Common variants in the SLCO1B3 locus are associated with bilirubin levels and unconjugated hyperbilirubinemia

Abstract

Bilirubin, resulting largely from the turnover of hemoglobin, is found in the plasma in two main forms: unconjugated or conjugated with glucuronic acid. Unconjugated bilirubin is transported into hepatocytes. There, it is glucuronidated by UGT1A1 and secreted into the bile canaliculi. We report a genome wide association scan in 4300 Sardinian individuals for total serum bilirubin levels. In addition to the two known loci previously involved in the regulation of bilirubin levels, UGT1A1 (P = 6.2 x 10(-62)) and G6PD (P = 2.5 x 10(-8)), we observed a strong association on chromosome 12 within the SLCO1B3 gene (P = 3.9 x 10(-9)). Our findings were replicated in an independent sample of 1860 Sardinians and in 832 subjects from the Old Order Amish (combined P < 5 x 10(-14)). We also show that SLC01B3 variants contribute to idiopathic mild unconjugated hyperbilirubinemia. Thus, SLC01B3 appears to be involved in the regulation of serum bilirubin levels in healthy individuals and in some bilirubin-related disorders that are only partially explained by other known gene variants.

Figure 1.

Genome-wide scan of serum total bilirubin. The figure summarizes association P-values (additive test) for all SNPs that passed quality control tests (N = 362,129). Position of UGT1A, SLCO1B3 and G6PD genes are annotated. Red dotted line marks Bonferroni threshold (1.3 × 10⁻⁷).

Figure 2.

Evidence of (A) association with serum total bilirubin and (B) linkage disequilibrium around the SLCO1B3 locus. (A) All SNPs in the SLCO1B3 region (700 Kb) are plotted with association P-values (additive test) compared with physical position. Genomic position and gene annotations refer NCBI Build 36 map. SNPs are colored according to their linkage disequilibrium with the top variant (rs17680137). Blue line represents the recombination rate (in cM/Mb). Black diamonds represent combined P-values from SardiNIA and SardiNIA stage 2 cohorts. (B) Patterns of linkage disequilibrium (r²) for the CEU HapMap population (Utah residents with European ancestry (16)) are plotted and colored as indicated in the palette.