ABCMdb

PMID: 17632509

Buch S, Schafmayer C, Volzke H, Becker C, Franke A, von Eller-Eberstein H, Kluck C, Bassmann I, Brosch M, Lammert F, Miquel JF, Nervi F, Wittig M, Rosskopf D, Timm B, Holl C, Seeger M, ElSharawy A, Lu T, Egberts J, Fandrich F, Folsch UR, Krawczak M, Schreiber S, Nurnberg P, Tepel J, Hampe J
A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease.
Nat Genet. 2007 Aug;39(8):995-9. Epub 2007 Jul 15., [PubMed]

Sentences

No. Mutations Sentence Comment

2 ABCG8 p.Asp19His A follow-up study of the 235 most significant SNPs in 1,105 affected individuals and 873 controls replicated the disease association of SNP A-1791411 in ABCG8 (allelic P value PCCA ¼ 4.1 Â 10-9), which was subsequently attributed to coding variant rs11887534 (D19H). Login to comment 4 ABCG8 p.Asp19His The overall odds ratio for D19H carriership was 2.2 (95% confidence interval: 1.8-2.6, P ¼ 1.4 Â 10-14) in the full German sample. Login to comment 48 ABCG8 p.Met429Val ABCG8 p.Gly575Arg ABCG8 p.Leu36Pro The coding SNPs responsible for amino acid changes L36P, Q340E, M429V and G575R were monomorphic. Login to comment 49 ABCG8 p.Trp361* ABCG8 p.Arg121* For the sake of completeness, we also included two sitosterolemia SNPs: the SNP in ABCG8 responsible for premature stop R121X, which was monomorphic, and the SNP responsible for premature stop W361X in ABCG8, for which we observed one heterozygote each in panel B controls and affected individuals. Login to comment 50 ABCG8 p.Asp19His Using P o 0.01 in both the allelic and the genotypic test as a criterion for statistical significance, only the SNP responsible for D19H in the ABCG8 gene was significantly associated with gallstone disease (PCCA ¼ 8.8 Â 10-10, PCCG ¼ 3.0 Â 10-9 in panel B). Login to comment 51 ABCG8 p.Asp19His We confirmed SNPlex genotyping of the SNP responsible for D19H using a TaqMan assay (100% genotype concordance in panel B). Login to comment 52 ABCG8 p.Asp19His In a logistic regression analysis of panel B, no other SNP significantly improved the statistical model in the presence of D19H (P 4 0.05). Login to comment 54 ABCG8 p.Asp19His We used an additional panel (C) of independent cases and controls partly overlapping with panel B (Table 1) for the fine mapping and replication of the D19H association. Login to comment 55 ABCG8 p.Asp19His The strength and localization of the association signal, as well as the haplotype assignment of D19H, were replicated in a panel of 728 independent German affected individuals (panel C, Table 1, PCCA ¼ 2.8 Â 10-7, PCCG ¼ 9.2 Â 10-7) and in 167 affected individuals and 167 controls from Chile (panel D, Table 1, PCCA ¼ 0.02). Login to comment 63 ABCG8 p.Asp19His Furthermore, none of the interaction terms was significant in the presence of D19H. Login to comment 81 ABCG8 p.Asp19His This lack of concordance may be due to population differences or may reflect the lower power of nonparametric linkage analysis for a relatively infrequent genetic risk variant like D19H. Login to comment 88 ABCG8 p.Asp19His The D19H variant is marked by an arrow. Login to comment 96 ABCG8 p.Asp19His Although the genetic gallstone disease risk is clearly attributable to variant D19H in the ABCG8 gene in our study, we cannot exclude the possibility that other as-yet-unidentified variants at the ABCG5/ ABCG8 locus might also contribute to gallstone susceptibility. Login to comment 101 ABCG8 p.Asp19His However, additional functional studies are needed to determine the effect of the D19H variant on the ABCG8/ABCG5 heterodimer. Login to comment 148 ABCG8 p.Asp19His ABCG8 p.Tyr54Cys Table 3 Haplotype analysis of seven SNPs at the ABCG8 locus in panels B and C Fine mapping, panel B Fine mapping, panel C Haplotype fcases fcontrols ORcase-control PCOCAPHASE fcases fcontrols ORcase-control PCOCAPHASE C-G-A-T-G-T-C 0.340 0.382 0.8 0.01 0.349 0.392 0.8 0.02 T-G-G-T-G-T-G 0.342 0.325 1.1 0.24 0.340 0.325 1.1 0.38 C-G-G-T-G-T-G 0.066 0.071 0.9 0.53 0.077 0.069 1.1 0.42 C-G-A-T-G-T-G 0.067 0.068 1.0 0.89 0.060 0.068 0.9 0.33 C-C-A-C-A-T-C 0.097 0.045 2.3 7.75 Â 10-7 0.080 0.038 2.2 8.76 Â 10-7 C-G-A-T-G-A-C 0.023 0.043 0.5 5.73 Â 10-4 0.028 0.042 0.7 0.03 T-G-A-T-G-A-C 0.025 0.033 0.8 0.12 0.020 0.033 0.6 0.03 T-G-A-T-G-A-C 0.028 0.024 1.2 0.53 0.036 0.028 1.3 0.305 SNPs included in the haplotype analysis (rs4148187, rs11887534 (D19H), rs4148211 (Y54C), SNP_A-1791411, rs4953023, rs17424122 and rs17409589) are marked by an asterisk in Figure 1. Login to comment 150 ABCG8 p.Asp19His Nonsynonymous SNP rs11887534 (D19H) is in boldface, and the risk allele is underlined. Login to comment