Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Br J Haematol. 2013 Oct;163(2):268-76. doi: 10.1111/bjh.12507. Epub 2013 Aug 16.
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.
人类β-球蛋白基因座的遗传多样性已被认为是镰状细胞贫血（SCA）严重程度的修饰因子。然而，横跨β-球蛋白基因座的限制片段长度多态性位点定义的单倍型与临床表型并不一致。为了更彻底地定义β-球蛋白基因座的遗传结构，我们对 820 名纯合镰状突变（HbSS）的儿童进行了高密度单核苷酸多态性（SNP）图谱分析。基因分型结果显示，在跨越基因调控区和 HBB（β-珠蛋白基因）簇的大片段上存在非常高的连锁不平衡。我们确定了三个主要的单倍型，占该人群中携带β（S）染色体的 96%，可以使用一组常见的 SNP 来区分。与之前的研究一致，胎儿血红蛋白水平与β（S）-单倍型显著相关。在控制协变量后，单倍型与急性胸部综合征（ACS）住院率之间存在关联（发病率比 0.51，95%置信区间 0.29-0.89），但与血管阻塞性疼痛的发生率或无症状性脑梗死（SCI）的存在无关。我们的研究结果表明，在 SCA 儿童的研究人群中，这些 SNP 定义的β（S）-单倍型可能与 ACS 相关，但与疼痛或 SCI 无关。
