A Genome-Wide Association Study of Total Bilirubin and Cholelithiasis Risk in Sickle Cell Anemia

作者:Milton Jacqueline N*; Sebastiani Paola; Solovieff Nadia; Hartley Stephen W; Bhatnagar Pallav; Arking Dan E; Dworkis Daniel A; Casella James F; Barron Casella Emily; Bean Christopher J; Hooper W Craig; DeBaun Michael R; Garrett Melanie E; Soldano Karen; Telen Marilyn J; Ashley Koch Allison; Gladwin Mark T; Baldwin Clinton T; Steinberg Martin H; Klings Elizabeth S
来源:PLos One, 2012, 7(4): e34741.
DOI:10.1371/journal.pone.0034741

摘要

Serum bilirubin levels have been associated with polymorphisms in the UGT1A1 promoter in normal populations and in patients with hemolytic anemias, including sickle cell anemia. When hemolysis occurs circulating heme increases, leading to elevated bilirubin levels and an increased incidence of cholelithiasis. We performed the first genome-wide association study (GWAS) of bilirubin levels and cholelithiasis risk in a discovery cohort of 1,117 sickle cell anemia patients. We found 15 single nucleotide polymorphisms (SNPs) associated with total bilirubin levels at the genome-wide significance level (p value <5x10(-8)). SNPs in UGT1A1, UGT1A3, UGT1A6, UGT1A8 and UGT1A10, different isoforms within the UGT1A locus, were identified (most significant rs887829, p = 9.08x10(-25)). All of these associations were validated in 4 independent sets of sickle cell anemia patients. We tested the association of the 15 SNPs with cholelithiasis in the discovery cohort and found a significant association (most significant p value 1.15x10(-4)). These results confirm that the UGT1A region is the major regulator of bilirubin metabolism in African Americans with sickle cell anemia, similar to what is observed in other ethnicities.

  • 出版日期2012-4-27

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