ABCMdb

PMID: 20497293

Katsika D, Magnusson P, Krawczyk M, Grunhage F, Lichtenstein P, Einarsson C, Lammert F, Marschall HU
Gallstone disease in Swedish twins: risk is associated with ABCG8 D19H genotype.
J Intern Med. 2010 Sep;268(3):279-85. Epub 2010 Apr 28., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCG8 p.Asp19His doi: 10.1111/j.1365-2796.2010.02249.x Gallstone disease in Swedish twins: risk is associated with ABCG8 D19H genotype D.Katsika1 ,P.Magnusson2 ,M.Krawczyk3 , F.Gru¨nhage3 ,P.Lichtenstein2 , C. Einarsson1 ,F.Lammert3 &H.-U.Marschall1 FromtheDepartmentsof1 MedicineatKarolinskaUniversityHospitalHuddingeand 2 MedicalEpidemiologyandBiostatistics, KarolinskaInstitutet, Stockholm,Sweden,and 3 DepartmentofMedicineII,SaarlandUniversity Hospital,Homburg,Germany Abstract. Login to comment 2 ABCG8 p.Asp19His Gallstone disease in Swedish twins: risk is associated with ABCG8 D19H genotype. Login to comment 5 ABCG8 p.Asp19His Recently, variants of the hepatocanalicular cholesterol hemitransporters ABCG5/8 were linked to gallstone disease; ABCG8 D19H in Caucasians andABCG5Q604E inChinese. Login to comment 11 ABCG5 p.Gln604Glu ABCG8 p.Asp19His ABCG5 Q604E and ABCG8 D19H genotyping was performed in 24 unique MZ and eight dizygotic (DZ) twins from concordant pairs. Login to comment 15 ABCG8 p.Asp19His Amongst the 341 twins, 20.8% carried at least one D19H allele as compared to 9.4% of stone-free controls. Login to comment 16 ABCG8 p.Asp19His The association analysis showed that D19H positivity significantly increased the risk of gallstone disease [odds ratio (OR), 2.54; 95% confidence interval (CI), 1.33-4.82; P = 0.004]. Login to comment 17 ABCG5 p.Gln604Glu We also found a trend for a positive association between gallstone disease and the Q604E variant (OR, 1.47; 95% CI, 1.00-2.16; P = 0.052). Login to comment 19 ABCG8 p.Asp19His Twins carrying a heterozygous or homozygous ABCG8 D19H genotype have a significantly increased risk of gallstone disease. Login to comment 20 ABCG8 p.Asp19His Our study confirms the ABCG8 D19H genotype as a major risk factor for gallstone disease. Login to comment 29 ABCG8 p.Asp19His A genome-wide association study of patients with gallstones from Germany and Chile [14] and a linkage study in affected sibling pairs from Germany and Romania [15] then identified the D19H variant of ABCG8, located on chromosome 2, as a susceptibility factor for human GD. Login to comment 30 ABCG5 p.Gln604Glu In Chinese populations, another nonsynonymous polymorphism, Q604E on the ABCG5 gene, was found to be associated with GD [16]. Login to comment 31 ABCG5 p.Gln604Glu ABCG8 p.Asp19His To further validate the contribution of the lithogenic ABCG5 Q604E and ABCG8 D19H variants to GD, we tested for these alleles in a twin-based association study after selected sampling from the Swedish Twin Registry(STR). Login to comment 68 ABCG8 p.Asp19His For genotyping using TaqMan assays, we selected the functionally relevant nonsynonymous coding single-nucleotide polymorphisms (SNPs) ABCG5 rs672017 (c.1810G>C, p.E604Q) and ABCG8 rs11887534 (c.55G>C, D19H), as described [15]. Login to comment 74 ABCG5 p.Gln604Glu ABCG8 p.Asp19His Results The ABCG5 Q604E and ABCG8 D19H variants were successfully genotyped in all samples. Login to comment 76 ABCG5 p.Gln604Glu ABCG8 p.Asp19His Table 2 summarizes the allele and genotype distributions for the ABCG5 Q604E and ABCG8 D19H variants. Login to comment 78 ABCG5 p.Gln604Glu ABCG8 p.Asp19His Seven and six MZ twin pairs were heterozygous Q604E and D19H carriers, respectively. Login to comment 79 ABCG5 p.Gln604Glu ABCG8 p.Asp19His Concordance for GD was found in five twin pairs with Q604E or D19H variants, respectively. Login to comment 81 ABCG5 p.Gln604Glu ABCG8 p.Asp19His Discordant MZ twins were disregarded from further calculations, as they cannot be Table 2 Alleles and genotypes (count / frequency) for ABCG8 D19H (A) and ABCG5 Q604E (B) in all unique monozygotic, dizygotic andcontrolgenomesforSwedishtwins MZ DZ NoGD GD NoGD GD n % n % n % n % (A)AllelefrequenciesofABCG8 D19HinSwedishtwins Allele / genotype Totalscreeningpopulation GG 99 90.8 36 81.8 114 90.5 48 77.4 GC 9 8.3 8 18.2 11 8.7 13 21.0 CC 1 0.9 0 0 1 0.8 1 1.6 StockholmCountyscreeningpopulation GG 7 87.5 19 79.2 0 4 50.0 GC 1 12.5 5 20.8 0 3 37.5 CC 0 0 0 0 0 1 12.5 Nationwidescreeningpopulation GG 99 90.9 17 85.0 114 90.5 44 81.5 GC 9 8.3 3 15.0 11 8.7 10 18.5 CC 1 0.9 0 0 1 0.8 0 0.0 (B)AllelefrequenciesofABCG5Q604EinSwedishtwins Allele / genotype Totalscreeningpopulation GG 74 67.9 32 72.7 85 67.5 26 41.9 GC 32 29.4 11 25.0 33 26.2 32 51.6 CC 3 2.7 1 2.3 8 6.3 4 6.5 StockholmCountyscreeningpopulation GG 6 75.0 18 75.0 0 0 1 12.5 GC 2 25.0 5 20.8 0 0 7 87.5 CC 0 0 1 4.2 0 0 0 0 Nationwidescreeningpopulation GG 74 67.9 14 70.0 85 67.5 25 46.3 GC 32 29.4 6 30.0 33 26.2 25 46.3 CC 3 2.7 0 0 8 6.3 4 7.4 MZ,uniquegenomesinconcordantMZpairswithGDandstone-freeuniqueMZgenomes;DZ,twinsinconcordantDZpairswith GDandnonrelated stone-freeDZtwins. Login to comment 88 ABCG8 p.Asp19His There were 297 D19H wild-type subjects; 84 with GD and 213 without GD. Login to comment 89 ABCG8 p.Asp19His Of the 41 heterozygous D19H carriers, 21 had GD and 20 did not. There were only three homozygous D91H carriers (one with GD). Login to comment 90 ABCG8 p.Asp19His We observed that hetero- or homogeneous carriage of the D19H allele conferred a significantly increased risk of developing GD [odds ratio (OR), 2.54; 95% confidence interval (CI), 1.33-4.82; P = 0.004]. Login to comment 91 ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His Amongst MZ cases, 18.2% were D19H carriers compared to 8.3% of MZ controls. Amongst the DZ cases, 22.6% were D19H carriers compared to 9.5% of DZ controls. Overall, 20.8% (22 of 106) of cases were positive for the D19H allele, compared to 9.4% (22 of 235) of controls. Login to comment 93 ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu Of the 108 heterozygous Q604E carriers, 43 had GD and 65 did not. There were only 16 homozygous Q604E carriers, five of whom had GD. Login to comment 95 ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu Amongst the MZ cases, 27.3% were Q604E carriers compared to 32.1% of MZ controls. Amongst the DZ cases, 58.1% were Q604E carriers comparedto32.5%ofDZcontrols.Overall,45.3%(48 of 106) of cases were positive for the Q604E allele, compared to 32.3% (76 of 235) of controls. Login to comment 98 ABCG8 p.Asp19His Gru¨nhage et al. demonstrated significant single-point linkage for the ABCG8 D19H variant but not for other ABCG5/ G8 SNPs [15]. Login to comment 103 ABCG8 p.Asp19His Notwithstanding, in our Stockholm County population, 20.8% of concordant MZ pairs carried at least one D19H allele, which is in accordance with the results of Gru¨nhage et al. who found this allele in 21.4% of Caucasian patients with gallstones but only in 8.6% of controls [15]. Login to comment 104 ABCG8 p.Asp19His ABCG8 p.Asp19His The D19H variant was also reported to be a susceptibility factor for GD inChilean Hispanics [14] and in a Chinese population [16] in which D19H increased the risk of gallstones with an OR of 12.4 in predominantly male patients below 50 years of age. Login to comment 105 ABCG5 p.Gln604Glu In the same study, the ABCG5 Q604E polymorphism was also found to be associated with GD, with an OR of 6.4 in (male) patients above 50 years of age [16]. Login to comment 108 ABCG8 p.Asp19His ABCG8 p.Asp19His Considering the whole cohort of MZ and DZ cases and matched controls from the TwinGene database, we found that the ABCG8 D19H genotype was more common in both MZ and DZ twins with GD than in MZ and DZ controls. Overall, D19H positivity was significantly (P = 0.004) higher in cases (20.8%) than in controls (9.4%), which clearly points to a genetic impact, in accordance with previous publications [15] and our results from the Stockholm County population. Login to comment 109 ABCG8 p.Asp19His Of note, despite the old age of the majority of the Stockholm County cohort, no twin with GD and ABCG8 D19H had an elevated level of serum total or low-density lipoprotein (LDL) cholesterol. Login to comment 110 ABCG8 p.Asp19His This, at least, is not in contrast to previous studies [21-23] that have shown significantly lower levels of total and LDL cholesterol in D19H carriers. Login to comment 111 ABCG8 p.Asp19His This finding led to the assumption that D19H increases the ABCG5/G8-mediatedtransferofcholesterol into bile, resulting in biliary cholesterol hypersaturation, which is the major pathogenetic defect in GD [1, 2]. Login to comment 122 ABCG5 p.Gln604Glu ABCG8 p.Asp19His Moreover, such misclassification would be expected to bias the estimates to the null, which means that the relationship between D19H (and Q604E) and GD would be, if anything, underestimated. Login to comment 125 ABCG8 p.Asp19His In summary, our study in MZ and DZ twins confirms the ABCG8 D19H variant as a significant risk factor for GD. Login to comment