Association between the UGT1A1 TA-Repeat Polymorphism and Bilirubin Concentration in Patients with Intermittent Claudication: Results from the CAVASIC Study

Abstract

Background: Bilirubin has antioxidative and cytoprotective properties. Low plasma concentrations of bilirubin are reportedly associated with the development of coronary and cerebrovascular disease, and bilirubin concentrations are strongly correlated with the enzyme activity of the hepatic uridine diphosphate glucuronosyltransferase (UGT1A1). The activity of UGT1A1 is influenced by a TA-repeat polymorphism in the promoter of the UGT1A1 gene (UDP glucuronosyltransferase 1 family, polypeptide A1). In a case-control study, we investigated the association between the UGT1A1 polymorphism, bilirubin concentration, and intermittent claudication. Methods: We included 255 consecutive male patients presenting with intermittent claudication in the investigation and matched the patients by age and diabetes mellitus with 255 control individuals. Results: Plasma bilirubin concentrations were significantly lower in patients than in controls [mean (SD), 12.5 (5.3) μmol/L vs 15.4 (7.9) μmol/L; P < 0.001]. We found a clear association between the number of TA repeats and plasma bilirubin concentration. Considering the 6/6 TA-repeat genotype as the wild type, we observed a slight increase in bilirubin concentration individuals with the heterozygous 6/7 genotype and pronounced increases for those with the homozygous 7/7 genotype. This association occurred in both controls and patients; however, patients and controls were not significantly different with respect to UGT1A1 TA-repeat genotype frequencies. Conclusions: Our study of a well-phenotyped group of patients with intermittent claudication and control individuals revealed a clear association between low bilirubin concentrations and peripheral arterial disease but no association between the UGT1A1 polymorphism and the disease.

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

“…The largest of these studies analysed 7,075 individuals from the National Health and Nutrition Examination Survey, and reported that increased bilirubin levels were associated with a reduced prevalence of PAD [19]. However, hard clinical endpoints were not explored in that and other similar smaller case-control studies [17][18][19][20]. Our study therefore for the first time extends these findings to amputation events.…”

“…Consistent with this notion, case-control studies have reported that individuals with elevated bilirubin levels caused by Gilbert's syndrome have a decreased incidence of atherosclerotic disease compared with normal controls [12,14]. Also, previous studies reported an inverse relationship between bilirubin levels and PAD prevalence [17][18][19][20]. However, the association between bilirubin and the hard clinical endpoint of amputation events has not been reported, to our knowledge.…”

“…Subsequently, a prospective study involving 1,780 individuals from the Framingham Heart Study Offspring cohort found that UGT1A1 polymorphism resulting in higher bilirubin levels was associated with lower risk of cardiovascular events [36]. Again, however, some other smaller studies have failed to show the same association between UGT1A1 polymorphism and CVD [18,34,47]. It is possible that these smaller studies lack the statistical power to detect this association.…”

“…Age ≥65 years 162 (37) 1360 (41) 744 (43) 187 (44) 118 (45) 0.019 205 (32) 925 (39) 185 (39) 40 (38) 27 ( (24) 770 (23) 305 (18) 67 (16) 38 (14) 0.000 229 (36) 901 (38) 156 (33) 21 (20) 11 (21) 0.001 Smoker 96 (22) 383 (12) 120 (7) 29 (7) 10 (4) 0.000 69 (11) 184 (8) 28 (6) 3 ( 1514 (46) 727 (42) 156 (36) 93 (35) 0.000…”

The Fate of Patients with Intermittent Claudication in the 21st Century Revisited – Results from the CAVASIC Study

“…The CAVASIC (CArdioVAScular disease in Intermittent Claudication) Study is a case-control study with a prospective follow-up investigation of patients to identify cardiovascular risk factors in male patients with intermittent claudication [8][9][10] Inclusion criterion for patients (n = 256) was a history of intermittent claudication (PAD IIa or IIb according to the criteria of Fontaine) irrespective of any former treatment procedure (bypass surgery or intervention). Patients who presented with acute or critical limb ischemia (Fontaine III or IV), impaired kidney function with serum creatinine > 1.5 mg/dL, malignancy, previous organ transplantation, and therapy with nicotinic acid or corticosteroids were excluded from the study.…”