ABSTRACT
BACKGROUND & AIMS: The Gilbert syndrome-associated functional TATA box variant UGT1A1*28 (A(TA)7TAA) was found to increase susceptibility to pigment gallstone formation in patients with haemolytic anaemia. Further studies in extensive cohorts demonstrated an increased risk of this variant for cholesterol gallstone disease (GD). We now investigated this polymorphism as a determinant of symptomatic GD in Swedish twins. METHODS: The Swedish Twin Registry was merged with the Hospital Discharge and Causes of Death Registries and searched for GD-related diagnoses among monozygotic (MZ) twins living in the Stockholm area. In addition, we screened the TwinGene database for GD. In total, we found 44 MZ twin pairs with and eight MZ twins without GD to be evaluable. GD-free twins from TwinGene (109 concordantly MZ and 126 independent DZ) served as controls. UGT1A1*28 genotyping was performed using TaqMan assays. RESULTS: Overall, 58 and 8 of 106 twins with GD were hetero- and homozygous UGT1A1 risk allele carriers respectively. The case-control association tests showed a significantly (P < 0.05) increased risk of developing GD (OR = 1.62, 95% CI 1.00-2.63) in heterozygotes carriers and in addition, a trend (P = 0.075) for an increased risk among carriers (OR = 1.52, 95% CI 0.97-2.44) of the risk allele. CONCLUSION: These data from Swedish twins confirm the Gilbert variant as risk factor for GD. Our observation is in line with nucleation in bilirubin supersaturated bile representing an initial step in cholelithogenesis.
Subject(s)
Gallstones/genetics , Gilbert Disease/genetics , Glucuronosyltransferase/genetics , Polymorphism, Single Nucleotide , Twins, Monozygotic/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 8 , ATP-Binding Cassette Transporters/genetics , Aged , Aged, 80 and over , Case-Control Studies , Chi-Square Distribution , Female , Gallstones/diagnostic imaging , Gallstones/enzymology , Gene Frequency , Genetic Predisposition to Disease , Gilbert Disease/enzymology , Heterozygote , Homozygote , Humans , Male , Middle Aged , Odds Ratio , Phenotype , Registries , Risk Factors , Sweden , UltrasonographyABSTRACT
Gallstone disease is one of the most prevalent gastrointestinal diseases with a substantial burden to health care systems that is expected to increase in ageing populations at risk. This review summarizes recent data on the genetic background of cholesterol gallstones and the role of biliary lipid composition. Three previously unknown non-synonymous mutations in the ABCB4 gene encoding the hepatobiliary phospholipid-flippase MDR3 are presented.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B/genetics , Bile Pigments/metabolism , Gallstones/genetics , Genetic Predisposition to Disease , Gallstones/metabolism , HumansABSTRACT
We report two patients with uncommon Gilbert's syndrome with severe unconjugated hyperbilirubinemia which was reduced from 200 to 60-90 micromol/L by long-term administration of rifampicin. Hepatic induction of bilirubin-glucuronosyltransferase was suggested by increased relative amounts of conjugated serum bilirubin. This molecular mechanism was confirmed in primary cultures of human hepatocytes.
Subject(s)
Enzyme Inhibitors/therapeutic use , Gilbert Disease/drug therapy , Glucuronosyltransferase/antagonists & inhibitors , Rifampin/therapeutic use , Adult , Bilirubin/blood , Cells, Cultured , Female , Follow-Up Studies , Gilbert Disease/blood , Gilbert Disease/pathology , Glucuronosyltransferase/blood , Hepatocytes/pathology , Humans , Male , Time FactorsABSTRACT
The contribution of hereditary and environmental factors to the pathogenesis of symptomatic gallstone disease is still unclear. We estimated the relative importance of genetic and environmental factors by analyzing a large population of twins. For this purpose, the Swedish Twin Registry was linked with the Swedish inpatient-discharge and causes of death registries for symptomatic gallstone disease and gallstone surgery-related diagnoses in 43,141 twin pairs born between 1900 and 1958. Concordance rates, correlations, and odds ratios were calculated for males, females, monozygotic, and dizygotic twins, respectively, as well as for twin pairs of opposite sex. Structural equation modeling techniques were used to estimate the contributions of genetic effects as well as shared and non-shared environmental factors to the development of symptomatic gallstone disease. We found that concordances and correlations were higher in monozygotic compared with dizygotic twins, both for males and females. Of note, there were no significant sex differences in heritability. In the full model, genetic effects accounted for 25% (95% CI, 9%-40%), shared environmental effects for 13% (95% CI, 1%-25%), and unique environmental effects for 62% (95% CI, 56%-68%) of the phenotypic variance among twins. In conclusion, our results show heritability to be a major susceptibility factor for symptomatic gallstone disease, consistent with results from previous, much smaller studies.