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

2014; Nature Portfolio; Volume: 46; Issue: 6 Linguagem: Inglês

10.1038/ng.2962

1546-1718

Paul L. Auer, Alexander Teumer, Ursula M. Schick, Andrew O’Shaughnessy, Ken Sin Lo, Nathalie Chami, Chris Carlson, Simon de Denus, Marie‐Pierre Dubé, Jeff Haessler, Rebecca D. Jackson, Charles Kooperberg, Louis‐Philippe Lemieux Perreault, Matthias Nauck, Ulrike Peters, John D. Rioux, Frank Schmidt, Valérie Turcot, Uwe Völker, Henry Völzke, Andreas Greinacher, Li Hsu, Jean‐Claude Tardif, George A. Díaz, Alexander P. Reiner, Guillaume Lettre,

Immunodeficiency and Autoimmune Disorders

Guillaume Lettre, Alexander Reiner, George Diaz and colleagues use an exome array to identify rare and low-frequency coding variants influencing hematological traits. They find several missense variants in CXCR2 associated with reduced white blood cell counts, and, in a separate family-based study, they identify a homozygous CXCR2 frameshift mutation in two siblings with congenital neutropenia. 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.