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PLoS Genet. 2017 Apr 28;13(4):e1006760. doi: 10.1371/journal.pgen.1006760. eCollection 2017 Apr.

Genome-wide association study of red blood cell traits in Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos.

Author information

1
Department of Epidemiology, University of North Carolina Gillings School of Public Health, Chapel Hill, NC, United States of America.
2
Department of Biostatistics, University of Washington, Seattle, WA, United States of America.
3
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
4
The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
5
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.
6
New York Genome Center, New York, NY, United States of America.
7
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, United States of America.
8
School of Medicine, Wake Forest University, Winston-Salem, NC, United States of America.
9
Joseph J. Zilber School of Public Health, University of Wisconsin Milwaukee, Milwaukee, WI, United States of America.
10
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA United States of America.
11
Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA United States of America.
12
Department of Medicine, University of Washington, Seattle, WA United States of America.
13
Department of Genetics, University of North Carolina, Chapel Hill, NC, United States of America.
14
Department of Biostatistics, University of North Carolina, Chapel Hill, NC, United States of America.
15
Department of Computer Science, University of North Carolina, Chapel Hill, NC, United States of America.
16
Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD, United States of America.
17
Research and Development Department, Central Blood Institute, Blood Service Headquarters, Japanese Red Cross Society, Tokyo, Japan.
18
Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan.
19
Comprehensive Human Sciences, Tsukuba University, Tsukuba, Ibaraki, Japan.
20
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
21
Division of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, MN, United States of America.
22
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, United States of America.
23
Department of Pediatrics, Harvard Medical School and Harvard Stem Cell Institute, Harvard University, Boston, MA, United States of America.

Abstract

Prior GWAS have identified loci associated with red blood cell (RBC) traits in populations of European, African, and Asian ancestry. These studies have not included individuals with an Amerindian ancestral background, such as Hispanics/Latinos, nor evaluated the full spectrum of genomic variation beyond single nucleotide variants. Using a custom genotyping array enriched for Amerindian ancestral content and 1000 Genomes imputation, we performed GWAS in 12,502 participants of Hispanic Community Health Study and Study of Latinos (HCHS/SOL) for hematocrit, hemoglobin, RBC count, RBC distribution width (RDW), and RBC indices. Approximately 60% of previously reported RBC trait loci generalized to HCHS/SOL Hispanics/Latinos, including African ancestral alpha- and beta-globin gene variants. In addition to the known 3.8kb alpha-globin copy number variant, we identified an Amerindian ancestral association in an alpha-globin regulatory region on chromosome 16p13.3 for mean corpuscular volume and mean corpuscular hemoglobin. We also discovered and replicated three genome-wide significant variants in previously unreported loci for RDW (SLC12A2 rs17764730, PSMB5 rs941718), and hematocrit (PROX1 rs3754140). Among the proxy variants at the SLC12A2 locus we identified rs3812049, located in a bi-directional promoter between SLC12A2 (which encodes a red cell membrane ion-transport protein) and an upstream anti-sense long-noncoding RNA, LINC01184, as the likely causal variant. We further demonstrate that disruption of the regulatory element harboring rs3812049 affects transcription of SLC12A2 and LINC01184 in human erythroid progenitor cells. Together, these results reinforce the importance of genetic study of diverse ancestral populations, in particular Hispanics/Latinos.

PMID:
28453575
PMCID:
PMC5428979
DOI:
10.1371/journal.pgen.1006760
[Indexed for MEDLINE]
Free PMC Article

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