The HBS1L-MYB intergenic region on chromosome 6q23.3 influences erythrocyte, platelet, and monocyte counts in humans

Abstract

IntroductionHematologic variables that are routinely measured for clinical purposes are influenced by the individual genetic constitution of the patients 1,2 : in an ethnically homogenous population, we found that 62% of the variance in white blood cell counts, 57% of that in platelet counts, and 42% of the red cell count variance were due to genetic factors. 3 The identification of the underlying genes and sequence variants will not only help to explain the variability seen between patients, but should advance our understanding of hematopoiesis in human health and disease.HMIP (HBS1L-MYB intergenic polymorphism) refers to an array of single-nucleotide polymorphisms (SNPs) situated in the interval between the gene for HBS1L (a G-protein/elongation factor) and the MYB oncogene, on chromosome 6q23.3. The physiological significance of this sequence variability was recently discovered through the investigation of persistent fetal hemoglobin synthesis in adults 4 : HMIP SNPs exist in 3 linkage disequilibrium (LD) blocks, HMIP-1, HMIP-2, and HMIP-3, and the genotype at each block influences the number of F cells and fetal hemoglobin (HbF) levels. 4 Strong LD between the SNPS within blocks permits the selection of a single tag SNP for each block: rs52090901 for HMIP-1, rs9399137 for HMIP-2, and rs6929404 for HMIP-3. The HMIP locus accounts for approximately 17% of the variation in F-cell numbers, with most of the effect contributed by the 22-kb haplotype block 2 (HMIP-2). HMIP-2 has 2 common haplotypes, designated haplotype 1 and haplotype 2. Haplotype 2, with a frequency of 0.2 to 0.25, is associated with raised F-cell levels in white Europeans. Initial functional studies have provided evidence that the locus acts through the regulation of the flanking genes, HBS1L and MYB. 4 The sequence between these genes 5 and the MYB gene product itself [6][7][8] have been shown to affect proliferation, survival, and differentiation of hematopoietic progenitor cells as well as peripheral blood cell counts in animal studies. We therefore investigated the influence of HMIP genotypes on hematologic indices in a healthy human population. Patients and methodsOne thousand seven hundred ninety-four participants of North European ancestry including 740 same-sex dizygotic twin pairs, 114 monozygotic twin pairs, and 86 singletons from the St Thomas' Hospital Twin Register 9 were studied. HMIP genotypes and full blood counts were available for all participants, and additional differential blood count data for 1420 of them. Due to the recruitment strategy of the Twin Register, most individuals (95%) were female.

Beta-thalassemia: from genotype to phenotype

“…9 In the present issue of Haematologica, the same group found that the JAK2 46/1 haplotype is associated with an increased frequency of acute myelomonocytic leukemia and a tendency to reduced survival because of death from infection in patients with NK-AML. 10 The latter findings need confirmation by other studies, for it is of great interest to establish whether the JAK2 46/1 haplotype is in fact a marker of myelomonocytic dysfunction and subsequently an unfavorable risk factor in NK-AML, as Nahajevszky et al suggest, and/or in other disease categories. 10 In fact, although the majority of studies have failed to detect any association of the 46/1 haplotype with hematologic and clinical parameters (Table 1), Tefferi et al found that the 46/1 haplotype status influenced survival in primary myelofibrosis, and evolution toward myelofibrosis in polycythemia vera.…”

“…10 The latter findings need confirmation by other studies, for it is of great interest to establish whether the JAK2 46/1 haplotype is in fact a marker of myelomonocytic dysfunction and subsequently an unfavorable risk factor in NK-AML, as Nahajevszky et al suggest, and/or in other disease categories. 10 In fact, although the majority of studies have failed to detect any association of the 46/1 haplotype with hematologic and clinical parameters (Table 1), Tefferi et al found that the 46/1 haplotype status influenced survival in primary myelofibrosis, and evolution toward myelofibrosis in polycythemia vera. 5 Moreover, it has been reported that the frequency of the JAK2 46/1 haplotype is increased in the context of severe inflammation, for instance Crohn's disease.…”

“…Different polymorphisms at the BCL11A gene on 2p16.1 8 and HBS1L-MYB intergenic region on 6q23.3 have been described. 9,10 Several polymorphisms within intron 2 of the BCL11A gene have been strongly associated with Hb F levels: rs766432, rs4671393, rs1427407 and rs11886868, all in high linkage disequilibrium (LD) with each other. [11][12][13][14][15] Other independent signals in the same area were also identified with rs10189857 and rs7599488, in high LD, as well as rs7606173 and rs6706648, 13 also in high LD with each other.…”

“…12,13 In the HBS1L-MYB intergenic region, different SNPs have been described as being associated with Hb F variations in different studies: rs9399137, as well as rs4895441, rs9402686 and rs28384513. 10,12 However, evidence has been reported of other contributing loci that have not been validated in recent genome-wide association studies, such as the 8q26-28 and Xp22.2-22.3 loci. 16,17 Together with these discoveries, the interest for prediction of Hb F levels and b-thalassemia phenotype has naturally grown in recent years, and the three loci previously mentioned have now been reported to be responsible for 20 to 50% of the Hb F trait variance in patients with bthalassemia or sickle cell disease, and in healthy Europeans.…”

Fetal hemoglobin chemical inducers for treatment of hemoglobinopathies

“…Studies on erythroid progenitors in vitro have clearly shown that only HBS1L expression correlates with high F-cell alleles [36]. It is of interest to note that the HBS1L-MYB intergenic region on chromosome 6q23.3 influences not only F-cell frequency but also a series of hematological parameters, including erythrocyte, platelet, and monocyte counts in humans [37].…”