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Genome wide association study of fetal hemoglobin in sickle cell anemia in Tanzania.

Mtatiro SN, Singh T, Rooks H, Mgaya J, Mariki H, Soka D, Mmbando B, Msaki E, Kolder I, Thein SL, Menzel S, Cox SE, Makani J, Barrett JC - PLoS ONE (2014)

Bottom Line: We successfully replicated known associations for HbF near BCL11A and the HBS1L-MYB intergenic polymorphisms (HMIP), including multiple independent effects near BCL11A, consistent with previous reports.This is the largest GWAS study in SCA in Africa.We have confirmed known associations and identified new genetic associations with HbF that require further replication in SCA populations in Africa.

View Article: PubMed Central - PubMed

Affiliation: Muhimbili Wellcome Programme, Department of Haematology and Blood Transfusion, Muhimbili University of Health and Allied Science, Dar-es-salaam, Tanzania; Department of Biological Sciences, Dar es Salaam University College of Education, Dar-es-salaam, Tanzania.

ABSTRACT

Background: Fetal hemoglobin (HbF) is an important modulator of sickle cell disease (SCD). HbF has previously been shown to be affected by variants at three loci on chromosomes 2, 6 and 11, but it is likely that additional loci remain to be discovered.

Methods and findings: We conducted a genome-wide association study (GWAS) in 1,213 SCA (HbSS/HbSβ0) patients in Tanzania. Genotyping was done with Illumina Omni2.5 array and imputation using 1000 Genomes Phase I release data. Association with HbF was analysed using a linear mixed model to control for complex population structure within our study. We successfully replicated known associations for HbF near BCL11A and the HBS1L-MYB intergenic polymorphisms (HMIP), including multiple independent effects near BCL11A, consistent with previous reports. We observed eight additional associations with P<10(-6). These associations could not be replicated in a SCA population in the UK.

Conclusions: This is the largest GWAS study in SCA in Africa. We have confirmed known associations and identified new genetic associations with HbF that require further replication in SCA populations in Africa.

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Related in: MedlinePlus

A snapshot of UCSC genome browser showing relevant ENCODE tracks.The positions of variants reported in this study have been indicated within a track labelled as “suggestive HbF variants in BCL11A”. The positions of variants reported in previous studies.
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pone-0111464-g005: A snapshot of UCSC genome browser showing relevant ENCODE tracks.The positions of variants reported in this study have been indicated within a track labelled as “suggestive HbF variants in BCL11A”. The positions of variants reported in previous studies.

Mentions: Our findings have confirmed the genetic association of BCL11A and HMIP in the regulation of HbF. Our work also supports the likely causality of rs1427407 at the BCL11A locus, as recently reported [16], as well as the presence of multiple independent risk variants. The rs1427407 falls within a peak of GATA1 andTAL1 binding and the minor T allele is believed to disrupt a composite motif bound by GATA1 [16]. Rs6545816 sits 3kb from rs1427407 while rs58955256 is further upstream of rs1427407 (130 kb). These variants sit near regions with regulative activity within the BCL11A gene (Figure 5), however, their specific functions have not yet been reported and should be considered for further research.


Genome wide association study of fetal hemoglobin in sickle cell anemia in Tanzania.

Mtatiro SN, Singh T, Rooks H, Mgaya J, Mariki H, Soka D, Mmbando B, Msaki E, Kolder I, Thein SL, Menzel S, Cox SE, Makani J, Barrett JC - PLoS ONE (2014)

A snapshot of UCSC genome browser showing relevant ENCODE tracks.The positions of variants reported in this study have been indicated within a track labelled as “suggestive HbF variants in BCL11A”. The positions of variants reported in previous studies.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4221031&req=5

pone-0111464-g005: A snapshot of UCSC genome browser showing relevant ENCODE tracks.The positions of variants reported in this study have been indicated within a track labelled as “suggestive HbF variants in BCL11A”. The positions of variants reported in previous studies.
Mentions: Our findings have confirmed the genetic association of BCL11A and HMIP in the regulation of HbF. Our work also supports the likely causality of rs1427407 at the BCL11A locus, as recently reported [16], as well as the presence of multiple independent risk variants. The rs1427407 falls within a peak of GATA1 andTAL1 binding and the minor T allele is believed to disrupt a composite motif bound by GATA1 [16]. Rs6545816 sits 3kb from rs1427407 while rs58955256 is further upstream of rs1427407 (130 kb). These variants sit near regions with regulative activity within the BCL11A gene (Figure 5), however, their specific functions have not yet been reported and should be considered for further research.

Bottom Line: We successfully replicated known associations for HbF near BCL11A and the HBS1L-MYB intergenic polymorphisms (HMIP), including multiple independent effects near BCL11A, consistent with previous reports.This is the largest GWAS study in SCA in Africa.We have confirmed known associations and identified new genetic associations with HbF that require further replication in SCA populations in Africa.

View Article: PubMed Central - PubMed

Affiliation: Muhimbili Wellcome Programme, Department of Haematology and Blood Transfusion, Muhimbili University of Health and Allied Science, Dar-es-salaam, Tanzania; Department of Biological Sciences, Dar es Salaam University College of Education, Dar-es-salaam, Tanzania.

ABSTRACT

Background: Fetal hemoglobin (HbF) is an important modulator of sickle cell disease (SCD). HbF has previously been shown to be affected by variants at three loci on chromosomes 2, 6 and 11, but it is likely that additional loci remain to be discovered.

Methods and findings: We conducted a genome-wide association study (GWAS) in 1,213 SCA (HbSS/HbSβ0) patients in Tanzania. Genotyping was done with Illumina Omni2.5 array and imputation using 1000 Genomes Phase I release data. Association with HbF was analysed using a linear mixed model to control for complex population structure within our study. We successfully replicated known associations for HbF near BCL11A and the HBS1L-MYB intergenic polymorphisms (HMIP), including multiple independent effects near BCL11A, consistent with previous reports. We observed eight additional associations with P<10(-6). These associations could not be replicated in a SCA population in the UK.

Conclusions: This is the largest GWAS study in SCA in Africa. We have confirmed known associations and identified new genetic associations with HbF that require further replication in SCA populations in Africa.

Show MeSH
Related in: MedlinePlus