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Gallstone Disease Meta-Analysis Leads to Bile Transport, Cholesterol Pathways

NEW YORK (GenomeWeb) – Results from a genome-wide association meta-analysis revealed variants at 20 loci with ties to gallstone disease risk, pointing to the importance of bile acid transport and circulation, cholesterol homeostasis, and other biological processes.

As they reported online today in Nature Communications, researchers from Amgen subsidiary Decode Genetics, the University of Iceland, and elsewhere brought together data from two large GWAS for the meta-analysis, which included 27,174 individuals from Iceland and the UK with gallstone disease and more than 736,800 unaffected controls from the same regions. Their search led to 21 new gallstone risk variants at 20 loci, including 17 common variants.

The team also detected a handful of gallstone disease-associated low-frequency missense changes in the SERPINA1 gene, which codes for a protease enzyme inhibitor, the hepatocyte nuclear factor-alpha liver regulator-coding gene HNF4A, and the apical sodium-dependent bile acid transporter (ASBT)-coding gene SLC10A2. Available functional data indicated that the disease-linked variants in SLC10A2 contribute to diminished bile acid transport in the intestine, the group reported.

"With the discovery of gallstone-associated variants in SLC10A2, we highlight a role of the intestinal compartment of the enterohepatic circulation of bile acids in gallstone disease susceptibility," co-corresponding authors Kari Stefansson, a University of Iceland researcher and CEO and cofounder of Decode, and Decode researcher Patrick Sulem, and their colleagues wrote.

"The associations presented emphasize the role of sequence variants in genes involved in cholesterol homeostasis and specifically highlight the intestinal compartment of the enterohepatic circulation in the pathogenesis of gallstone disease," the authors concluded, noting that "sequence variants affecting the amount of cholesterol secreted into bile, or the cholesterol/bile acid ratio, are likely to cause gallstone formation."

For their meta-analysis, the researchers considered data for 8,757 gallstone disease cases and 346,688 controls from Iceland, who were assessed at 32 million genome-wide markers, along with 18,417 UK cases and 390,150 controls with directly genotyped or imputed SNPs information at some 40 million sites in the genome. With these data, they tracked down 32 gallstone disease-associated variants at 28 loci: 11 common variants identified previously, 17 new common variants, and four low-frequency variants not implicated in the disease in the past.

The authors cautioned that a subset of the UK disease cases involved self-reported gallstone disease. But while the effect sizes were slightly shifted for two of the associated variants in the self-reported gallstone disease group compared with the group of gallstone patients with International Classification of Diseases diagnostic codes, the same set of variants remained associated with the condition in both groups.

Variants at five of the gallstone disease-associated loci showed ties to other biliary system conditions such as acute pancreatitis, cholecystitis, and cholestasis of pregnancy, the team reported, while several variants appeared to influence liver biomarker levels or lipid traits.

Likewise, the researchers noted that the gallstone disease-associated variants were also over-represented in the sets of variants linked to high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, or blood serum triglyceride levels.

"In total, 23 of the 203 unique variants associating with one or more of the HDL cholesterol, LDL cholesterol, total cholesterol, and triglycerides also associate with gallstone disease," the authors wrote. "However, there is no consistency in the directions of the effects on serum cholesterol and gallstone disease risk. This indicates that lipid serum levels are not by themselves causative factors in gallstone formation, even though cholesterol metabolism appears to have an impact on gallstone risk."

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