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A genome-wide association study of total Bilirubin and Cholelithiasis risk in sickle cell anemia

Milton, JN and Sebastiani, P and Solovieff, N and Hartley, SW and Bhatnagar, P and Arking, DE and Dworkis, DA and Casella, JF and Barron-Casella, E and Bean, CJ and Hooper, WC and DeBaun, MR and Garrett, ME and Soldano, K and Telen, MJ and Ashley-Koch, A and Gladwin, MT and Baldwin, CT and Steinberg, MH and Klings, ES (2012) A genome-wide association study of total Bilirubin and Cholelithiasis risk in sickle cell anemia. PLoS ONE, 7 (4).

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Abstract

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 <5×10-8). SNPs in UGT1A1, UGT1A3, UGT1A6, UGT1A8 and UGT1A10, different isoforms within the UGT1A locus, were identified (most significant rs887829, p = 9.08×10-25). 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 1.15×10-4). 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. © 2012 Milton et al.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Milton, JN
Sebastiani, P
Solovieff, N
Hartley, SW
Bhatnagar, P
Arking, DE
Dworkis, DA
Casella, JF
Barron-Casella, E
Bean, CJ
Hooper, WC
DeBaun, MR
Garrett, ME
Soldano, K
Telen, MJ
Ashley-Koch, A
Gladwin, MT
Baldwin, CT
Steinberg, MH
Klings, ES
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorArez, Ana PaulaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 27 April 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 4
DOI or Unique Handle: 10.1371/journal.pone.0034741
Schools and Programs: School of Medicine > Critical Care Medicine
Refereed: Yes
MeSH Headings: African Americans--genetics; Anemia, Sickle Cell--blood; Anemia, Sickle Cell--complications; Anemia, Sickle Cell--genetics; Bilirubin--blood; Bilirubin--genetics; Cholelithiasis--blood; Cholelithiasis--etiology; Cohort Studies; Genome-Wide Association Study; Genotype; Glucuronosyltransferase--genetics; Humans; Inheritance Patterns--genetics; Isoenzymes--genetics; Polymorphism, Single Nucleotide--genetics; Principal Component Analysis; Risk Factors
Other ID: NLM PMC3338756
PubMed Central ID: PMC3338756
PubMed ID: 22558097
Date Deposited: 24 Sep 2012 20:06
Last Modified: 22 Jun 2021 13:56
URI: http://d-scholarship.pitt.edu/id/eprint/14179

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