A genome scan for loci influencing anti-atherogenic serum bilirubin levels

Abstract

Epidemiological studies have shown an association of decreased serum bilirubin levels with coronary artery disease. Two segregation analyses in large pedigrees have suggested a major gene responsible for high bilirubin levels occurring in about 12% of the population. Based on a recessive model from a previous segregation analysis, we performed a genome scan using 587 markers genotyped in 862 individuals from 48 Utah pedigrees to detect loci linked to high bilirubin levels. As a complementary approach, non-parametric linkage (NPL) analysis was performed. These two methods identified four regions showing evidence for linkage. The first region is on chromosome 2q34 -37 with multipoint LOD and NPL scores of 3.01 and 3.22, respectively, for marker D2S1363. This region contains a previously described gene, uridine diphosphate glycosyltransferase 1, which has been associated with high bilirubin levels. A polymorphism in the promoter of this gene was recently shown to be responsible for Gilbert syndrome which is associated with mild hyperbilirubinemia. The other regions were found on chromosomes 9q21, 10q25 -26, and 18q12 with maximum NPL scores of 2.39, 1.55, and 2.79, respectively. Furthermore, we investigated in these pedigrees the association between bilirubin levels and coronary artery disease. One-hundred and sixty-one male and 41 female subjects had already suffered a coronary artery disease event. Male patients showed significantly lower bilirubin concentrations than age-matched controls. This association, however, was not observed in females. These results provide evidence that loci influencing bilirubin variation exist on chromosomes 2q34 -37, 9q21, 10q25 -26, and 18q12 and confirms the association of low bilirubin levels with coronary artery disease in males.

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

“…Previous studies suggest that the TA repeats might be the key polymorphism within the UGT1A1 gene controlling bilirubin levels in people free of kidney failure (16,17). In the study presented here, for the first time, we demonstrated that UGT1A1*28 polymorphism may modify serum bilirubin levels and associate with CV events and mortality among patients undergoing chronic HD.…”

“…Recent independent genome-wide linkage scans have identified a major locus in the chromosomal 2q telomere controlling serum bilirubin concentrations (16,17). The identified chromosomal region harbors the uridine diphosphate-glucuronosyltransferase (UGT1A1) gene.…”

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

“…By linkage analysis we recently identified a region on chromosome 2q significantly linked to bilirubin concentration (17 ), a finding that was subsequently confirmed by investigators for the Framingham Heart Study (18 ). The identified chromosomal region harbors the gene for the uridine diphosphate glucuronosyltransferase (UGT1A1, 6 UDP glucuronosyltransferase 1 family, polypeptide A1), the major enzyme of bilirubin glucuronidation, which mainly determines bilirubin elimination in humans.…”

Association Between the UGT1A1*28 Allele, Bilirubin Levels, and Coronary Heart Disease in the Framingham Heart Study

“…[11][12][13] Previous linkage studies identified a major locus at the chromosome 2q telomere that affects bilirubin concentrations. 14,15 These 2 studies revealed a logarithm of the odds score of 3.8 and 3.2, respectively, spanning a region of 22 centimorgans (logarithm of the odds-1 supporting interval). One obvious candidate gene under the linkage peak is the gene that encodes hepatic bilirubin uridine diphosphateglucuronosyltransferase (UGT1A1), which is the only enzyme that contributes substantially to bilirubin glucuronidation and thus enhances bilirubin elimination.…”