Acute chest syndrome is associated with single nucleotide polymorphism‐defined beta globin cluster haplotype in children with sickle cell anaemia

Abstract

Summary 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 βS-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 βS-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 βS-haplotypes may be associated with ACS, but not pain or SCI in a study population of children with SCA.

Beta-Globin Gene Haplotypes Among Cameroonians and Review of the Global Distribution: Is There a Case for a Single Sickle Mutation Origin in Africa?

“…1). Contrary to our findings, a recent report argues that the S haplotype itself (beyond HbF regulation) correlates with disease severity (Bean et al, 2013).…”

Children with HbSβ0 thalassemia have higher hemoglobin levels and lower incidence rate of acute chest syndrome compared to children with HbSS

“…Not all of the original SIT cohort had genotypic analyses done due to limited genotyping service availability, as samples were shipped to an outside laboratory at the time of the trial. A total of 893 had alpha‐ and beta‐globin genotyping done as part of the SIT trial . However, due to missing laboratory and clinical data, 808 samples were available for analysis for this manuscript.…”

The intersection between asthma and acute chest syndrome in children with sickle-cell anaemia

“…9–13 Other clinical risk factors include baseline higher haemoglobin concentration and white blood cell count and lower haemoglobin F concentration. 6 Genetic variation in multiple loci has been associated with the incidence of acute chest syndrome; they include the beta-globin gene cluster haplotype, 14 a (GT)(n) dinucleotide repeat located in the promoter region of HMOX1 (protein HO-1), 15 a single nucleotide roughly 8 kilobases upstream of COMMD7 , 16 and plasma concentrations of HO-1. 17 However, neither laboratory findings nor genetic risk factors are sufficient to stratify children into groups of high or low risk for future acute chest syndrome episodes.…”