The genetics of hemoglobin A2 regulation in sickle cell anemia

Hemoglobin A(2), a tetramer of - and -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 -globin gene expression and fetal hemoglobin (HbF) levels. The association of polymorphisms downstream of the -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 -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. (c) 2014 Wiley Periodicals, Inc.