Leukocyte Counts Influenced by Genetic Variants

White blood cell (WBC) levels are influenced by genetic variants at more than a dozen loci for different ethnic groups.

Large genome wide association studies (GWAS), found some genetic variants affecting total WBC counts and some influencing leukocyte subtypes such as lymphocytes, neutrophils, basophils, eosinophils, or monocytes.

Numerous international collaborators, in separate studies, supported by the US National Institutes of Health, Bethesda, MD, USA), examined the WBC counts in 14,792 Japanese, 16,388 African-Americans, and 19,509 white participants, as well as additional replication and comparison cohorts, looking for genetic variants. Benign neutropenia, defined as absolute neutrophil count of less than 1.56 × 109 cells/L on repeated occasions, is found in up to 40% of populations of African descent, and approximately 5% of those of African descent living in America, but less than 1% of white Americans of European descent.

The total WBC counts, and neutrophil counts in particular, are typically 10% to 20% lower in African-Americans than in whites. This difference has been attributed to a variant of the Duffy Antigen Receptor for Chemokines (DARC), common in Africa, which provides a selective advantage in malarial regions and influences production and migration of neutrophils. The authors suggest that characterizing the variants associated with WBC and neutrophil counts could help to inform clinical approaches to cancer-associated neutropenia or hematopoietic stem cell mobilization.

The Japanese study found nine GWAS-significant associations between genetic loci and WBC subtype counts and confirmed three loci already known to influence WBC counts. The study on whites, found multiple loci having GWAS-significant association with WBC counts. Data from more than 19,000 individuals were analyzed in the discovery stage, and 11,823 more in replication, finding that 10 regions significantly associated with total WBC counts and five with specific WBC subtypes spread across seven genomic loci. Only three of these associations were previously known.

The investigation identified an additional genetic region that significantly influences WBC counts: A variant in the chemokine ligand 2 (CXCL2), codes for a cytokine affecting polymorphonuclear leukocytes. This association has been recognized in Hispanic, white, and Japanese populations as well. The authors of the African-American study concluded that the new findings will contribute to our understanding of genetic factors underlying variation in WBC counts within and between populations and highlight the importance of common genetic variants in genomic regions encoding chemokine ligands and receptors to regulation of myelopoiesis and circulating leukocyte counts in human populations." The three studies were published online on June 30, 2011, in the Public Library of Science Genetics.

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