title: Acute chest syndrome is associated with single nucleotide polymorphism-defined beta globin cluster haplotype in children with sickle cell anaemia.
abstract: Genetic diversity at the human β-globin locus has been implicated as a modifier of sickle cell anaemia (SCA) severity. However, haplotypes defined by restriction fragment length polymorphism sites across the β-globin locus have not been consistently associated with clinical phenotypes. To define the genetic structure at the β-globin locus more thoroughly, we performed high-density single nucleotide polymorphism (SNP) mapping in 820 children who were homozygous for the sickle cell mutation (HbSS). Genotyping results revealed very high linkage disequilibrium across a large region spanning the locus control region and the HBB (β-globin gene) cluster. We identified three predominant haplotypes accounting for 96% of the β(S) -carrying chromosomes in this population that could be distinguished using a minimal set of common SNPs. Consistent with previous studies, fetal haemoglobin level was significantly associated with β(S) -haplotypes. After controlling for covariates, an association was detected between haplotype and rate of hospitalization for acute chest syndrome (ACS) (incidence rate ratio 0·51, 95% confidence interval 0·29-0·89) but not incidence rate of vaso-occlusive pain or presence of silent cerebral infarct (SCI). Our results suggest that these SNP-defined β(S) -haplotypes may be associated with ACS, but not pain or SCI in a study population of children with SCA.
authors: Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors: Christopher J
authors: CJ
authors: Bean
authors: Sheree L
authors: SL
authors: Boulet
authors: Genyan
authors: G
authors: Yang
authors: Amanda B
authors: AB
authors: Payne
authors: Nafisa
authors: N
authors: Ghaji
authors: Meredith E
authors: ME
authors: Pyle
authors: W Craig
authors: WC
authors: Hooper
authors: Pallav
authors: P
authors: Bhatnagar
authors: Jeffrey
authors: J
authors: Keefer
authors: Emily A
authors: EA
authors: Barron-Casella
authors: James F
authors: JF
authors: Casella
authors: Michael R
authors: MR
authors: Debaun
mesh_terms: D056586:Acute Chest Syndrome / Q000209:etiology*; D000293:Adolescent; D000483:Alleles; D000755:Anemia, Sickle Cell / Q000150:complications* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D005810:Multigene Family; D010343:Patient Admission / Q000706:statistics & numerical data; D020641:Polymorphism, Single Nucleotide; D055544:beta-Globins / Q000235:genetics*
chemical_list: D055544:beta-Globins; D005319:Fetal Hemoglobin
keywords: acute chest syndrome; genetic analysis; haplotype; sickle cell anaemia; β-globin
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