Genome-wide association of white blood cell counts in Hispanic/Latino Americans: the Hispanic Community Health Study/Study of Latinos.
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).
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Deepti
D
Jain
Department of Epidemiology, University of North Carolina Gillings School of Public Health, Chapel Hill, NC 27514, USA.
Chani J
CJ
Hodonsky
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98195, USA.
Ursula M
UM
Schick
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Jean V
JV
Morrison
Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Sharon
S
Minnerath
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Lisa
L
Brown
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Claudia
C
Schurmann
Department of Epidemiology and Prevention, School of Medicine, Wake Forest University, Winston-Salem, NC 27101, USA.
Yongmei
Y
Liu
Department of Biostatistics, Joseph J. Zilber School of Public Health, University of Wisconsin Milwaukee, Milwaukee, WI 53201, USA.
Paul L
PL
Auer
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Cecelia A
CA
Laurie
Institute for Translational Genomics and Population Sciences at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.|Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Kent D
KD
Taylor
Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Brian L
BL
Browning
Division of Cardiovascular Sciences, National Heart, Lung and Blood Institute, Bethesda, MD 20824, USA.
George
G
Papanicolaou
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Sharon R
SR
Browning
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Ruth J F
RJF
Loos
Department of Epidemiology, University of North Carolina Gillings School of Public Health, Chapel Hill, NC 27514, USA.|Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA.
Kari E
KE
North
Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Bharat
B
Thyagarajan
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Cathy C
CC
Laurie
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Timothy A
TA
Thornton
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Tamar
T
Sofer
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98195, USA.
Alexander P
AP
Reiner
D001741:Black or African American / Q000235:genetics; D001491:Basophils / Q000166:cytology; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D007958:Leukocyte Count; D008214:Lymphocytes / Q000166:cytology; D008297:Male; D009000:Monocytes / Q000166:cytology; D009504:Neutrophils / Q000166:cytology; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
D022762:CCAAT-Enhancer-Binding Proteins; C070790:CEBPE protein, human; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3