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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.

Original publication

DOI

10.1093/hmg/ddt010

Type

Journal article

Journal

Human molecular genetics

Publication Date

05/2013

Volume

22

Pages

2119 - 2127

Addresses

Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, USA. davidcr@u.washington.edu

Keywords

CHARGE Hematology Working Group, electronic Medical Records and Genomics (eMERGE) Network, Monocytes, Chromosomes, Human, Humans, Membrane Proteins, Receptors, Chemokine, Receptors, Lysophosphatidic Acid, Integrin alpha4, Leukocyte Count, Mutation, Missense, Adult, Aged, Middle Aged, Female, Male, Atherosclerosis, Interferon Regulatory Factors, GATA2 Transcription Factor, Genome-Wide Association Study