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Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study.

Publication ,  Journal Article
Sebastiani, P; Solovieff, N; Hartley, SW; Milton, JN; Riva, A; Dworkis, DA; Melista, E; Klings, ES; Garrett, ME; Telen, MJ; Ashley-Koch, A ...
Published in: Am J Hematol
January 2010

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.

Duke Scholars

Published In

Am J Hematol

DOI

EISSN

1096-8652

Publication Date

January 2010

Volume

85

Issue

1

Start / End Page

29 / 35

Location

United States

Related Subject Headings

  • Young Adult
  • Tankyrases
  • Severity of Illness Index
  • Potassium Channels, Tandem Pore Domain
  • Polymorphism, Single Nucleotide
  • Phenotype
  • Middle Aged
  • MAP Kinase Kinase Kinases
  • Immunology
  • Humans
 

Citation

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Sebastiani, P., Solovieff, N., Hartley, S. W., Milton, J. N., Riva, A., Dworkis, D. A., … Steinberg, M. H. (2010). Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study. Am J Hematol, 85(1), 29–35. https://doi.org/10.1002/ajh.21572
Sebastiani, Paola, Nadia Solovieff, Stephen W. Hartley, Jacqueline N. Milton, Alberto Riva, Daniel A. Dworkis, Efthymia Melista, et al. “Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study.Am J Hematol 85, no. 1 (January 2010): 29–35. https://doi.org/10.1002/ajh.21572.
Sebastiani P, Solovieff N, Hartley SW, Milton JN, Riva A, Dworkis DA, et al. Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study. Am J Hematol. 2010 Jan;85(1):29–35.
Sebastiani, Paola, et al. “Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study.Am J Hematol, vol. 85, no. 1, Jan. 2010, pp. 29–35. Pubmed, doi:10.1002/ajh.21572.
Sebastiani P, Solovieff N, Hartley SW, Milton JN, Riva A, Dworkis DA, Melista E, Klings ES, Garrett ME, Telen MJ, Ashley-Koch A, Baldwin CT, Steinberg MH. Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study. Am J Hematol. 2010 Jan;85(1):29–35.
Journal cover image

Published In

Am J Hematol

DOI

EISSN

1096-8652

Publication Date

January 2010

Volume

85

Issue

1

Start / End Page

29 / 35

Location

United States

Related Subject Headings

  • Young Adult
  • Tankyrases
  • Severity of Illness Index
  • Potassium Channels, Tandem Pore Domain
  • Polymorphism, Single Nucleotide
  • Phenotype
  • Middle Aged
  • MAP Kinase Kinase Kinases
  • Immunology
  • Humans