Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits

Nat Genet. 2014 Jun;46(6):629-34. doi: 10.1038/ng.2962.

Paul L Auer ¹, Alexander Teumer ², Ursula Schick ³, Andrew O'Shaughnessy ⁴, Ken Sin Lo ⁵, Nathalie Chami ⁵, Chris Carlson ³, Simon de Denus ⁶, Marie-Pierre Dubé ⁶, Jeff Haessler ³, Rebecca D Jackson ⁷, Charles Kooperberg ³, Louis-Philippe Lemieux Perreault ⁵, Matthias Nauck ⁸, Ulrike Peters ⁹, John D Rioux ⁶, Frank Schmidt ², Valérie Turcot ⁵, Uwe Völker ², Henry Völzke ¹⁰, Andreas Greinacher ¹¹, Li Hsu ³, Jean-Claude Tardif ⁶, George A Diaz ¹², Alexander P Reiner ¹³, Guillaume Lettre ¹⁴

Affiliations

1 1] School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA. [2] Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
2 Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
3 Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
4 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
5 Montreal Heart Institute, Montreal, Quebec, Canada.
6 1] Montreal Heart Institute, Montreal, Quebec, Canada. [2] Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada. [3] Faculty of Pharmacy, Université de Montréal, Montreal, Québec, Canada.
7 Division of Endocrinology, Diabetes and Metabolism, Ohio State University, Columbus, Ohio, USA.
8 Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
9 1] Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. [2] Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA.
10 Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
11 Institute for Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
12 1] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [3].
13 1] Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. [2] Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA. [3].
14 1] Montreal Heart Institute, Montreal, Quebec, Canada. [2] Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada. [3] Faculty of Pharmacy, Université de Montréal, Montreal, Québec, Canada. [4].

PMID: 24777453 DOI: 10.1038/ng.2962

Abstract

Hematological traits are important clinical parameters. To test the effects of rare and low-frequency coding variants on hematological traits, we analyzed hemoglobin concentration, hematocrit levels, white blood cell (WBC) counts and platelet counts in 31,340 individuals genotyped on an exome array. We identified several missense variants in CXCR2 associated with reduced WBC count (gene-based P = 2.6 × 10(-13)). In a separate family-based resequencing study, we identified a CXCR2 frameshift mutation in a pedigree with congenital neutropenia that abolished ligand-induced CXCR2 signal transduction and chemotaxis. We also identified missense or splice-site variants in key hematopoiesis regulators (EPO, TFR2, HBB, TUBB1 and SH2B3) associated with blood cell traits. Finally, we were able to detect associations between a rare somatic JAK2 mutation (encoding p.Val617Phe) and platelet count (P = 3.9 × 10(-22)) as well as hemoglobin concentration (P = 0.002), hematocrit levels (P = 9.5 × 10(-7)) and WBC count (P = 3.1 × 10(-5)). In conclusion, exome arrays complement genome-wide association studies in identifying new variants that contribute to complex human traits.

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