title: Phospholipase A2Receptor Gene Polymorphisms Alter its Functions and Present a Genetic Risk of an Increased Intima-Media Thickness of the Carotid Artery.
abstract: OBJECTIVE
  Phospholipase A2receptor 1 (PLA2R) has multiple biological functions other than functioning as a receptor for secretory PLA2s. Two nonsynonymous polymorphisms in the C-type lectin-like domains (CTLD) 1 of PLA2R gene have been associated with idiopathic membranous nephropathy. This study examined whether the same PLA2R polymorphisms may alter functions of PLA2R in cells expressing the variant PLA2R. In addition, the clinical relevance of the experiment was examined.
  
  
  METHODS
  Two nonsynonymous polymorphisms (T/C at rs3749117 and G/C at rs35771982) in CTLD1 of PLA2R gene were completely linked. HEK293 cells expressing human wild-type PLA2R (T at rs3749117 and G at rs35771982) or human mutant PLA2R that had double mutations (C at rs3749117 and C at rs35771982) were constructed.
  
  
  RESULTS
  HEK293 cells expressing mutant PLA2R had lower migratory and proliferative responses to collagen I compared with cells expressing wild-type PLA2R. In 580 male patients, PLA2R gene polymorphisms were associated with an increase in maximum intima-media thickness (maxIMT) of the carotid artery. The multivariate regression model showed that PLA2R gene polymorphisms were a risk factor of an increased maxIMT that was independent of conventional risk factors (OR=1.93, 95% CI: 1.17-3.19, p＜0.01).
  
  
  CONCLUSIONS
  The nonsynonymous common variants of PLA2R gene altered biological functions in cells expressing variant PLA2R. PLA2R gene polymorphisms present a genetic risk of an increased IMT of the carotid artery in male. The functional changes in the variant PLA2R may potentially be responsible for its association with an increased IMT of the carotid artery.
authors.affiliation: Department of Internal Medicine Ⅱ, University of Yamanashi, Faculty of Medicine.
authors.forename: Nguyen Van
authors.initials: NV
authors.lastname: Si
authors.forename: Daisuke
authors.initials: D
authors.lastname: Fujioka
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Kazunori
authors.initials: K
authors.lastname: Watanabe
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nakamura
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Manabu
authors.initials: M
authors.lastname: Uematsu
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Kugiyama
mesh_terms: D000368:Aged; D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D059168:Carotid Intima-Media Thickness; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002637:Chest Pain / Q000503:physiopathology*; D005260:Female; D005434:Flow Cytometry; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D054507:Receptors, Phospholipase A2 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment
chemical_list: D015415:Biomarkers; C516360:PLA2R1 protein, human; D012333:RNA, Messenger; D054507:Receptors, Phospholipase A2