ABCMdb

PMID: 18457353

Kuo KK, Shin SJ, Chen ZC, Yang YH, Yang JF, Hsiao PJ
Significant association of ABCG5 604Q and ABCG8 D19H polymorphisms with gallstone disease.
Br J Surg. 2008 Aug;95(8):1005-11., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCG8 p.Asp19His Original article Significant association of ABCG5 604Q and ABCG8 D19H polymorphisms with gallstone disease K.-K. Kuo1 , S.-J. Shin2 , Z.-C. Chen3 , Y.-H. C. Yang4 , J.-F. Yang5 and P.-J. Hsiao2 1 Division of Hepatobiliopancreatic Surgery, Department of Surgery and 2 Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Medical University Hospital, 3 Section of General Medicine, Chi-Mei Medical Centre, and 4 Statistical Analysis Laboratory, Department of Clinical Research and 5 Department of Preventive Medicine, Kaohsiung Medical University Hospital, Taiwan Correspondence to: Dr P.-J. Hsiao, Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Medical University Hospital, 100 Tzyou 1st Road, Kaohsiung 807, Taiwan (e-mail: pjhsiao@cc.kmu.edu.tw) Background: Adenosine triphosphate-binding cassette (ABC) transporters ABCG5 and ABCG8 are sterol export pumps regulating biliary cholesterol excretion. Login to comment 5 ABCG8 p.Asp19His ABCG8 p.Thr400Lys Five non-synonymous polymorphisms, E604Q (ABCG5), D19H, C54Y, T400K and A632V (ABCG8), were analysed using the TaqMan genotyping assay. Login to comment 7 ABCG8 p.Asp19His 604Q (CC) and D19H (GC) genotypes were significantly associated with gallstone disease, even when adjusted for age, sex and body mass index. Login to comment 9 ABCG8 p.Asp19His The risk was greatly increased in subjects younger than 50 years with the D19H genotype and those of 50 years or more with the 604Q genotype. Login to comment 10 ABCG8 p.Asp19His Conclusion: Carriers of ABCG5 604Q or ABCG8 D19H polymorphisms have an increased risk of gallstone disease independent of age, sex and body mass index. Login to comment 26 ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCB4 p.Glu604Gln In previous studies, five non-synonymous polymorphisms in ABCG5 (E604Q) and ABCG8 (C54Y, D19H, T400K, A632V) have been linked to cholesterol homeostasis, especially in cholesterol absorption efficiency and cholesterol saturation of bile. Login to comment 44 ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCB4 p.Glu604Gln Relevant non-synonymous polymorphisms of ABCG5 (E604Q) and ABCG8 (C54Y, D19H, T400K, A632V) associated with biliary cholesterol secretion were chosen for this study. Login to comment 46 ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCB4 p.Glu604Gln The specific primers were designed using Primer 3 software according to SNP reference of GenBank mapping in the National Center for Biotechnology Information database (rs6720173 for E604Q, rs11887534 for D19H, rs4148211 for C54Y, rs4148217 for T400K, rs6544718 for A632V). Login to comment 56 ABCG8 p.Asp19His ABCB4 p.Glu604Gln Binary logistic regression gave odds ratios of having gallstones under the influence of genotypes E604Q (CC versus GG + GC), D19H (GC versus GG) and C54Y (AA versus GG + GA). Login to comment 57 ABCG8 p.Asp19His ABCB4 p.Glu604Gln For the crude odds ratio, the presence or absence of gallstones was the dependent variable, and the E604Q, D19H or C54Y genotype was the independent variable. Login to comment 67 ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCB4 p.Glu604Gln Table 2 shows allele frequencies of the five nonsynonymous polymorphisms (ABCG5: E604Q; ABCG8: D19H, C54Y, T400K, A632V). Login to comment 70 ABCG8 p.Asp19His The C allele of D19H was quite rare (1·4 per cent) and the CC (His19) genotype was absent in the study population. Login to comment 75 ABCG8 p.Asp19His ABCB4 p.Glu604Gln There was a significant correlation of gallstone disease with the genotype distribution of E604Q, D19H and C54Y polymorphisms. Login to comment 76 ABCG8 p.Asp19His ABCB4 p.Glu604Gln The minor alleles of E604Q, D19H and C54Y polymorphisms were overexpressed in patients with gallstones compared with controls. Login to comment 77 ABCG8 p.Asp19His ABCB4 p.Glu604Gln For example, in the E604Q polymorphism, the frequency of the CC genotype was 4 per cent in the gallstone group compared with 0·7 per cent in the stone-free group, and the frequency of the D19H (GC) variant was 8 per cent in the gallstone group compared with 2·1 per cent in the group without gallstones. Login to comment 78 ABCB4 p.Glu604Gln For further analysis of the odds ratios of minor genotypes with gallstone disease, carriers of GG and GC genotypes of E604Q and those of GG and GA genotypes of C54Y were combined. Login to comment 80 ABCG8 p.Asp19His The 604Q (CC) and D19H (GC) variant contributed a significant and independent risk of gallstone formation, even after adjusting for age, sex and BMI. Login to comment 83 ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCB4 p.Glu604Gln *Two-sample Student`s t test, except †Pearson χ2 test. Table 2 Allele frequencies of the polymorphisms in ABCG5 and ABCG8 genes in 979 subjects Gene Allele NCBI SNP reference Ratio Frequency (%) ABCG5: E604Q G1810C rs 6720173 G : C 89·5 : 10·5 ABCG8: D19H G55C rs 11887534 G : C 98·6 : 1·4 ABCG8: C54Y G161A rs 4148211 G : A 90·3 : 9·7 ABCG8: T400K C1199A rs 4148217 C : A 92·0 : 8·0 ABCG8: A632V T1895C rs 6544718 T : C 0 : 100 NCBI, National Center for Biotechnology Information; SNP, single nucleotide polymorphism. Login to comment 84 ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCB4 p.Glu604Gln Table 3 Association of genotype frequency of ABCG5 and ABCG8 with gallstone development No stones (n = 905) Gallstones (n = 74) P* Power (%) ABCG5: E604Q (G1810C) Genotype GG 691 (79·2) 52 (74) 0·011 18 GC 175 (20·1) 15 (21) CC 6 (0·7) 3 (4) ABCG8: D19H (G55C) Genotype GG 851 (97·9) 66 (92) 0·001 79 GC 18 (2·1) 6 (8) ABCG8: C54Y (G161A) Genotype GG 747 (82·5) 54 (73) 0·041 53 GA 152 (16·8) 18 (24) AA 6 (0·7) 2 (3) ABCG8: T400K (C1199A) Genotype CC 739 (84·5) 58 (79) 0·463 22 CA 134 (15·3) 15 (21) AA 2 (0·2) 0 (0) Values in parentheses are percentages. Login to comment 85 ABCG8 p.Asp19His ABCB4 p.Glu604Gln *Pearson χ2 test. Table 4 Gallstone risk associated with ABCG5 and ABCG8 polymorphisms Genotype Crude odds ratio P† Adjusted odds ratio* P† E604Q GG + GC 1·0 CC 6·5 (1·6, 26·4) 0·009 4·7 (1·1, 21·1) 0·042 D19H GG 1·0 GC 4·3 (1·7, 11·2) 0·003 3·5 (1·2, 9·6) 0·018 C54Y GG + GA 1·0 AA 4·1 (0·8, 20·9) 0·085 3·2 (0·6, 17·3) 0·170 Values in parentheses are 95 per cent confidence intervals. Login to comment 91 ABCG8 p.Asp19His The gallstone risk associated with 604Q and D19H polymorphisms was further stratified into different age groups (Table 5). Login to comment 94 ABCG8 p.Asp19His The result clearly demonstrated a significant risk of gallstone disease associated with 604Q in subjects older than 50 years and a greater risk associated with the D19H polymorphism in those younger than 50 years. Login to comment 95 ABCG8 p.Asp19His ABCB4 p.Glu604Gln Discussion This study found a significant correlation between the distribution of E604Q and D19H (GC) polymorphisms and gallstone disease in the Taiwanese population. Login to comment 96 ABCG8 p.Asp19His In addition, after adjusting for other confounding risk factors (age, sex and BMI), the 604Q (CC) and D19H (GC) polymorphisms were still significant independent risk factors for developing gallstone disease. Login to comment 97 ABCG8 p.Asp19His The risk associated with 604Q was stronger in older people, whereas the risk associated with D19H was greater in those younger than 50 years. Login to comment 98 ABCG8 p.Asp19His ABCB4 p.Glu604Gln The study also found that serum levels of total Table 5 Gallstone risk associated with ABCG5 and ABCG8 polymorphisms stratified by age Age < 50 years Age ≥ 50 years Genotype Crude odds ratio P‡ Adjusted odds ratio* P‡ Crude odds ratio P‡ Adjusted odds ratio* P‡ E604Q GG + GC 1·0 CC† 6·0 (1·3, 27·7) 0·022 6·4 (1·3, 30·7) 0·020 D19H GG 1·0 1·0 GC 6·4 (1·3, 32·7) 0·025 12·4 (1·7, 90·0) 0·013 2·8 (0·9, 9·2) 0·088 2·5 (0·8, 8·6) 0·133 Values in parentheses are 95 per cent confidence intervals. Login to comment 105 ABCG8 p.Asp19His In this study population, polymorphism of 604Q or D19H and age were independently associated with gallstone disease in univariable analysis. Login to comment 110 ABCG8 p.Asp19His In this large-scale ultrasonography study, carriers of 604Q and D19H variants retained their high risk of gallstone formation even after adjusting for age, sex and BMI status. Login to comment 111 ABCG8 p.Asp19His The gallstone risk for D19H carriers was much greater in those younger than 50 years. Login to comment 112 ABCG8 p.Asp19His Consistent with previous studies in Caucasians19,20, this finding supports the hypothesis that the D19H polymorphism may affect the transporter function resulting in gallstone formation in earlier life. Login to comment 114 ABCG8 p.Asp19His One implication of this study is that 604Q and D19H polymorphisms could be considered as susceptible gene markers for gallstone disease in the Taiwanese population. Login to comment 125 ABCG5 p.Gln604Glu ABCG8 p.Asp19His Acalovschi and co-workers17 found that polymorphisms at D19H and Q604E were significantly associated with a lithogenic plasma lipid profile in siblings with gallstone disease. Login to comment 135 ABCG8 p.Asp19His Compared with the reports by Buch and colleagues19 and Gr¨unhage and co-workers20, the lower prevalence of the minor allele of D19H (1·4 versus 8·5 per cent) in the present study may explain the lower prevalence of gallstone formation (8·3 versus 21·4 per cent) in Taiwanese compared with Caucasian populations. Login to comment 136 ABCG8 p.Asp19His Even the lower prevalence of the minor allele in the present population supports the previous suggestion that the D19H variant contributes to the genetic risk of gallstone disease, especially in the young. Login to comment