ORPHA: 251380, 46532;
Cytogenetic location: 2p16.1 Genomic coordinates (GRCh38): 2:54,700,001-61,000,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p16.1 | [Fetal hemoglobin QTL5] | 142335 | Autosomal dominant | 2 |
In healthy adults, fetal hemoglobin (HbF) is present at residual levels (less than 0.06% of total hemoglobin) with over 20-fold variation. Ten to fifteen percent of adults fall within the upper tail of the distribution and have HbF levels between 0.8% and 5%, a condition referred to as heterocellular hereditary persistence of fetal hemoglobin Although these HbF levels are modest in otherwise healthy individuals, interaction of heterocellular HPFH with beta-thalassemia (see 613985) or sickle cell disease (SS; 603903) can increase HbF output in these individuals to levels that are clinically beneficial (Menzel et al., 2007).
For a general phenotypic description and a discussion of loci that may affect fetal hemoglobin levels, see HBFQTL1 (141749).
Menzel et al. (2007) applied a genomewide association mapping strategy to individuals with contrasting extreme trait values and mapped an F cell quantitative trait locus (QTL) to a region on chromosome 2p15 that included the BCL11A gene (606557). The 2p15 QTL accounted for 15.1% of the trait variance. The strongest associations were in a region spanning 14 kb in the second intron of the BCL11A gene. The second association cluster spanned 67 kb in the 3-prime region of the gene downstream of exon 5 of the BCL11A gene.
By genomewide analysis of 4,305 Sardinian individuals, Uda et al. (2008) found a significant association between the BCL11A gene and hepatocellular persistent fetal hemoglobin. The strongest association was with the C allele of a SNP (rs11886868) in intron 2 of the BCL11A gene (p = 10(-35)). In addition, the C allele was associated with an ameliorated phenotype in patients with beta-thalassemia and sickle cell anemia, indicating that SNPs in the BCL11A gene may modify these phenotypes by augmenting HbF levels.
Among 1,275 African Americans and 350 Brazilians with sickle cell disease, Lettre et al. (2008) found a significant association between HbF levels and SNPs in the BCL11A gene. The most significant association among both groups was with rs4671393 (p = 2 x 10(-42) among African Americans, p = 3 x 10(-8) among Brazilians). The effect of these SNPs could explain 6.7 to 14.1% of variance in HbF levels.
To fine map HbF association signals at the BCL11A, HBS1L-MYB (612450-189990), 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 17 at the BCL11A locus, in 1,032 African Americans with sickle cell anemia. Consistent with earlier reports, rs4671393 in BCL11A intron 2 was the genetic marker most strongly associated with HbF levels (p = 3.7 x 10(-37)). Stepwise conditional analyses found 2 other SNPs in BCL11A intron 2, rs7599488 and rs10189857, that independently associated with HbF levels. These 2 SNPs were in weak linkage disequilibrium (LD) with rs4671393 (r(2) = 0.17 and r(2) = 0.15, respectively) but were in strong LD with each other (r(2) = 0.96). These 3 SNPs form 4 haplotypes that represent 99.7% of all haplotypes at this locus. These haplotypes were more strongly associated with HbF levels (p = 4.0 x 10(-45)) than was rs4671393 and explained 18.1% of the phenotypic variation in HbF levels. Thus, these haplotypes explain more phenotypic variance than the sum of the 3 BCL11A SNPs taken individually (14.7%). Galarneau et al. (2010) concluded that it is likely that the difference in phenotypic variance explained is due to the presence of HbF-increasing and HbF-decreasing alleles on the same haplotype background, where associated SNPs in LD masked each other's phenotypic effect.
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]
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., Garner, C., Gut, I., Matsuda, F., Yamaguchi, M., Heath, S., Foglio, M., Zelenika, D., Boland, A., Rooks, H., Best, S., Spector, T. D., Farrall, M., Lathrop, M., Thein, S. L. A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nature Genet. 39: 1197-1199, 2007. [PubMed: 17767159] [Full Text: https://doi.org/10.1038/ng2108]
Uda, M., Galanello, R., Sanna, S., Lettre, G., Sankaran, V. G., Chen, W., Usala, G., Busonero, F., Maschio, A., Albai, G., Piras, M. G., Sestu, N., and 18 others. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc. Nat. Acad. Sci. 105: 1620-1625, 2008. [PubMed: 18245381] [Full Text: https://doi.org/10.1073/pnas.0711566105]