ABCMdb

PMID: 21039838

Srivastava A, Srivastava A, Srivastava K, Choudhuri G, Mittal B
Role of ABCG8 D19H (rs11887534) variant in gallstone susceptibility in northern India.
J Gastroenterol Hepatol. 2010 Nov;25(11):1758-62. doi: 10.1111/j.1440-1746.2010.06349.x., [PubMed]

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0 ABCG8 p.Asp19His GASTROENTEROLOGYjgh_6349 1758..1762 Role of ABCG8 D19H (rs11887534) variant in gallstone susceptibility in northern India Anshika Srivastava,* Anvesha Srivastava,* Kshitij Srivastava,* Gourdas Choudhuri† and Balraj Mittal* Departments of *Genetics and † Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India Abstract Background and Aim: The excretion of cholesterol from the liver is regulated by the ATP-binding cassette transporter ABCG8. Login to comment 1 ABCG8 p.Asp19His A common genetic polymorphism D19H of ABCG8 might be related to the genetic predisposition of gallstone disease, which is causatively related to supersaturation of cholesterol in bile. Login to comment 2 ABCG8 p.Asp19His We aimed to examine the role of the ABCG8 D19H (rs11887534) polymorphism in susceptibility to gallstone disease in the northern Indian population. Login to comment 4 ABCG8 p.Asp19His Genotyping for the ABCG8 D19H polymorphism was carried out using the PCR-RFLP method. Login to comment 7 ABCG8 p.Asp19His The risk as a result of ABCG8 D19H variation was more pronounced in female gallstone patients at genotype (P = 0.026; OR = 3.01, 95% CI = 1.1-7.9) as well as allele level (P = 0.030; OR = 2.85; 95% CI = 1.17.3). Login to comment 9 ABCG8 p.Asp19His Conclusion: Carriers of the DH genotype and H allele of the ABCG8 D19H polymorphism harbor a higher risk for gallstone susceptibility in the northern Indian population. Login to comment 18 ABCG8 p.Asp19His ABCG8 p.Asp19His Genetic analyses showed that despite the close proximity between these two genes, ABCG8 shows much greater genetic variability in comparison with ABCG5.13,14 ABCG8 contains 13 exons and spans approximately 28 kb.15 Linkage and association studies have proposed cholesterol transporter ABCG5/G8 as a potential candidate for the genetic determinant of gallstone formation, or LITH gene.16,17 Buch et al.,18 using genome wide association, identified a single nucleotide polymorphism (SNP) (rs11887534) in the ABCG8 gene, conferring G>C transversion corresponding to asp19-to-his (D19H) substitution, which was significantly associated with gallstone disease. Login to comment 20 ABCG8 p.Asp19His ABCG8 p.Asp19His Considering the importance of the ABCG8 transporter in maintaining the cholesterol homeostasis and the association of the D19H genetic variant with gallstone disease, we aimed to explore the role of the ABCG8 D19H polymorphism in susceptibility to gallstone disease in a high-risk northern Indian population. Login to comment 32 ABCG8 p.Asp19His The ABCG8 D19H polymorphic site containing the fragment was amplified by PCR. Login to comment 33 ABCG8 p.Asp19His The genotyping for the ABCG8 D19H polymorphism was carried out as described previously.22 To improve the genotyping quality and validation, 10% of the samples were genotyped by Taqman probes and no discrepancy in genotyping was observed. Login to comment 42 ABCG8 p.Asp19His The false-positive report probability (FPRP) for statistically significant observations was estimated using the methods described by Wacholder et al.23 Evaluation of coding single nucleotide polymorphisms Polymorphism phenotyping algorithm (PolyPhen) (http:// www.bork.embl-eidelberg.de/PolyPhen/)24,25 was chosen for functional impact prediction of ABCG8 D19H. Login to comment 44 ABCG8 p.Asp19His Predictions are based on a combination of phylogenetic, structural and sequence annotation information characterizing a substitution and its position in the protein.26 Molecular modeling of ABCG8 D19H polymorphism Molecular modeling studies were carried out to understand the effect of aspartate to histidine change (rs11887534) on the geometry of ABCG8 protein. Login to comment 49 ABCG8 p.Asp19His Table 1 Characteristic profile of healthy controls and gallbladder cancer patients Characteristic Control subjects Gallstone patients n (%) n (%) Total 220 230 Sex Male 77 (35.0) 83 (36.1) Female 143 (65.0) 147 (63.9) Age at interview, years Ϯ SD 49.0 Ϯ 9.8 48.6 Ϯ 11.9 A Srivastava et al. ABCG8 D19H polymorphism and gallstone disease 1759Journal Type of stone analysis All the samples analyzed were of the cholesterol type (98.51%), except one that was of the pigment type (1.49%). Login to comment 51 ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 D19H polymorphism in control group In our population, the observed genotype distribution of the ABCG8 D19H polymorphism in healthy controls was consistent with the Hardy-Weinberg equilibrium. Login to comment 53 ABCG8 p.Asp19His ABCG8 D19H polymorphism in gallstone patients On comparing the genotype frequency distribution in gallstone patients with that of controls, the frequency of heterozygous DH genotype was considerably higher (10.4%) in gallstone patients than that of controls (5.0%). Login to comment 61 ABCG8 p.Asp19His Molecular modeling of the ABCG8 D19H (rs11887534) polymorphism The general root mean square (RMS) deviation for the average structures of the wild-type and polymorphic proteins was only 0.22 A. Furthermore, at the site of the polymorphism at residue 19, there was a minimal deviation between the two structures (Fig. Login to comment 70 ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Thr400Lys Various recent studies have identified the ABCG8 D19H variant as the first common susceptibility factor for cholesterol gallstones in humans.16,34,35 However, Wang et al.17 showed that the ABCG8 T400K polymorphism, not D19H, might play a role in the lipid metabolism and formation of gallstones in the Chinese population. Login to comment 72 ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His Also, the results stood true when replicated in the Chilean population.18 The D19H variant confers OR of 2-3 and 7 for heterozygous and homozygous carriers, respectively, and therefore 8-11% of the total gallstone risk can be attributed to this variant.36 The molecular modeling of the ABCG8 D19H variant polymorphism, which leads to the substitution of a positively charged amino acid (aspartic acid) with a negatively charged amino acid (histidine), showed that the overall RMS deviation was negligible between the wild-type and polymorphic ABCG8 protein structures, and the D19H SNP was predicted by PolyPhen to be benign. Login to comment 74 ABCG8 p.Asp19His It is well established that ABCG8 plays an important role in the secretion of cholesterol into intestinal lumen in enterocytes and the Table 2 Genotype and allele frequencies for the ABCG8 D19H (rs11887534) polymorphism in gallstone patients and healthy subjects Genotype/allele Gallstone Controls P-value OR (95% CI) n (%) (230) n (%) (220) DD 206 (89.6) 209 (95.0) - 1 (reference) DH/HH 24 (10.4) 11 (5.0) 0.038 2.20 (1.1-4.6) D 436 (94.8) 429 (97.5) - 1 (reference) H 24 (5.2) 11 (2.5) 0.043 2.12 (1.2-4.3) Significant values are represented in bold. CI, confidence interval; GBC, gallbladder cancer; HC, healthy control; OR, odds ratio. Login to comment 75 ABCG8 p.Asp19His ABCG8 D19H polymorphism and gallstone disease A Srivastava et al. 1760 secretion of cholesterol into bile in hepatocytes.17,37 The protein encoded by ABCG8 functions along with ABCG5 as a heterodimer.,38 An aspartic acid at amino acid 19 in ABCG8 is highly conserved from plants to vertebrates, and its substitution to histidine results in the loss of negative charge. Login to comment 76 ABCG8 p.Asp19His The variant H allele of the ABCG8 D19H polymorphism is suggested to increase the expression or function of the ABCG8 transporter, resulting in a positive correlation with high biliary cholesterol secretion and the accumulation in the gallbladder, which serves as an initial step in gallstone formation.17,39,40 Mice overexpressing human Abcg8 show reduced intestinal cholesterol absorption and hepatic cholesterol synthesis and biliary cholesterol secretion, thus leading to the supersaturation of bile with cholesterol.41,42 Biliary cholesterol level has also been directly related to gene copy number of the transgene ABCG8, and vice versa, in Abcg8 knockout mice.43,44 Establishing the role of the ABCG8 19H variant might be clinically relevant, because it would be possible to predict if HMG-CoA reductase inhibitors could be particularly effective in lowering biliary cholesterol levels in patients carrying the ABCG8 risk allele. Login to comment 77 ABCG8 p.Asp19His The importance of our study lies in the fact that there is no data available exploring the role of the ABCG8 D19H variant in the high-risk population of northern India. Login to comment