Bilirubin, Serum Level Of, Quantitative Trait Locus 1

A number sign (#) is used with this entry because the serum level of bilirubin as a quantitative trait is associated with variation in the UGT1A1 gene (191740).

Mapping

Schwertner et al. (1994) reported an association of low serum bilirubin concentration and increased risk of coronary artery disease (CAD). Hopkins et al. (1996) showed that higher total serum bilirubin values have a protective effect on CAD comparable to that of HDL cholesterol. In a study of 1,240 adults in 24 Utah pedigrees, Hunt et al. (1996) used modeling by bivariant maximum-likelihood segregation analysis of serum bilirubin levels obtained from 2 clinic visits to determine whether there was statistical evidence for a major gene explaining the reported inverse relationship between serum bilirubin levels and coronary heart disease (CHD). Their data indicated that a major gene was responsible for elevated levels of bilirubin in 11.5% of persons analyzed.

Because there is an inverse relationship between serum bilirubin concentrations and the risk of coronary artery disease, Lin et al. (2003) carried out a genomewide scan in a Framingham Heart Study. Their study sample consisted of 330 with 1,394 sib pairs, 681 cousin pairs, and 89 avuncular pairs. Using variance-component methods, the heritability was estimated to be 49% +/- 6%, and the genome scan demonstrated significant evidence of linkage of serum bilirubin to chromosome 2q with a lod score of 3.8 at location 243 cM. The peak multipoint lod score is located 1 cM away from the UGT1A1 gene. Lin et al. (2003) concluded that their findings suggest that UGT1A1 may be a major gene controlling serum bilirubin levels in the population.

Johnson et al. (2009) combined results from 3 genomewide association studies (Framingham Heart Study, Rotterdam Study, and AGES-Reykjavik) to assess genetic factors affecting serum bilirubin levels in 9,464 individuals. Metaanalysis showed strong replication of a genetic influence at the UGT1A1 locus for a G-T transversion in intron 1 (rs6742078, 191740.0025; combined p value less than 5.0 x 10(-324)). In a subset of 490 individuals with UGT1A1*28 (191740.0011) and rs6742078 genotypes available, they found the markers to be in high linkage disequilibrium, suggesting the signal may be attributed to the UGT1A1*28 polymorphism. Johnson et al. (2009) stated that rs6742078 in the UGT1A1 gene explained approximately 18% of the variation in total serum bilirubin levels.

In a population-based study examining serum total bilirubin in 3 Asian groups from Xinjiang, China, including 502 Kazakh herdsmen, 769 Uygur farmers, and 789 Han farmers, Lin et al. (2009) found a significant association with 2 polymorphisms in the UGT1A1 gene: the TA(n) repeat polymorphism (191740.0011) and rs4148323 (191740.0016) (p = 2.05 x 10(-26) and p = 5.21 x 10(-16) respectively). The TA(7) allele and the A allele of rs4148323 were independently associated with increased total bilirubin levels. Combined, these SNPs could explain between 3.9 to 9.8% of the variance in these populations. However, there were differences in total bilirubin levels between the populations, suggesting that other factors must be involved.

Genetic Heterogeneity

In the metaanalysis of 9,464 individuals from 3 genomewide association studies, Johnson et al. (2009) identified significant association for a nonsynonymous SNP (rs4149056; combined p = 6.7 x 10(-13)) in the exon 6 of the SLCO1B1 gene (604843) on chromosome 12p12.2. The T-C transition resulted in a val174-to-ala (V174A) substitution. Under conditional analysis for the rs6742078 UGT1A1 SNP, the SLCO1B1 rs4149056 showed similar genomewide significance. Johnson et al. (2009) stated that rs4149056 in the SLCO1B1 gene explained approximately 1% of the variation in total serum bilirubin levels.

Sanna et al. (2009) reported a genomewide association scan in 4,300 Sardinian individuals for total serum bilirubin levels. The authors reported a strong association for rs17680137 in intron 7 of the SLCO1B3 gene (605495) on chromosome 12p12.2 (p = 3.9 x 10(-9)). The findings were replicated in an independent sample of 1,860 Sardinians and in 832 subjects from the Old Order Amish community of Lancaster, Pennsylvania (combined p less than 5.0 x 10(-14)). Sanna et al. (2009) noted that the SLCO1B3 SNP rs17680137 also contributed to idiopathic mild unconjugated hyperbilirubinemia.

Lin et al. (2009) performed a population-based study examining polymorphisms that could potentially affect serum bilirubin in 3 Asian groups, including 502 Kazakh herdsmen, 769 Uygur farmers, and 789 Han farmers. Significant associations across all 3 populations were not found for polymorphisms in the BLVRA (109750), SLCO1B1, or HMOX1 (141250) genes, although there was some suggestion of an association with the HMOX1 gene in the Uygur population only.