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

被引：105

作者：

Auer, Paul L. ^{[1
,2
]}

Teumer, Alexander ^{[3
]}

Schick, Ursula ^{[2
]}

O'Shaughnessy, Andrew ^{[4
]}

Lo, Ken Sin ^{[5
]}

Chami, Nathalie ^{[5
]}

Carlson, Chris ^{[2
]}

de Denus, Simon ^{[5
,6
,7
]}

Dube, Marie-Pierre ^{[5
,6
,7
]}

Haessler, Jeff ^{[2
]}

Jackson, Rebecca D. ^{[8
]}

Kooperberg, Charles ^{[2
]}

Perreault, Louis-Philippe Lemieux ^{[5
]}

Nauck, Matthias ^{[9
]}

Peters, Ulrike ^{[2
,10
]}

Rioux, John D. ^{[5
,6
,7
]}

Schmidt, Frank ^{[3
]}

Turcot, Valerie ^{[5
]}

Voelker, Uwe ^{[3
]}

Voelzke, Henry ^{[11
]}

Greinacher, Andreas ^{[12
]}

Hsu, Li ^{[2
]}

Tardif, Jean-Claude ^{[5
,6
,7
]}

Diaz, George A. ^{[4
,13
]}

Reiner, Alexander P. ^{[2
,9
,10
]}

Lettre, Guillaume ^{[5
,6
,7
]}

机构：

[1] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA

[2] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA

[3] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany

[4] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[5] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada

[6] Univ Montreal, Fac Med, Montreal, PQ H3C 3J7, Canada

[7] Univ Montreal, Fac Pharm, Montreal, PQ H3C 3J7, Canada

[8] Ohio State Univ, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA

[9] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany

[10] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA

[11] Univ Med Greifswald, Inst Community Med, Greifswald, Germany

[12] Univ Med Greifswald, Inst Immunol & Transfus Med, Greifswald, Germany

[13] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY USA

来源：

NATURE GENETICS | 2014年 / 46卷 / 06期

基金：

美国国家卫生研究院;

关键词：

TYROSINE KINASE JAK2; MYELOPROLIFERATIVE DISORDERS; POLYCYTHEMIA-VERA; RECEPTOR GENE; HUMAN GENOME; MUTATION; CELL; POPULATION; EXPRESSION; ERYTHROCYTOSIS;

D O I：

10.1038/ng.2962

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 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 SH283) associated with blood cell traits. Finally, we were able to detect associations between a rare somatic JAK2 mutation (encoding p.VaI617Phe) and platelet count (P = 3.9 x 10(-22)) as well as hemoglobin concentration (P = 0.002), hematocrit levels (P = 9.5 x 10(-7)) and WBC count (P = 3.1 x 10(-5)). In conclusion, exome arrays complement genome-wide association studies in identifying new variants that contribute to complex human traits.

引用

页码：629 / 634

页数：6

共 38 条

[21] Breaking the waves:: improved detection of copy number variation from microarray-based comparative genomic hybridization [J].

Marioni, John C. ;

Thorne, Natalie P. ;

Valsesia, Armand ;

Fitzgerald, Tomas ;

Redon, Richard ;

Fiegler, Heike ;

Andrews, T. Daniel ;

Stranger, Barbara E. ;

Lynch, Andrew G. ;

Dermitzakis, Emmanouil T. ;

Carter, Nigel P. ;

Tavare, Simon ;

Hurles, Matthew E. .

GENOME BIOLOGY, 2007, 8 (10)

[22] A nonsynonymous LNK polymorphism associated with idiopathic erythrocytosis [J].

McMullin, Mary Frances ;

Wu, Chao ;

Percy, Melanie J. ;

Tong, Wei .

AMERICAN JOURNAL OF HEMATOLOGY, 2011, 86 (11) :962-964

[23]

Nails M.A., 2011, PLOS GENET, V7

[24] When the brakes are lost: LNK dysfunction in mice, men, and myeloproliferative neoplasms [J].

Oh, Stephen T. .

THERAPEUTIC ADVANCES IN HEMATOLOGY, 2011, 2 (01) :11-19

[25] Structure of the chemokine receptor CXCR1 in phospholipid bilayers [J].

Park, Sang Ho ;

Das, Bibhuti B. ;

Casagrande, Fabio ;

Tian, Ye ;

Nothnagel, Henry J. ;

Chu, Mignon ;

Kiefer, Hans ;

Maier, Klaus ;

De Angelis, Anna A. ;

Marassi, Francesca M. ;

Opella, Stanley J. .

NATURE, 2012, 491 (7426) :779-+

[26] Expression of hepcidin and other iron-related genes in type 3 hemochromatosis due to a novel mutation in transferrin receptor-2 [J].

Pelucchi, Sara ;

Mariani, Raffaella ;

Trombini, Paola ;

Coletti, Sabina ;

Pozzi, Matteo ;

Paolini, Valentina ;

Barisani, Donatella ;

Piperno, Alberto .

HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, 2009, 94 (02) :276-279

[27] A Meta-Analysis and Genome-Wide Association Study of Platelet Count and Mean Platelet Volume in African Americans [J].

Qayyum, Rehan ;

Snively, Beverly M. ;

Ziv, Elad ;

Nalls, Michael A. ;

Liu, Yongmei ;

Tang, Weihong ;

Yanek, Lisa R. ;

Lange, Leslie ;

Evans, Michele K. ;

Ganesh, Santhi ;

Austin, Melissa A. ;

Lettre, Guillaume ;

Becker, Diane M. ;

Zonderman, Alan B. ;

Singleton, Andrew B. ;

Harris, Tamara B. ;

Mohler, Emile R. ;

Logsdon, Benjamin A. ;

Kooperberg, Charles ;

Folsom, Aaron R. ;

Wilson, James G. ;

Becker, Lewis C. ;

Reiner, Alexander P. .

PLOS GENETICS, 2012, 8 (03)

[28] Genome-wide detection and characterization of positive selection in human populations [J].

Sabeti, Pardis C. ;

Varilly, Patrick ;

Fry, Ben ;

Lohmueller, Jason ;

Hostetter, Elizabeth ;

Cotsapas, Chris ;

Xie, Xiaohui ;

Byrne, Elizabeth H. ;

McCarroll, Steven A. ;

Gaudet, Rachelle ;

Schaffner, Stephen F. ;

Lander, Eric S. .

NATURE, 2007, 449 (7164) :913-U12

[29] A common intracellular allosteric binding site for antagonists of the CXCR2 receptor [J].

Salchow, K. ;

Bond, M. E. ;

Evans, S. C. ;

Press, N. J. ;

Charlton, S. J. ;

Hunt, P. A. ;

Bradley, M. E. .

BRITISH JOURNAL OF PHARMACOLOGY, 2010, 159 (07) :1429-1439

[30] Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis [J].

Sawcer, Stephen ;

Hellenthal, Garrett ;

Pirinen, Matti ;

Spencer, Chris C. A. ;

Patsopoulos, Nikolaos A. ;

Moutsianas, Loukas ;

Dilthey, Alexander ;

Su, Zhan ;

Freeman, Colin ;

Hunt, Sarah E. ;

Edkins, Sarah ;

Gray, Emma ;

Booth, David R. ;

Potter, Simon C. ;

Goris, An ;

Band, Gavin ;

Oturai, Annette Bang ;

Strange, Amy ;

Saarela, Janna ;

Bellenguez, Celine ;

Fontaine, Bertrand ;

Gillman, Matthew ;

Hemmer, Bernhard ;

Gwilliam, Rhian ;

Zipp, Frauke ;

Jayakumar, Alagurevathi ;

Martin, Roland ;

Leslie, Stephen ;

Hawkins, Stanley ;

Giannoulatou, Eleni ;

D'alfonso, Sandra ;

Blackburn, Hannah ;

Boneschi, Filippo Martinelli ;

Liddle, Jennifer ;

Harbo, Hanne F. ;

Perez, Marc L. ;

Spurkland, Anne ;

Waller, Matthew J. ;

Mycko, Marcin P. ;

Ricketts, Michelle ;

Comabella, Manuel ;

Hammond, Naomi ;

Kockum, Ingrid ;

McCann, Owen T. ;

Ban, Maria ;

Whittaker, Pamela ;

Kemppinen, Anu ;

Weston, Paul ;

Hawkins, Clive ;

Widaa, Sara .

NATURE, 2011, 476 (7359) :214-219

← 1 2 3 4 →