Document Detail

Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study.
MedLine Citation:
PMID:  20029952     Owner:  NLM     Status:  MEDLINE    
We conducted a genome-wide association study (GWAS) to discover single nucleotide polymorphisms (SNPs) associated with the severity of sickle cell anemia in 1,265 patients with either "severe" or "mild" disease based on a network model of disease severity. We analyzed data using single SNP analysis and a novel SNP set enrichment analysis (SSEA) developed to discover clusters of associated SNPs. Single SNP analysis discovered 40 SNPs that were strongly associated with sickle cell severity (odds for association >1,000); of the 32 that we could analyze in an independent set of 163 patients, five replicated, eight showed consistent effects although failed to reach statistical significance, whereas 19 did not show any convincing association. Among the replicated associations are SNPs in KCNK6 a K(+) channel gene. SSEA identified 27 genes with a strong enrichment of significant SNPs (P < 10(-6)); 20 were replicated with varying degrees of confidence. Among the novel findings identified by SSEA is the telomere length regulator gene TNKS. These studies are the first to use GWAS to understand the genetic diversity that accounts the phenotypic heterogeneity sickle cell anemia as estimated by an integrated model of severity. Additional validation, resequencing, and functional studies to understand the biology and reveal mechanisms by which candidate genes might have their effects are the future goals of this work.
Paola Sebastiani; Nadia Solovieff; Stephen W Hartley; Jacqueline N Milton; Alberto Riva; Daniel A Dworkis; Efthymia Melista; Elizabeth S Klings; Melanie E Garrett; Marilyn J Telen; Allison Ashley-Koch; Clinton T Baldwin; Martin H Steinberg
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  American journal of hematology     Volume:  85     ISSN:  1096-8652     ISO Abbreviation:  Am. J. Hematol.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2009-12-28     Completed Date:  2010-01-13     Revised Date:  2013-12-05    
Medline Journal Info:
Nlm Unique ID:  7610369     Medline TA:  Am J Hematol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  29-35     Citation Subset:  IM    
Copyright Information:
(c) 2009 Wiley-Liss, Inc.
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MeSH Terms
Anemia, Sickle Cell / complications*,  genetics*,  physiopathology
Complement C8 / genetics
Computational Biology
Genome-Wide Association Study
MAP Kinase Kinase Kinases / genetics
Middle Aged
Polymorphism, Single Nucleotide*
Potassium Channels, Tandem Pore Domain / genetics
Severity of Illness Index
Tankyrases / genetics
Young Adult
Grant Support
R01 HL 068970/HL/NHLBI NIH HHS; R01 HL068970-09S1/HL/NHLBI NIH HHS; R01 HL068970-09S2/HL/NHLBI NIH HHS; R01 HL087681-03/HL/NHLBI NIH HHS; R01 HL87681/HL/NHLBI NIH HHS; T32 GM074905/GM/NIGMS NIH HHS
Reg. No./Substance:
0/Complement C8; 0/KCNK6 protein, human; 0/Potassium Channels, Tandem Pore Domain; EC; EC protein, human; EC Kinase Kinase Kinases; EC protein, human

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