The genetics of hemoglobin A 2 regulation in sickle cell anemia

Hemoglobin A 2 , a tetramer of α‐ and δ‐globin chains, comprises less than 3% of total hemoglobin in normal adults. In northern Europeans, single nucleotide polymorphisms (SNPs) in the HBS1L‐MYB locus on chromosome 6q and the HBB cluster on chromosome 11p were associated with HbA 2 levels . We examined the genetic basis of HbA 2 variability in sickle cell anemia using genome‐wide association studies. HbA 2 levels were associated with SNPs in the HBS1L‐MYB interval and SNPs in BCL11A . These effects are mediated by the association of these loci with γ‐globin gene expression and fetal hemoglobin (HbF) levels. The association of polymorphisms downstream of the β‐globin gene ( HBB ) cluster on chromosome 11 with HbA 2 was not mediated by HbF. In sickle cell anemia, levels of HbA 2 appear to be modulated by trans‐acting genes that affect HBG expression and perhaps also elements within the β‐globin gene cluster. HbA 2 is expressed pancellularly and can inhibit HbS polymerization. It remains to be seen if genetic regulators of HbA 2 can be exploited for therapeutic purposes. Am. J. Hematol. 89:1019–1023, 2014. © 2014 Wiley Periodicals, Inc.