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Reduced Neutrophil Count in People of African Descent Is Due To a Regulatory Variant in the Duffy Antigen Receptor for Chemokines Gene
- Source :
- PLoS genetics, vol 5, iss 1, PLoS Genetics, Vol 5, Iss 1, p e1000360 (2009), PLoS Genetics
- Publication Year :
- 2009
- Publisher :
- Public Library of Science (PLoS), 2009.
-
Abstract
- Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8×10−5), establishing a novel phenotype for this genetic variant.<br />Author Summary Many African Americans have white blood cell counts (WBC) that are persistently below the normal range for people of European descent, a condition called “benign ethnic neutropenia.” Because most African Americans have both African and European ancestors, selected genetic variants can be analyzed to assign probable African or European origin to each region of each such person's chromosomes. Previously, we found a region on chromosome 1 where increased local African ancestry completely accounted for differences in WBC between African and European Americans, suggesting the presence of an African-derived variant causing low WBC. Here, we show that low neutrophil count is predominantly responsible for low WBC; that a dominant, European-derived allele contributes to high neutrophil count; and that the frequency of this allele differs in Africans and Europeans by >91%. Across the chromosome 1 locus, only the well-characterized “Duffy” polymorphism was this differentiated. Neutrophil count was more strongly associated to the Duffy variant than to ancestry, suggesting that the variant itself causes benign ethnic neutropenia. The African, or “null,” form of this variant abolishes expression of the “Duffy Antigen Receptor for Chemokines” on red blood cells, perhaps altering the concentrations and distribution of chemokines that regulate neutrophil production or migration.
- Subjects :
- Male
Cancer Research
Neutrophils
Cohort Studies
Leukocyte Count
0302 clinical medicine
Polymorphism (computer science)
Receptors
Genotype
80 and over
10. No inequality
Genetics (clinical)
African Continental Ancestry Group
Aged, 80 and over
Genetics
0303 health sciences
Single Nucleotide
Middle Aged
Blacks
3. Good health
Phenotype
Chromosomes, Human, Pair 1
030220 oncology & carcinogenesis
Cell Surface
Pair 1
Absolute neutrophil count
Genetics and Genomics/Gene Discovery
Female
Research Article
Human
Adult
lcsh:QH426-470
European Continental Ancestry Group
Black People
Genetic admixture
Receptors, Cell Surface
Single-nucleotide polymorphism
and over
Biology
Polymorphism, Single Nucleotide
White People
Chromosomes
03 medical and health sciences
Rare Diseases
Genetics and Genomics/Population Genetics
Humans
SNP
Polymorphism
Allele
Molecular Biology
Ecology, Evolution, Behavior and Systematics
Aged
030304 developmental biology
Whites
Case-control study
Genetics and Genomics
lcsh:Genetics
Good Health and Well Being
Case-Control Studies
Immunology
Duffy Blood-Group System
Developmental Biology
Subjects
Details
- ISSN :
- 15537404
- Volume :
- 5
- Database :
- OpenAIRE
- Journal :
- PLoS Genetics
- Accession number :
- edsair.doi.dedup.....3cb70da0a2275f2a1a44bd96afdac88f