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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.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.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.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.