Genetic association of fetal-hemoglobin levels in individuals with XXXX in Tanzania maps to conserved regulatory elements within the @entity13327 core enhancer.

@entity1 @entity72073 @entity13327 @entity3458 @entity72074 @entity72072 @entity2395
BACKGROUND: Common genetic variants residing near upstream regulatory elements for @entity13327 , the gene encoding transcription factor @entity13327 , promote the persistence of fetal hemoglobin (HbF) into adulthood. While they have no consequences in healthy individuals, high HbF levels have major clinical benefits in @entity1 with @entity3458 ( @entity3458 ) or b @entity2395 . Here, we present our detailed investigation of HBS1L- @entity13327 intergenic polymorphism block 2 ( @entity72072 -2), the central component of the complex quantitative-trait locus upstream of @entity13327 , in 1,022 individuals with @entity3458 in Tanzania. METHODS: We have looked at 1022 individuals with HbSS or HbS/b(0) in Tanzania. In order to achieve a detailed analysis of @entity72072 -2, we performed targeted genotyping for a total of 10 SNPs and extracted additional 528 SNPs information from a genome wide scan involving the same population. Using MACH, we utilized the existing YRI data from 1000 genomes to impute 54 SNPs situated within HIMP-2. RESULTS: Seven HbF-increasing, low-frequency variants (b   >   0.3, p   <   10(-5), f    <=   0.05) were located in two partially-independent sub-loci, @entity72072 -2A and @entity72072 -2B. The spectrum of haplotypes carrying such alleles was diverse when compared to European and West African reference populations: we detected one such haplotype at sub-locus @entity72072 -2A, two at @entity72072 -2B, and a fourth including high-HbF alleles at both sub-loci ('Eurasian' haplotype clade). In the region of @entity72072 -2A a putative functional variant (a 3-bp indel) has been described previously, but no such candidate causative variant exists at @entity72072 -2B. Extending our dataset through imputation with 1000 Genomes, whole-genome-sequence data, we have mapped peak association at @entity72072 -2B to an 11-kb region around @entity72073 and @entity72074 , flanked by two conserved regulatory elements for @entity13327 . CONCLUSIONS: Studies in populations from the African continent provide distinct opportunities for mapping disease-modifying genetic loci, especially for conditions that are highly prevalent there, such as @entity3458 . Population-genetic characteristics of our cohort, such as ethnic diversity and the predominance of shorter, African-type haplotypes, can add to the power of such studies.
