Genetic variation associated with circulating monocyte count in the eMERGE Network by 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, CHARGE Hematology Working Group, Larson Eric B, Carlson Chris S, Jarvik Gail P, electronic Medical Records and Genomics (eMERGE) Network in Human molecular genetics (2013). PubMed

Abstract

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), beta = -0.22). Other monocyte associations include novel missense variants in the chemokine-binding protein 2 (CCBP2) gene (P-value = 1.88×10(-7), beta = 0.30) and a region of replication found in ribophorin I (RPN1) (P-value = 2.63×10(-16), beta = -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), beta = 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), beta = -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.

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