Genetic variation associated with circulating monocyte count in the eMERGE Network

With white blood cell count emerging as an important risk factor for chronic inflammatory diseases, genetic associations of differential leukocyte types, specifically monocyte count, are providing novel candidate genes and pathways to further investigate. Circulating monocytes play a critical role i...

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Published in:	Human molecular genetics Vol. 22; no. 10; pp. 2119 - 2127
Main Authors:	Crosslin, David R, McDavid, Andrew, Weston, Noah, Zheng, Xiuwen, Hart, Eugene, de Andrade, Mariza, Kullo, Iftikhar J, McCarty, Catherine A, Doheny, Kimberly F, Pugh, Elizabeth, Kho, Abel, Hayes, M Geoffrey, Ritchie, Marylyn D, Saip, Alexander, Crawford, Dana C, Crane, Paul K, Newton, Katherine, Carrell, David S, Gallego, Carlos J, Nalls, Michael A, Li, Rongling, Mirel, Daniel B, Crenshaw, Andrew, Couper, David J, Tanaka, Toshiko, van Rooij, Frank J A, Chen, Ming-Huei, Smith, Albert V, Zakai, Neil A, Yango, Qiong, Garcia, Melissa, Liu, Yongmei, Lumley, Thomas, Folsom, Aaron R, Reiner, Alex P, Felix, Janine F, Dehghan, Abbas, Wilson, James G, Bis, Joshua C, Fox, Caroline S, Glazer, Nicole L, Cupples, L Adrienne, Coresh, Josef, Eiriksdottir, Gudny, Gudnason, Vilmundur, Bandinelli, Stefania, Frayling, Timothy M, Chakravarti, Aravinda, van Duijn, Cornelia M, Melzer, David, Levy, Daniel, Boerwinkle, Eric, Singleton, Andrew B, Hernandez, Dena G, Longo, Dan L, Witteman, Jacqueline C M, Psaty, Bruce M, Ferrucci, Luigi, Harris, Tamara B, O'Donnell, Christopher J, Ganesh, Santhi K, Larson, Eric B, Carlson, Chris S, Jarvik, Gail P
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 15-05-2013
Subjects:	Adult Aged Association Studies Atherosclerosis - blood Atherosclerosis - genetics Chromosomes, Human - genetics Chromosomes, Human - metabolism Female GATA2 Transcription Factor - genetics GATA2 Transcription Factor - metabolism Genome-Wide Association Study Humans Integrin alpha4 - genetics Integrin alpha4 - metabolism Interferon Regulatory Factors - genetics Interferon Regulatory Factors - metabolism Leukocyte Count Male Membrane Proteins - genetics Membrane Proteins - metabolism Middle Aged Monocytes Mutation, Missense Receptors, Chemokine - genetics Receptors, Chemokine - metabolism Receptors, Lysophosphatidic Acid - genetics Receptors, Lysophosphatidic Acid - metabolism
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Summary:	With white blood cell count emerging as an important risk factor for chronic inflammatory diseases, genetic associations of differential leukocyte types, specifically monocyte count, are providing novel candidate genes and pathways to further investigate. Circulating monocytes play a critical role in vascular diseases such as in the formation of atherosclerotic plaque. We performed a joint and ancestry-stratified genome-wide association analyses to identify variants specifically associated with monocyte count in 11 014 subjects in the electronic Medical Records and Genomics Network. In the joint and European ancestry samples, we identified novel associations in the chromosome 16 interferon regulatory factor 8 (IRF8) gene (P-value = 2.78×10(-16), β = -0.22). Other monocyte associations include novel missense variants in the chemokine-binding protein 2 (CCBP2) gene (P-value = 1.88×10(-7), β = 0.30) and a region of replication found in ribophorin I (RPN1) (P-value = 2.63×10(-16), β = -0.23) on chromosome 3. The CCBP2 and RPN1 region is located near GATA binding protein2 gene that has been previously shown to be associated with coronary heart disease. On chromosome 9, we found a novel association in the prostaglandin reductase 1 gene (P-value = 2.29×10(-7), β = 0.16), which is downstream from lysophosphatidic acid receptor 1. This region has previously been shown to be associated with monocyte count. We also replicated monocyte associations of genome-wide significance (P-value = 5.68×10(-17), β = -0.23) at the integrin, alpha 4 gene on chromosome 2. The novel IRF8 results and further replications provide supporting evidence of genetic regions associated with monocyte count.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0964-6906 1460-2083
DOI:	10.1093/hmg/ddt010