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 genomewide 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 =2.7x10(-16), β=-0.22). Other monocyte associations include novel missense variants in the chemokine-binding protein 2 (CCBP2) gene (P-value =1.88x10(-7), β=0.30) and a region of replication found in ribophorin I (RPN1) (P-value=2.63x10(-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 =2.29x10(-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 =5.68x10(-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.
Bibliographical noteFunding Information:
component of the National Institutes of Health (NIH), Bethesda, MD, USA: (i) HG004610, AG06781 (Group Health Cooperative), (ii) HG04599 (Mayo Clinic), (iii) HG004608 (Marshfield Clinic), (iv) HG004609 (Northwestern University), (v) HG004438 (CIDR), (vi) HG004424 (BROAD) and (vii) HG004603 (Vanderbilt University). Additional support was provided by a State of Washington Life Sciences Discovery Fund award to the Northwest Institute of Genetic Medicine (GPJ). CHARGE: This research was made possible by NIA/NIH contract AG000932-02 (2009) Characterization of Normal Genomic Variability. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih. gov). The Age, Gene/Environment Susceptibility Reykjavik Study was funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022 and grants R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The BLSA was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. A portion of that support was through a R&D contract with MedStar Research Institute. The National Heart, Lung, and Blood Institute’s Fra-mingham Heart Study is a joint project of the National Institutes of Health and Boston University School of Medicine and was supported by the National Heart, Lung, and Blood Institute’s Fra-mingham Heart Study (contract No. N01-HC-25195) and its contract with Affymetrix for genotyping services (contract No. N02-HL-6-4278). Analyses reflect the efforts and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The Health ABC Study was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, NIA contracts N01AG62101, N01AG62103 and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences, and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. The InChianti Study was supported as a ‘targeted project’ (ICS 110.1RS97.71) by the Italian Ministry of Health, by the U.S. National Institute on Aging (Contracts N01-AG-916413, N01-AG-821336, 263 MD 9164 13 and 263 MD 821336), and in part by the Intramural Research Program, National Institute on Aging, National Institutes of Health, USA. The GWAS database of the Rotterdam Study was funded through the Netherlands Organization of Scientific Research NWO (nr. 175.010.2005.011, 911.03.012) and the Research Institute for Diseases in the Elderly (RIDE). This study was supported by the Netherlands Genomics Initiative (NGI)/NWO project number 050 060 810 (Netherlands Consortium for Healthy Ageing). The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands organization for scientific research (NWO), the Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Netherlands Heart Foundation, the Ministry of Education, Culture, and Science, the Ministry of Health, Welfare, and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. J.F.F. and A.D. were supported by the Netherlands Organization for Scientific Research (NWO, VICI no. 918-76-619). The participation of A.P.R. was supported by National Heart, Lung, and Blood Institute grant R01 HL-071862.