Reduced Neutrophil Count in People of African Descent Is Due To a Regulatory Variant in the Duffy Antigen Receptor for Chemokines Gene

TLDR

Low WBC and neutrophil counts are a well‑described but unexplained phenomenon in people of African ancestry, and the highly differentiated Duffy Null polymorphism (rs2814778) is a strong candidate due to its known malaria protection. The study aimed to pinpoint the specific genetic variant underlying the WBC difference between African and European Americans. The authors performed a large‑scale genotype–phenotype association study in 6,005 African Americans from the Jackson Heart Study, Health ABC, and ARIC cohorts. Admixture mapping identified a 1‑Mb region on chromosome 1, and the Duffy Null variant rs2814778—present at a 91 % frequency difference between West Africans and European Americans—was shown to predict WBC and neutrophil counts in African Americans, establishing a new phenotype for this variant.

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.