Genetic variation associated with circulating monocyte count in the eMERGE Network.
Crosslin DR., McDavid A., Weston N., Zheng X., Hart E., de Andrade M., Kullo IJ., McCarty CA., Doheny KF., Pugh E., Kho A., Hayes MG., Ritchie MD., Saip A., Crawford DC., Crane PK., Newton K., Carrell DS., Gallego CJ., Nalls MA., Li R., Mirel DB., Crenshaw A., Couper DJ., Tanaka T., van Rooij FJA., Chen M-H., Smith AV., Zakai NA., Yango Q., Garcia M., Liu Y., Lumley T., Folsom AR., Reiner AP., Felix JF., Dehghan A., Wilson JG., Bis JC., Fox CS., Glazer NL., Cupples LA., Coresh J., Eiriksdottir G., Gudnason V., Bandinelli S., Frayling TM., Chakravarti A., van Duijn CM., Melzer D., Levy D., Boerwinkle E., Singleton AB., Hernandez DG., Longo DL., Witteman JCM., Psaty BM., Ferrucci L., Harris TB., O'Donnell CJ., Ganesh SK., CHARGE Hematology Working Group None., Larson EB., Carlson CS., Jarvik GP., electronic Medical Records and Genomics (eMERGE) Network None.
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.