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Genetic variation associated with circulating monocyte count in the eMERGE Network.

TitleGenetic variation associated with circulating monocyte count in the eMERGE Network.
Publication TypeJournal Article
Year of Publication2013
AuthorsCrosslin DR, McDavid A, Weston N, Zheng X, Hart E, de Andrade M, Kullo IJ, McCarty CA, Doheny KF, Pugh E, Kho A, M Hayes G, 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, L Cupples A, Coresh JJ, 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, Larson EB, Carlson CS
Secondary AuthorsJarvik GP
Corporate AuthorsCHARGE Hematology Working Group, electronic Medical Records and Genomics(eMERGE) Network
JournalHum Mol Genet
Volume22
Issue10
Pagination2119-27
Date Published2013 May 15
ISSN1460-2083
KeywordsAdult, Aged, Atherosclerosis, Chromosomes, Human, Female, GATA2 Transcription Factor, Genome-Wide Association Study, Humans, Integrin alpha4, Interferon Regulatory Factors, Leukocyte Count, Male, Membrane Proteins, Middle Aged, Monocytes, Mutation, Missense, Receptors, Chemokine, Receptors, Lysophosphatidic Acid
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), 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.

DOI10.1093/hmg/ddt010
Alternate JournalHum Mol Genet
PubMed ID23314186
PubMed Central IDPMC3633369
Grant ListUL1RR025005 / RR / NCRR NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
U01 HG004610 / HG / NHGRI NIH HHS / United States
U01 HG04599 / HG / NHGRI NIH HHS / United States
N01-AG-821336 / AG / NIA NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01AG62101 / AG / NIA NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
R01 HL-071862 / HL / NHLBI NIH HHS / United States
1R01AG032098-01A1 / AG / NIA NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
U01 HG006389 / HG / NHGRI NIH HHS / United States
/ / Intramural NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
U01 HG004438 / HG / NHGRI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
U01 AG006781 / AG / NIA NIH HHS / United States
U01 AG06781 / AG / NIA NIH HHS / United States
U01 HG006378 / HG / NHGRI NIH HHS / United States
N01-AG-916413 / AG / NIA NIH HHS / United States
N01-AG-12100 / AG / NIA NIH HHS / United States
U01 HG004603 / HG / NHGRI NIH HHS / United States
N01AG62103 / AG / NIA NIH HHS / United States
N01AG62106 / AG / NIA NIH HHS / United States
AG000932-02 / AG / NIA NIH HHS / United States
N02-HL-64278 / HL / NHLBI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
U01 HG004609 / HG / NHGRI NIH HHS / United States
U01 HG004608 / HG / NHGRI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States