ABCMdb

PMID: 22213168

Krawczyk M, Lutjohann D, Schirin-Sokhan R, Villarroel L, Nervi F, Pimentel F, Lammert F, Miquel JF
Phytosterol and cholesterol precursor levels indicate increased cholesterol excretion and biosynthesis in gallstone disease.
Hepatology. 2012 May;55(5):1507-17. doi: 10.1002/hep.25563. Epub 2012 Apr 4., [PubMed]

Sentences

No. Mutations Sentence Comment

23 ABCG8 p.Asp19His Although the precise source of cholesterol (i.e., exogenous or endogenous) present in gallstones has not been fully clarified, the ongoing working hypothesis is that the underlying molecular mechanism leading to cholesterol hypersecretion is a gain of sterol transport activity at the canalicular level.11,12 Indeed, a recent genome-wide association study (GWAS) and the analysis of sib-pairs with gallstones have demonstrated that the common ABCG8 variant p.D19H is a major determinant of gallstone formation in humans, presumably by gain-of- function of the transporter.13,14 Furthermore, carriers of other rare loss-of-function mutations in ABCG5/8 suffer from phytosterolemia, a disease characterized by intestinal hyperabsorption and diminished biliary secretion of phytosterols and cholesterol. Login to comment 39 ABCG5 p.Gln604Glu ABCG8 p.Asp19His All studied individuals were genotyped for the ABCG5 p.Q604E (rs6720173, c__29001998_10) and ABCG8 p.D19H (rs11887534, c__26135643_10), Address reprint requests to: Prof. Dr. Frank Lammert, Department of Medicine II, Saarland University Medical Center, Saarland University, Kirrberger Str. Login to comment 47 ABCG8 p.Thr400Lys ABCG8 p.Tyr54Cys p.Y54C (rs4148211, c__29535502_10), p.T400K (rs4148217, c__375061_10), and p.A632V (rs6544718, c__25642779_10) variants, as described in Supporting Methods. Login to comment 48 ABCG8 p.Asp19His ABCG8 p.Thr400Lys The ABCG8 p.D19H and p.T400K coding variants have been described previously as putative susceptibility variants for gallstone formation in humans.13-15 Measurement of Sterols and Clinical Chemical Parameters. Login to comment 99 ABCG8 p.Asp19His The p.Y53C variant in the Chilean cohort, the p.D19H variant in Chilean controls, and the p.A632V variant in German cases depart from Hardy-Weinberg equilibrium. Login to comment 102 ABCG8 p.Asp19His As shown in Supporting Table 3A, German carriers of the ABCG8 p.D19H gallstone risk allele [C]13,14 are characterized by a trend to elevated serum lathosterol as well as lower phytosterol (sitosterol, campesterol) levels, indicating increased hepatic synthesis and lower intestinal absorption of cholesterol. Login to comment 104 ABCG8 p.Tyr54Cys Interestingly, the p.Y54C variant is associated with phytosterol levels in the Chilean but not the German cohort (Supporting Table 4A). Login to comment 184 ABCG8 p.Asp19His In fact, previous studies showed that an increased expression of these proteins enhances biliary cholesterol output and reduces intestinal absorption.29 Our previous genetic studies in large cohorts have shown that the common lithogenic variant p.D19H of the ABCG8 transporter predisposes to GSD.13,14 However, the overall genetic association does not reach statistical significance in the present study, most likely due to the smaller cohort size. Login to comment