Serum Bilirubin Links UGT1A1*28 Polymorphism and Predicts Long-Term Cardiovascular Events and Mortality in Chronic Hemodialysis Patients

Abstract

SummaryBackground and objectives Bilirubin is a protective factor with antioxidant and anti-inflammatory properties, but its association with clinical outcomes of hemodialysis patients is unknown. Bilirubin degradation is mainly determined by the activity of hepatic bilirubin uridine diphosphate-glucuronosyltransferase (UGT1A1), which is significantly influenced by a TA-repeat polymorphism in the gene's promoter, an allele designated UGT1A1*28. The study aimed to clarify the association between serum bilirubin and UGT1A1*28 polymorphism and their respective effect on outcomes of chronic hemodialysis patients. Design, setting, participants, & measurementsThe cohort study comprised 661 chronic hemodialysis patients who were prospectively followed for 12 years. The endpoints were cardiovascular events (CVEs) and allcause mortality.Results After adjustment for traditional and dialysis-related risk factors, individuals with bilirubin in the upper tertile had an adjusted hazard ratio of 0.32 for CVEs and 0.48 for all-cause mortality compared with those in the lower tertile. Individuals homozygous for UGT1A1*28 (genotype 7/7) had significantly higher bilirubin levels than those with 6/6 and 7/6 genotypes. In the same multivariable-adjusted model, individuals with 7/7 had approximately one tenth the risk for CVEs and one fourth the risk for all-cause mortality as compared with carriers of the 6 allele.Conclusions A graded, reverse association was noted between serum bilirubin and adverse outcomes among chronic hemodialysis patients. Moreover, the UGT1A1*28 polymorphism had strong effects on bilirubin levels and the 7/7 genotype might have an important effect on reducing CVEs and death.

Bilirubin scavenges chloramines and inhibits myeloperoxidase-induced protein/lipid oxidation in physiologically relevant hyperbilirubinemic serum

“…Epidemiological studies report that individuals with elevated UCB are protected from the development of intimal hyperplasia, atherosclerosis and cardiovascular disease (CVD) [1][2][3][4][5][6][7]. Furthermore, higher UCB concentrations (in the absence of haemolytic or liver disease) are associated with reduced incidence of CVD-related mortality [8][9][10][11][12]. The mechanisms responsible for CVD protection are not clear, however may be related to the potent antioxidant properties of UCB, given the potential role of oxidation in the development and progression of atherosclerosis [13].…”

Cardiovascular Events as a Function of Serum Bilirubin Levels in a Large, Statin-Treated Cohort

“…Furthermore, cohort studies have shown that homozygosity for the UGT1A1*28 allele is associated with a much lower risk of CVD events. 15,16 UGT1A1*28 is not associated with conventional CVD risk factors 12,13 but has been linked to a significantly smaller brachial artery diameter and increased cold pressor test reactivity in young people, suggesting a beneficial influence on the size and structure of arteries. 3 Thus, serum bilirubin level may be an independent marker for environmental and genetically determined CVD risk.…”

Association of serum bilirubin levels with mortality in patients with diabetes initiating chronic hemodialysis: a competing risks analysis of a single-center cohort

“…Our study restricting to patients with diabetes yielded the consistent results; however, the previous study used conventional Kaplan-Meier survival analysis and Cox proportional hazard model for estimating the event-free survival and hazard ratio, despite the presence of competing risks including kidney transplantation and losses to follow-up. These classical survival analyses have been shown to be inappropriate in the presence of competing risks, yielding the potential for biases [22]. To overcome these limitations, we used competing risks analysis and confirmed that the inverse association of serum bilirubin and ASCVD-related mortality was robust.…”

“…Total bilirubin levels and the bilirubin-associated UGT1A SNPs tended to be associated with all-cause mortality in patients with type 2 diabetes without kidney disease [25]. Furthermore, the above Taiwanese cohort study of hemodialysis patients showed that UGT1A1 gene polymorphism had strong effects on serum bilirubin levels and also influenced the incidence of ASCVD and all-cause mortality [22]. These clinical studies strongly implicate lower levels of bilirubin in the pathogenesis of ACSCVDs through increased oxidant properties.…”

“…A previous cohort study from Taiwan first identified lower bilirubin levels as a risk factor for incident ASCVD-related and all-cause mortality in dialysis patients with non-specific underlying kidney diseases [22]. Our study restricting to patients with diabetes yielded the consistent results; however, the previous study used conventional Kaplan-Meier survival analysis and Cox proportional hazard model for estimating the event-free survival and hazard ratio, despite the presence of competing risks including kidney transplantation and losses to follow-up.…”