Circulating white blood cell (WBC) counts (neutrophils, monocytes, lymphocytes, eosinophils, basophils) differ by ethnicity. The genetic factors underlying basal WBC traits in Hispanics/Latinos are unknown. We performed a genome-wide association study of total WBC and differential counts in a large, ethnically diverse US population sample of Hispanics/Latinos ascertained by the Hispanic Community Health Study and Study of Latinos (HCHS/SOL). We demonstrate that several previously known WBC-associated genetic loci (e.g. the African Duffy antigen receptor for chemokines null variant for neutrophil count) are generalizable to WBC traits in Hispanics/Latinos. We identified and replicated common and rare germ-line variants at FLT3 (a gene often somatically mutated in leukemia) associated with monocyte count. The common FLT3 variant rs76428106 has a large allele frequency differential between African and non-African populations. We also identified several novel genetic loci involving or regulating hematopoietic transcription factors (CEBPE-SLC7A7, CEBPA and CRBN-TRNT1) associated with basophil count. The minor allele of the CEBPE variant associated with lower basophil count has been previously associated with Amerindian ancestry and higher risk of acute lymphoblastic leukemia in Hispanics. Together, these data suggest that germline genetic variation affecting transcriptional and signaling pathways that underlie WBC development and lineage specification can contribute to inter-individual as well as ethnic differences in peripheral blood cell counts (normal hematopoiesis) in addition to susceptibility to leukemia (malignant hematopoiesis).
Bibliographical noteFunding Information:
We thank the participants and staffof the HCHS/SOL study for their contributions to this study. Conflict of Interest statement. None declared. The baseline examination of HCHS/SOL was carried out as a collaborative study supported by contracts from the National Heart, Lung and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236) and San Diego State University (N01-HC65237). The following Institutes/Centers/Offices contributed to the first phase of HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, NIH Institution-Office of Dietary Supplements. The Genetic Analysis Center at Washington University was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03). Additional analysis support was provided by 1R01DK101855-01 and 13GRNT16490017. Genotyping efforts were supported by NHLBI HSN 26220/20054C, NCATS CTSI grant UL1TR000123 and NIDDK Diabetes Research Center (DRC) grant DK063491. This manuscript has been reviewed by the HCHS/SOL Publications Committee for scientific content and consistency of data interpretation with previous HCHS/SOL publications. This research was supported in part by the SOL (Study of Latinos) Grant-a sub-award issued under the Prime Contract No. HHSB268201200054C between HHS, NIH, National Heart, Lung and Blood Institute and Illumina, Inc. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124 and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. SRB was supported by R01-GM110068. The Mount Sinai BioMe Biobank Program is supported by The Andrea and Charles Bronfman Philanthropies. Analyses of BioMe data was supported in part through the computational resources and staffexpertize provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. The UW genetic analysis center was supported by a contract from NHLBI for HCHS/SOL (HHSN268201300005C). A.P.R. was supported by NHLBI (R01HL129132). D.E.B. is supported by NIDDK (K08DK093705) and the Doris Duke Charitable Foundation, Charles H. Hood Foundation, American Society of Hematology, Burroughs Wellcome Fund and Cooley's Anemia Foundation.