Plasma Bilirubin and UGT1A1*28 Are Not Protective Factors Against First-Time Myocardial Infarction in a Prospective, Nested Case–Referent Setting

Abstract

Background-Bilirubin, an effective antioxidant, shows a large variation in levels between individuals and has been positively associated with reduced cardiovascular disease risk. A major reason for the variability is a common promoter polymorphism, UGT1A1*28, which reduces the transcription of the enzyme that conjugates bilirubin, UDPglucuronosyltransferase 1A1. The aim of the study was to evaluate a possible protective effect of plasma bilirubin and the UGT1A1*28 polymorphism against myocardial infarction in a prospective case-referent setting. Methods and Results-Subjects (nϭ618) with a first-ever myocardial infarction (median event age, 60.5 years; median lag time, 3.5 years) and 1184 matched referents were studied. Plasma bilirubin was lower in cases versus referents. Despite a strong gene-dosage effect on bilirubin levels in both cases and referents, the UGT1A1*28 polymorphism did not influence the risk of myocardial infarction. Among multiple other variables, serum iron showed one of the strongest associations with bilirubin levels. Conclusions-We found no evidence for a protective effect of the UGT1A1*28 polymorphism against myocardial infarction and consequently neither for bilirubin. The lower bilirubin levels in cases might be caused by decreased production, increased degradation, or increased elimination. (Circ Cardiovasc Genet. 2010;3:340-347.)

Plasma total bilirubin levels predict amputation events in type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

“…Analysis according to sex Consistent with previous studies [4,5,19,27,28], our study showed that women had lower median bilirubin concentrations than men (8 vs 10 μmol/l). We found that the inverse relationship between bilirubin concentrations and risk of first amputation was highly significant for men (HR 1.60 per 5 μmol/l decrease in bilirubin concentration, 95% CI 1.19, 2.14, p=0.0017), but not women (HR 1.90 per 5 μmol/l decrease in bilirubin concentration, 95% CI 0.84, 4.33, p=0.126; p for interaction by sex= 0.71; Fig.…”

“…This inverse association is further supported by studies showing a similar relationship between bilirubin levels and CHD, ischaemic stroke, and surrogate markers of atherosclerosis including endothelial dysfunction and carotid intima-media thickness [12,14,[29][30][31][32][33][34][35][36][37][38][39][40][41][42]. A number of prospective studies found a Uor reversed J-shaped relationship rather than an inverse relationship between bilirubin levels and CHD [4,5,27,28,30,33,34,37]. The differences between our study and these earlier studies are that they concentrated on CHD and mainly enrolled men, although whether these differences could plausibly explain the differing relationships reported is unclear.…”

Extreme Neonatal Hyperbilirubinemia and a Specific Genotype: A Population-Based Case-Control Study

“…The UGT1A1*28 genotype frequencies in our data correspond well with those expected for a white north European population. 15,26 Interpretation Our study diverges from previous studies by being population-based, by containing multiple causes of hyperbilirubinemia (eg, AB0 incompatibility, early discharge, starvation), by its case-control design, and by being to our knowledge the first to directly explore the association between UGT1A1*28 genotypes and extreme hyperbilirubinemia. Most studies find that the UGT1A1*28 allele is unrelated to neonatal hyperbilirubinemia, [27][28][29] but some studies have shown that UGT1A1*28 allele status is associated with increased levels of plasma bilirubin in conjunction with hemolytic factors (AB0 serum incompatibility, spherocytosis, and some variants of glucose-6-phosphate dehydrogenase deficiency).…”

“…For the AB0 incompatible subgroup, the number of cases, and thus statistic power, was more limited, which is reflected in wider confidence intervals. Because of the dose-response relationship between UGT1A1*28 genotypes and UGT1A1 enzyme activity, 15,16,26 in the primary analysis the genotypes were treated as a continuous variable and as a categorical variable in the secondary analysis. Effect estimates were similar for the 2 analytic strategies, but the primary analysis had a higher statistical power and a better precision of estimates.…”

“…The promoter region controls expression of the UGT1A1 gene, and for UGT1A1*28 alleles, UGT1A1 enzyme activity is reduced to 30% of common allele levels. [14][15][16][17] The contribution of UGT1A1*28 alleles to the development of hyperbilirubinemia among newborn infants is not yet settled, but it has been proposed that additional icterogenic factors are necessary for the allele to influence the incidence of hyperbilirubinemia, and that 1 such factor could be AB0 blood type incompatibility. 13,18 The association between the UGT1A1*28 allele and the development of extreme hyperbilirubinemia has not been studied, and a call for such studies has been made in recent international reviews.…”