title: Genetic variation associated with circulating monocyte count in the eMERGE Network.
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.
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, USA. davidcr@u.washington.edu
authors: David R
authors: DR
authors: Crosslin
authors: Andrew
authors: A
authors: McDavid
authors: Noah
authors: N
authors: Weston
authors: Xiuwen
authors: X
authors: Zheng
authors: Eugene
authors: E
authors: Hart
authors: Mariza
authors: M
authors: de Andrade
authors: Iftikhar J
authors: IJ
authors: Kullo
authors: Catherine A
authors: CA
authors: McCarty
authors: Kimberly F
authors: KF
authors: Doheny
authors: Elizabeth
authors: E
authors: Pugh
authors: Abel
authors: A
authors: Kho
authors: M Geoffrey
authors: MG
authors: Hayes
authors: Marylyn D
authors: MD
authors: Ritchie
authors: Alexander
authors: A
authors: Saip
authors: Dana C
authors: DC
authors: Crawford
authors: Paul K
authors: PK
authors: Crane
authors: Katherine
authors: K
authors: Newton
authors: David S
authors: DS
authors: Carrell
authors: Carlos J
authors: CJ
authors: Gallego
authors: Michael A
authors: MA
authors: Nalls
authors: Rongling
authors: R
authors: Li
authors: Daniel B
authors: DB
authors: Mirel
authors: Andrew
authors: A
authors: Crenshaw
authors: David J
authors: DJ
authors: Couper
authors: Toshiko
authors: T
authors: Tanaka
authors: Frank J A
authors: FJ
authors: van Rooij
authors: Ming-Huei
authors: MH
authors: Chen
authors: Albert V
authors: AV
authors: Smith
authors: Neil A
authors: NA
authors: Zakai
authors: Qiong
authors: Q
authors: Yango
authors: Melissa
authors: M
authors: Garcia
authors: Yongmei
authors: Y
authors: Liu
authors: Thomas
authors: T
authors: Lumley
authors: Aaron R
authors: AR
authors: Folsom
authors: Alex P
authors: AP
authors: Reiner
authors: Janine F
authors: JF
authors: Felix
authors: Abbas
authors: A
authors: Dehghan
authors: James G
authors: JG
authors: Wilson
authors: Joshua C
authors: JC
authors: Bis
authors: Caroline S
authors: CS
authors: Fox
authors: Nicole L
authors: NL
authors: Glazer
authors: L Adrienne
authors: LA
authors: Cupples
authors: Josef
authors: J
authors: Coresh
authors: Gudny
authors: G
authors: Eiriksdottir
authors: Vilmundur
authors: V
authors: Gudnason
authors: Stefania
authors: S
authors: Bandinelli
authors: Timothy M
authors: TM
authors: Frayling
authors: Aravinda
authors: A
authors: Chakravarti
authors: Cornelia M
authors: CM
authors: van Duijn
authors: David
authors: D
authors: Melzer
authors: Daniel
authors: D
authors: Levy
authors: Eric
authors: E
authors: Boerwinkle
authors: Andrew B
authors: AB
authors: Singleton
authors: Dena G
authors: DG
authors: Hernandez
authors: Dan L
authors: DL
authors: Longo
authors: Jacqueline C M
authors: JC
authors: Witteman
authors: Bruce M
authors: BM
authors: Psaty
authors: Luigi
authors: L
authors: Ferrucci
authors: Tamara B
authors: TB
authors: Harris
authors: Christopher J
authors: CJ
authors: O'Donnell
authors: Santhi K
authors: SK
authors: Ganesh
authors: Eric B
authors: EB
authors: Larson
authors: Chris S
authors: CS
authors: Carlson
authors: Gail P
authors: GP
authors: Jarvik
mesh_terms: D000328:Adult; D000368:Aged; D050197:Atherosclerosis / Q000097:blood* / Q000235:genetics*; D002877:Chromosomes, Human / Q000235:genetics* / Q000378:metabolism; D005260:Female; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D039441:Integrin alpha4 / Q000235:genetics / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D007958:Leukocyte Count; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes; D020125:Mutation, Missense; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8; D000097628:Chemokine Receptor D6
chemical_list: D050989:GATA2 Transcription Factor; D039441:Integrin alpha4; D050835:Interferon Regulatory Factors; D008565:Membrane Proteins; D019707:Receptors, Chemokine; D049368:Receptors, Lysophosphatidic Acid; D000099185:Interferon Regulatory Factor-8; C515708:ACKR2 protein, human; D000097628:Chemokine Receptor D6; C494711:GATA2 protein, human; C034241:ribophorin