ABCMdb

PMID: 23583734

Hirschfield GM, Chapman RW, Karlsen TH, Lammert F, Lazaridis KN, Mason AL
The genetics of complex cholestatic disorders.
Gastroenterology. 2013 Jun;144(7):1357-74. doi: 10.1053/j.gastro.2013.03.053. Epub 2013 Apr 10., [PubMed]

Sentences

No. Mutations Sentence Comment

122 ABCG8 p.Asp19His GWAS in Gallstone Disease The first GWAS for gallstones found a highly significant association with the p.D19H variant of ABCG8 (odds ratio, 2.2; population attributable fraction, 11%),57 which had been previously identified as a risk factor in animal models.58 This risk factor was confirmed globally.57,59-66 The ABCG5/G8 hepatocanalicular heterodimeric transporter for cholesterol is a member of the adenosine triphosphate-binding cassette (ABC) transporters. Login to comment 125 ABCG8 p.Asp19His ABCG8 p.Asp19His Subsequent studies showed that obese women older than 60 years of age homozygous with the p.D19H risk allele had a 13% absolute 10-year risk of symptomatic gallstone disease compared with a range of 2% to 4% in noncarriers in the same risk stratum.66 It is likely that decreased intestinal cholesterol absorption and increased hepatic cholesterol synthesis represent the primary defect intensifying the susceptibility for the development of stones.67 This indicates that the lithogenic ABCG8 p.D19H variant confers decreased cholesterol absorption, higher cholesterol synthesis, and a trend toward lower serum cholesterol levels as well as a better response to statins. Login to comment 126 ABCG8 p.Asp19His Accordingly, ABCG8 p.D19H might represent a "gain-of-function" mutation that increases clearance of sterol from the body.68-70 As a corollary, this genotype has also been shown to be protective against the development of atheromatous vascular disease by lowering cholesterol levels.71,72 Preliminary data from 2 other GWAS for gallstone disease have identified additional lithogenic candidate genes (Table 1).59,60 Data from a genome-wide association study of 4300 Sardinian subjects with increased serum bilirubin levels was used to identify the Gilbert syndrome variant in the promoter of the UGT1A1 gene as a candidate gene for gallstone disease73 that was verified in 2800 German and Chilean patients with gallstones.74 The link of diminished bilirubin conjugation with gallstone formation reinforces the concept of nucleation in supersaturated bile, because cholesterol gallstones usually contain small amounts of bilirubin pigment. Login to comment