery phase and tested 46 of the SNPs found at these loci in another 620 PBC cases and 2,514 controls.

In the process, they not only verified all six non-HLA loci reported in past studies, but also found links to 12 new loci. Bringing together data from their study with information on overlapping SNPs published in a past PBC GWAS added three more loci to the mix, bringing the total number of new risk loci to 15.

"A few of [the loci] were strongly significant in both studies, but in neither did they reach this magical threshold of genome-wide significance," Anderson explained. "By combining the summary statistics from the two papers, we were able to increase our power to detect associations at those loci."

When they looked at genes in and around the 15 PBC-associated loci, the team saw an over-representation of genes from three biological pathways with ties to innate and adaptive immune function: the T-lymphocyte differentiation pathway, the toll-like receptor/tumor necrosis factor signaling pathway, and the NF-kappaB transcription factor signaling pathway.

Though previous studies have pointed to a role for two of these pathways in cirrhosis, the team noted, this study marks the first time that mutations in the NF-kappaB pathway have been linked to PBC.

Many of the loci detected in the study overlap with risk loci for other autoimmune diseases, including asthma, rheumatoid arthritis, and multiple sclerosis, the researchers noted, though they also found some loci in these pathways that seem to be PBC-specific.

"These pathways have been implicated in other autoimmune diseases, but there are some particular genes within these pathways which, so far at least, have only really been associated with PBC," Anderson said.

"Working out how these shared, general autoimmune disease pathways and genes interact with what look to be PBC-specific genomic regions is really interesting," he added. "We've already started on some follow-up studies to try to understand that a little better."

For instance, he said, researchers plan to genotype individuals with PBC in collaboration with the Immunochip Consortium, an international group using custom Illumina arrays to assess SNPs with known or suspected ties to a range of autoimmune diseases. The group also is evaluating other autoimmune conditions such as type 1 diabetes, celiac disease, psoriasis, Crohn's disease, and so on.

"We're going to have a huge number — tens of thousands of autoimmune cases — all genotyped on this same chip across these loci, which we know already are associated with autoimmune disease," Anderson explained. "So this is a powerful means of helping us piece together what's going on in autoimmune disease more generally."

In addition, Anderson and his colleagues plan to do additional meta-analyses of PBC, as well as sequencing studies aimed at finding rare variants involved in the condition and studies looking for genetic factors linked to PBC patient outcomes.

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