ORPHA: 251380, 46532;
Cytogenetic location: 6q22.3-q23.1 Genomic coordinates (GRCh38): 6:118,100,001-130,900,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q22.3-q23.1 | Fetal hemoglobin quantitative trait locus 2 | 142470 | Autosomal dominant | 2 |
Fetal hemoglobin (HbF) levels vary considerably in healthy normal adults. The distribution of HbF and F cells, erythrocytes that contain measurable HbF, in healthy adults is continuous, although most adults have HbF of less than 0.6% of total Hb. Approximately 10 to 15% of individuals have increases of HbF ranging from 0.8% to 5%, a trait often referred to as hereditary persistence of fetal hemoglobin (HPFH), usually distributed unevenly among red cells. When coinherited with beta-thalassemia (see 613985) or sickle cell anemia (603903), HPFH can increase HbF output to levels that are clinically beneficial (Thein et al., 2007).
For a general phenotypic description and a discussion of loci that may affect fetal hemoglobin levels, see HBFQTL1 (141749).
Thein et al. (1994) reported a large family from the state of Gujarat in India in which members had beta-thalassemia and/or hereditary persistence of fetal hemoglobin. The presence of HbF-containing cells segregated as an independent trait from the beta-thalassemia. The proband had homozygous beta-thalassemia, but had a mild phenotype associated with high circulating levels of HbF. He married an unrelated woman with heterozygous beta-thalassemia. Two sons were homozygous for beta-thalassemia, but did not inherit HPFH from the father, as manifest by their severe disease. A detailed examination of the rest of the large kindred showed that many members had increased HbF at 0.8 to 3.4%, and that those heterozygous for beta-thalassemia had HbF levels ranging from 2.5 to 24%. F-cell levels ranged from 5.8 to 26%, consistent with a heterocellular form of HPFH.
Thein et al. (1994) excluded linkage to the beta-globin gene cluster on chromosome 11p in a large Indian family with HPFH. An effect of a major gene was suspected when the effects of genetic modifiers, notably beta-thalassemia on 11p and a polymorphism in the promoter of the gamma-G gene (HBG2; 142250), were accounted for in the analysis. By follow-up of the large Indian kindred reported by Thein et al. (1994), Craig et al. (1996) found linkage to a locus determining fetal hemoglobin production on chromosome 6q22.3-q23.1.
Garner et al. (1998) extended the Asian-Indian kindred studied by Craig et al. (1996) by 57 members, bringing the total studied to 210, and saturated the 6q23 region with 26 additional markers. Linkage analysis showed tight linkage of the quantitative trait locus (QTL) to markers D6S976 (lod score 11.3 at theta = 0.0) and D6S270 (lod score = 7.4 at theta = 0.0). Key recombination events placed the QTL within a 1- to 2-cM interval spanning approximately 1.5 Mb between D6S270 and D6S1626. Furthermore, haplotype analysis led to a reevaluation of the genealogy and to the identification of additional relationships in the kindred.
By genotyping 2 panels of twin pairs of North European origin consisting of 824 and 1,217 individuals, respectively, Thein et al. (2007) found a strong association (combined p values of 10(-50) to 10(-75) for both panels) between fetal Hb levels, and a 24-kb segment on chromosome 6q23 starting 33 kb upstream of HBS1L (612450). The region was termed 'HMIP' for HBS1L-MYB (189990) intergenic polymorphism. These 12 markers showed very strong linkage disequilibrium. The marker with the highest value within this interval was rs9399137 (p = 10(-45)), which is in intron 1a of the HBS1L gene. Two other markers also showed significant values: rs52090901 (p = 10(-5)), located in the 5-prime untranslated region upstream of exon 1a of the HBS1L gene, and rs6929404 (p = 0.0002), which is between exon 1a of HBS1L and the first exon of the MYB gene. Based on haplotype analysis, Thein et al. (2007) estimated that the markers in this region account for 17.6% of the trait variance. The variants associated with high F-cell levels were also strongly correlated with increased expression of HBS1L in cultured erythroid cells.
By analyzing 1,794 European individuals, Menzel et al. (2007) found that haplotype-2 of the HMIP2 block could explain variance of several hematologic traits, including red blood cell count (0.6%), mean corpuscular volume (1.7%), mean corpuscular hemoglobin (2.1%), platelet count (0.6%), and monocyte number (1.6%). The findings suggested that variation at the HMIP locus on 6q23.3 has an impact on other peripheral blood cell indices besides hemoglobin.
In a cohort of 238 Chinese carriers of beta-thalassemia, So et al. (2008) identified 29 SNPs within the HMIP segment on chromosome 6q23 that were mildly associated with HbF levels (p values between 0.003 and 0.039 after multiple testing correction). None of the SNPs identified by Thein et al. (2007) were significantly associated with HbF levels in 93 normal Chinese individuals. So et al. (2008) nevertheless concluded that this intergenic region plays a role in the regulation of fetal hemoglobin expression.
In 2 independent cohorts of patients with sickle cell anemia, Lettre et al. (2008) found a significant association between several SNPs in the HBS1L-MYB interval and HbF levels. The most significant associations among 1,275 African Americans and 350 Brazilians were with rs9399137 (p = 5 x 10(-11)) and rs4895441 (p = 4 x 10(-7)), respectively. The associations with different SNPs in this region were independent of one another, but overall could explain 5% of variance in HbF levels.
To fine map HbF association signals at the BCL11A (606557), HBS1L-MYB, and beta-globin loci (see 141749), Galarneau et al. (2010) resequenced 175.2 kb from these loci in 190 individuals including the HapMap European CEU and Nigerian YRI founders and 70 African Americans with sickle cell anemia. The authors discovered 1,489 sequence variants, including 910 previously unreported variants. Using this information and data from HapMap, Galarneau et al. (2010) selected and genotyped 95 SNPs, including 35 at the HBS1L-MYB locus, in 1,032 African Americans with sickle cell anemia. Single-marker regression analysis identified rs9402686 as more strongly associated with HbF levels than rs9399137, the previous index HbF SNP at this locus (p = 1.9 x 10(-13) for rs9402686; p = 3.5 x 10(-10) for rs9399137).
Pandit et al. (2008) provided evidence suggesting that a 32C-T SNP in the 5-prime untranslated region of the HBS1L gene (rs2297339) may influence HbF. The C allele was associated with increased HbF levels among Thai-Chinese patients with beta-thalassemia, particularly among those who were heterozygous for the HBG2 polymorphism (142250.0028). rs2297339 in HBS1L is predicted to confer a binding site for transcription factor AP4 (600743) and may influence gene expression.
Wahlberg et al. (2009) found 3 sites in the core intergenic HMIP2 block that were hypersensitive to DNase I cleavage, indicative of active chromatin, in erythroid cell lines. Chromatin immunoprecipitation with microarray (ChIP-chip) analysis showed strong histone acetylation in a 65-kb interval encompassing the HMIP2 and HMIP3 blocks in primary human erythroid cells, but not in non-MYB-expressing HeLa cells. Several potential cis-regulatory elements and strong GATA1 (305371) signals were identified in this area. The findings suggested that this region contains distal regulatory sequences that could be important in hematopoiesis by controlling MYB expression.
To establish the identity of the gene at the HBS1L-MYB locus that influences HbF levels, Galarneau et al. (2010) resequenced 70 individuals with sickle cell anemia and identified 6 and 4 rare missense variants in HBS1L and MYB, respectively. They genotyped these variants in 1,032 individuals with sickle cell anemia to assess their burden at the gene level by comparing normalized HbF levels in carriers and noncarriers. Results for HBS1L were not significant; however, a significant difference was observed for MYB (corrected p = 0.005), with the 25 carriers having on average 1.4% more HbF than the 937 noncarriers. These data suggested that MYB is the gene causally involved in controlling HbF production at the HBFQTL2 locus.
Craig, J. E., Rochette, J., Fisher, C. A., Weatherall, D. J., Marc, S., Lathrop, G. M., Demenais, F., Thein, S. Dissecting the loci controlling fetal haemoglobin production on chromosomes 11p and 6q by the regressive approach. Nature Genet. 12: 58-64, 1996. [PubMed: 8528252] [Full Text: https://doi.org/10.1038/ng0196-58]
Galarneau, G., Palmer, C. D., Sankaran, V. G., Orkin, S. H., Hirschhorn, J. N., Lettre, G. Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation. Nature Genet. 42: 1049-1051, 2010. [PubMed: 21057501] [Full Text: https://doi.org/10.1038/ng.707]
Garner, C., Mitchell, J., Hatzis, T., Reittie, J., Farrall, M., Thein, S. L. Haplotype mapping of a major quantitative-trait locus for fetal hemoglobin production, on chromosome 6q23. Am. J. Hum. Genet. 62: 1468-1474, 1998. [PubMed: 9585587] [Full Text: https://doi.org/10.1086/301859]
Lettre, G., Sankaran, V. G., Bezerra, M. A. C., Araujo, A. S., Uda, M., Sanna, S., Cao, A., Schlessinger, D., Costa, F. F., Hirschhorn, J. N. Orkin, S. H.: DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proc. Nat. Acad. Sci. 105: 11869-11874, 2008. [PubMed: 18667698] [Full Text: https://doi.org/10.1073/pnas.0804799105]
Menzel, S., Jiang, J., Silver, N., Gallagher, J., Cunningham, J., Surdulescu, G., Lathrop, M., Farrall, M., Spector, T. D., Thein, S. L. The HBS1L-MYB intergenic region on chromosome 6q23.3 influences erythrocyte, platelet, and monocyte counts in humans. Blood 110: 3624-3626, 2007. [PubMed: 17712044] [Full Text: https://doi.org/10.1182/blood-2007-05-093419]
Pandit, R. A., Svasti, S., Sripichai, O., Munkongdee, T., Triwitayakorn, K., Winichagoon, P., Fucharoen, S., Peerapittayamongkol, C. Association of SNP in exon 1 of HBS1L with hemoglobin F level in beta-0-thalassemia/hemoglobin E. Int. J. Hemat. 88: 357-361, 2008. [PubMed: 18839276] [Full Text: https://doi.org/10.1007/s12185-008-0167-3]
So, C.-C., Song, Y.-Q., Tsang, S. T., Tang, L.-F., Chan, A. Y., Ma, E. S., Chan, L.-C. The HBS1L-MYB intergenic region on chromosome 6q23 is a quantitative trait locus controlling fetal haemoglobin level in carriers of beta-thalassemia. J. Med. Genet. 45: 745-751, 2008. [PubMed: 18697826] [Full Text: https://doi.org/10.1136/jmg.2008.060335]
Thein, S. L., Menzel, S., Peng, X., Best, S., Jiang, J., Close, J., Silver, N., Gerovasilli, A., Ping, C., Yamaguchi, M., Wahlberg, K., Ulug, P., Spector, T. D., Garner, C., Matsuda, F., Farrall, M., Lathrop, M. Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults. Proc. Nat. Acad. Sci. 104: 11346-11351, 2007. [PubMed: 17592125] [Full Text: https://doi.org/10.1073/pnas.0611393104]
Thein, S. L., Sampietro, M., Rohde, K., Rochette, J., Weatherall, D. J., Lathrop, G. M., Demenais, F. Detection of a major gene for heterocellular hereditary persistence of fetal hemoglobin after accounting for genetic modifiers. Am. J. Hum. Genet. 54: 214-228, 1994. [PubMed: 7508182]
Wahlberg, K., Jiang, J., Rooks, H., Jawaid, K., Matsuda, F., Yamaguchi, M., Lathrop, M., Thein, S. L., Best, S. The HBS1L-MYB intergenic interval associated with elevated HbF levels shows characteristics of a distal regulatory region in erythroid cells. Blood 114: 1254-1262, 2009. [PubMed: 19528534] [Full Text: https://doi.org/10.1182/blood-2009-03-210146]