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

[1] Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes [J].

Barrett, Jeffrey C. ;

Clayton, David G. ;

Concannon, Patrick ;

Akolkar, Beena ;

Cooper, Jason D. ;

Erlich, Henry A. ;

Julier, Cecile ;

Morahan, Grant ;

Nerup, Jorn ;

Nierras, Concepcion ;

Plagnol, Vincent ;

Pociot, Flemming ;

Schuilenburg, Helen ;

Smyth, Deborah J. ;

Stevens, Helen ;

Todd, John A. ;

Walker, Neil M. ;

Rich, Stephen S. .

NATURE GENETICS, 2009, 41 (06) :703-707

[2] Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders [J].

Baxter, EJ ;

Scott, LM ;

Campbell, PJ ;

East, C ;

Fourouclas, N ;

Swanton, S ;

Vassiliou, GS ;

Bench, AJ ;

Boyd, EM ;

Curtin, N ;

Scott, MA ;

Erber, WN ;

Green, AR .

LANCET, 2005, 365 (9464) :1054-1061

[3] The Phosphate Transporter PiT1 (Slc20a1) Revealed As a New Essential Gene for Mouse Liver Development [J].

Beck, Laurent ;

Leroy, Christine ;

Beck-Cormier, Sarah ;

Forand, Anne ;

Salauen, Christine ;

Paris, Nadine ;

Bernier, Adeline ;

Urena-Torres, Pablo ;

Prie, Dominique ;

Ollero, Mario ;

Coulombel, Laure ;

Friedlander, Gerard .

PLOS ONE, 2010, 5 (02)

[4] Link controls mouse hematopoietic stem cell self-renewal and quiescence through direct interactions with JAK2 [J].

Bersenev, Alexey ;

Wu, Chao ;

Balcerek, Joanna ;

Tong, Wei .

JOURNAL OF CLINICAL INVESTIGATION, 2008, 118 (08) :2832-2844

[5] New TFR2 mutations in young Italian patients with hemochromatosis [J].

Biasiotto, Giorgio ;

Camaschella, Clara ;

Forni, Gian Luca ;

Polotti, Anna ;

Zecchina, Gabriella ;

Arosio, Paolo .

HAEMATOLOGICA, 2008, 93 (02) :309-310

[6] Fast-evolving noncoding sequences in the human genome [J].

Bird, Christine P. ;

Stranger, Barbara E. ;

Liu, Maureen ;

Thomas, Daryl J. ;

Ingle, Catherine E. ;

Beazley, Claude ;

MillerO, Webb ;

Hurles, Matthew E. ;

Dermitzakis, Emmanouil T. .

GENOME BIOLOGY, 2007, 8 (06)

[7] Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project [J].

Birney, Ewan ;

Stamatoyannopoulos, John A. ;

Dutta, Anindya ;

Guigo, Roderic ;

Gingeras, Thomas R. ;

Margulies, Elliott H. ;

Weng, Zhiping ;

Snyder, Michael ;

Dermitzakis, Emmanouil T. ;

Stamatoyannopoulos, John A. ;

Thurman, Robert E. ;

Kuehn, Michael S. ;

Taylor, Christopher M. ;

Neph, Shane ;

Koch, Christoph M. ;

Asthana, Saurabh ;

Malhotra, Ankit ;

Adzhubei, Ivan ;

Greenbaum, Jason A. ;

Andrews, Robert M. ;

Flicek, Paul ;

Boyle, Patrick J. ;

Cao, Hua ;

Carter, Nigel P. ;

Clelland, Gayle K. ;

Davis, Sean ;

Day, Nathan ;

Dhami, Pawandeep ;

Dillon, Shane C. ;

Dorschner, Michael O. ;

Fiegler, Heike ;

Giresi, Paul G. ;

Goldy, Jeff ;

Hawrylycz, Michael ;

Haydock, Andrew ;

Humbert, Richard ;

James, Keith D. ;

Johnson, Brett E. ;

Johnson, Ericka M. ;

Frum, Tristan T. ;

Rosenzweig, Elizabeth R. ;

Karnani, Neerja ;

Lee, Kirsten ;

Lefebvre, Gregory C. ;

Navas, Patrick A. ;

Neri, Fidencio ;

Parker, Stephen C. J. ;

Sabo, Peter J. ;

Sandstrom, Richard ;

Shafer, Anthony .

NATURE, 2007, 447 (7146) :799-816

[8] MYELOKATHEXIS - CHRONIC NEUTROPENIA WITH HYPERPLASTIC BONE-MARROW AND HYPERSEGMENTED NEUTROPHILS IN 2 SIBLINGS [J].

BOHINJEC, J .

BLUT, 1981, 42 (03) :191-196

[9] Effects of molgramostim, filgrastim and lenograstim in the treatment of myelokathexis [J].

Cernelc, P ;

Andoljsek, D ;

Mlakar, U ;

Pretnar, J ;

Modic, M ;

Zupan, IP ;

Zver, S .

PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, 2000, 440 (05) :R81-R82

[10] FAMILIAL ERYTHROCYTOSIS GENETICALLY LINKED TO ERYTHROPOIETIN RECEPTOR GENE [J].

DELACHAPELLE, A ;

SISTONEN, P ;

LEHVASLAIHO, H ;

IKKALA, E ;

JUVONEN, E .

LANCET, 1993, 341 (8837) :82-84

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