A locus on chromosome 5 shows African ancestry-limited association with alloimmunization in sickle cell disease

Lesedi M. Williams, Zhihua Qi, Ken Batai, Stanley Hooker, Nancy J. Hall, Roberto F. Machado, Alice Chen, Sally Campbell-Lee, Yongtao Guan, Rick A Kittles, Neil A. Hanchard

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Red blood cell (RBC) transfusion remains a critical therapeutic intervention in sickle cell disease (SCD); however, the apparent propensity of some patients to regularly develop RBC alloantibodies after transfusion presents a significant challenge to finding compatible blood for so-called alloimmunization responders. Predisposing genetic loci have long been thought to contribute to the responder phenomenon, but to date, no definitive loci have been identified. We undertook a genome-wide association study of alloimmunization responder status in 267 SCD multiple transfusion recipients, using genetic estimates of ancestral admixture to bolster our findings. Analyses revealed single nucleotide polymorphisms (SNPs) on chromosomes 2 and 5 approaching genome-wide significance (minimum P = 2.0 × 10-8 and 8.4 × 10-8, respectively), with local ancestry analysis demonstrating similar levels of admixture in responders and nonresponders at implicated loci. Association at chromosome 5 was nominally replicated in an independent cohort of 130 SCD transfusion recipients, with meta-analysis surpassing genome-wide significance (rs75853687, Pmeta = 6.6 × 10-9), and this extended to individuals forming multiple (>3) alloantibodies (Pmeta = 9.4 × 10-5). The associated variant is rare outside of African populations, and orthogonal genome-wide haplotype analyses, contingent on local ancestry, revealed genome-wide significant sharing of a ∼60-kb haplotype of African ancestry at the chromosome 5 locus (Bayes Factor = 4.95). This locus overlaps a putative cis-acting enhancer predicted to regulate transcription of ADRA1B and the lncRNA LINC01847, both members of larger ontologies associated with immune regulation. Our findings provide potential insights to the pathophysiology underlying the development of alloantibodies and implicate non-RBC ancestry-limited loci in the susceptibility to alloimmunization.

Original languageEnglish (US)
Pages (from-to)3637-3647
Number of pages11
JournalBlood advances
Volume2
Issue number24
DOIs
StatePublished - Dec 26 2018
Externally publishedYes

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Chromosomes, Human, Pair 5
Sickle Cell Anemia
Isoantibodies
Genome
Haplotypes
Long Noncoding RNA
Erythrocyte Transfusion
Genetic Loci
Chromosomes, Human, Pair 2
Genome-Wide Association Study
Single Nucleotide Polymorphism
Meta-Analysis
Blood Cells
Erythrocytes
Population
Therapeutics

Cite this

Williams, L. M., Qi, Z., Batai, K., Hooker, S., Hall, N. J., Machado, R. F., ... Hanchard, N. A. (2018). A locus on chromosome 5 shows African ancestry-limited association with alloimmunization in sickle cell disease. Blood advances, 2(24), 3637-3647. https://doi.org/10.1182/bloodadvances.2018020594

A locus on chromosome 5 shows African ancestry-limited association with alloimmunization in sickle cell disease. / Williams, Lesedi M.; Qi, Zhihua; Batai, Ken; Hooker, Stanley; Hall, Nancy J.; Machado, Roberto F.; Chen, Alice; Campbell-Lee, Sally; Guan, Yongtao; Kittles, Rick A; Hanchard, Neil A.

In: Blood advances, Vol. 2, No. 24, 26.12.2018, p. 3637-3647.

Research output: Contribution to journalArticle

Williams, LM, Qi, Z, Batai, K, Hooker, S, Hall, NJ, Machado, RF, Chen, A, Campbell-Lee, S, Guan, Y, Kittles, RA & Hanchard, NA 2018, 'A locus on chromosome 5 shows African ancestry-limited association with alloimmunization in sickle cell disease', Blood advances, vol. 2, no. 24, pp. 3637-3647. https://doi.org/10.1182/bloodadvances.2018020594
Williams, Lesedi M. ; Qi, Zhihua ; Batai, Ken ; Hooker, Stanley ; Hall, Nancy J. ; Machado, Roberto F. ; Chen, Alice ; Campbell-Lee, Sally ; Guan, Yongtao ; Kittles, Rick A ; Hanchard, Neil A. / A locus on chromosome 5 shows African ancestry-limited association with alloimmunization in sickle cell disease. In: Blood advances. 2018 ; Vol. 2, No. 24. pp. 3637-3647.
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abstract = "Red blood cell (RBC) transfusion remains a critical therapeutic intervention in sickle cell disease (SCD); however, the apparent propensity of some patients to regularly develop RBC alloantibodies after transfusion presents a significant challenge to finding compatible blood for so-called alloimmunization responders. Predisposing genetic loci have long been thought to contribute to the responder phenomenon, but to date, no definitive loci have been identified. We undertook a genome-wide association study of alloimmunization responder status in 267 SCD multiple transfusion recipients, using genetic estimates of ancestral admixture to bolster our findings. Analyses revealed single nucleotide polymorphisms (SNPs) on chromosomes 2 and 5 approaching genome-wide significance (minimum P = 2.0 × 10-8 and 8.4 × 10-8, respectively), with local ancestry analysis demonstrating similar levels of admixture in responders and nonresponders at implicated loci. Association at chromosome 5 was nominally replicated in an independent cohort of 130 SCD transfusion recipients, with meta-analysis surpassing genome-wide significance (rs75853687, Pmeta = 6.6 × 10-9), and this extended to individuals forming multiple (>3) alloantibodies (Pmeta = 9.4 × 10-5). The associated variant is rare outside of African populations, and orthogonal genome-wide haplotype analyses, contingent on local ancestry, revealed genome-wide significant sharing of a ∼60-kb haplotype of African ancestry at the chromosome 5 locus (Bayes Factor = 4.95). This locus overlaps a putative cis-acting enhancer predicted to regulate transcription of ADRA1B and the lncRNA LINC01847, both members of larger ontologies associated with immune regulation. Our findings provide potential insights to the pathophysiology underlying the development of alloantibodies and implicate non-RBC ancestry-limited loci in the susceptibility to alloimmunization.",
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AU - Williams, Lesedi M.

AU - Qi, Zhihua

AU - Batai, Ken

AU - Hooker, Stanley

AU - Hall, Nancy J.

AU - Machado, Roberto F.

AU - Chen, Alice

AU - Campbell-Lee, Sally

AU - Guan, Yongtao

AU - Kittles, Rick A

AU - Hanchard, Neil A.

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N2 - Red blood cell (RBC) transfusion remains a critical therapeutic intervention in sickle cell disease (SCD); however, the apparent propensity of some patients to regularly develop RBC alloantibodies after transfusion presents a significant challenge to finding compatible blood for so-called alloimmunization responders. Predisposing genetic loci have long been thought to contribute to the responder phenomenon, but to date, no definitive loci have been identified. We undertook a genome-wide association study of alloimmunization responder status in 267 SCD multiple transfusion recipients, using genetic estimates of ancestral admixture to bolster our findings. Analyses revealed single nucleotide polymorphisms (SNPs) on chromosomes 2 and 5 approaching genome-wide significance (minimum P = 2.0 × 10-8 and 8.4 × 10-8, respectively), with local ancestry analysis demonstrating similar levels of admixture in responders and nonresponders at implicated loci. Association at chromosome 5 was nominally replicated in an independent cohort of 130 SCD transfusion recipients, with meta-analysis surpassing genome-wide significance (rs75853687, Pmeta = 6.6 × 10-9), and this extended to individuals forming multiple (>3) alloantibodies (Pmeta = 9.4 × 10-5). The associated variant is rare outside of African populations, and orthogonal genome-wide haplotype analyses, contingent on local ancestry, revealed genome-wide significant sharing of a ∼60-kb haplotype of African ancestry at the chromosome 5 locus (Bayes Factor = 4.95). This locus overlaps a putative cis-acting enhancer predicted to regulate transcription of ADRA1B and the lncRNA LINC01847, both members of larger ontologies associated with immune regulation. Our findings provide potential insights to the pathophysiology underlying the development of alloantibodies and implicate non-RBC ancestry-limited loci in the susceptibility to alloimmunization.

AB - Red blood cell (RBC) transfusion remains a critical therapeutic intervention in sickle cell disease (SCD); however, the apparent propensity of some patients to regularly develop RBC alloantibodies after transfusion presents a significant challenge to finding compatible blood for so-called alloimmunization responders. Predisposing genetic loci have long been thought to contribute to the responder phenomenon, but to date, no definitive loci have been identified. We undertook a genome-wide association study of alloimmunization responder status in 267 SCD multiple transfusion recipients, using genetic estimates of ancestral admixture to bolster our findings. Analyses revealed single nucleotide polymorphisms (SNPs) on chromosomes 2 and 5 approaching genome-wide significance (minimum P = 2.0 × 10-8 and 8.4 × 10-8, respectively), with local ancestry analysis demonstrating similar levels of admixture in responders and nonresponders at implicated loci. Association at chromosome 5 was nominally replicated in an independent cohort of 130 SCD transfusion recipients, with meta-analysis surpassing genome-wide significance (rs75853687, Pmeta = 6.6 × 10-9), and this extended to individuals forming multiple (>3) alloantibodies (Pmeta = 9.4 × 10-5). The associated variant is rare outside of African populations, and orthogonal genome-wide haplotype analyses, contingent on local ancestry, revealed genome-wide significant sharing of a ∼60-kb haplotype of African ancestry at the chromosome 5 locus (Bayes Factor = 4.95). This locus overlaps a putative cis-acting enhancer predicted to regulate transcription of ADRA1B and the lncRNA LINC01847, both members of larger ontologies associated with immune regulation. Our findings provide potential insights to the pathophysiology underlying the development of alloantibodies and implicate non-RBC ancestry-limited loci in the susceptibility to alloimmunization.

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