A genome-wide search for non-UGT1A1 markers associated with unconjugated bilirubin level reveals significant association with a polymorphic marker near a gene of the nucleoporin family

Variants in the UGT1A1 gene and its promoter are known to determine levels of unconjugated bilirubin (UCB), but do not explain all cases of unconjugated hyperbilirubinemia. To discover associations with variants in genes other than UGT1A1, we undertook a genome-wide association study. We recruited 200 participants to cover the entire range of quantitative variation in UCB level. The data set -- after data curation, including analyses for population stratification and cryptic relatedness -- comprised genotypes at 512,349 SNP loci on 182 individuals. Quantitative trait locus (QTL) association analyses were performed, after adjusting the UCB level for effects of age, gender, and genotype at the dinucleotide (TA) insertion locus in UGT1A1 that is known to significantly modulate UCB level. A significant association of a polymorphic marker (rs2328136) near the NUP153 gene (which produces a 153 kDa nucleoporin) was obtained (p = 0.002, after multiple-testing correction). The frequency of the variant allele (A) at the rs2328136 locus in our study population is 40%, higher than most global populations. NUP153, whose product is a major regulatory factor in bidirectional transport of biomolecules across nucleus to cytosol, is associated with the transport of biliverdin reductase, which is important for bilirubin conjugation.