title: Genetic association between the PRKCH gene encoding protein kinase Ceta isozyme and rheumatoid arthritis in the Japanese population.
abstract: OBJECTIVE
  Analyses of families with rheumatoid arthritis (RA) have suggested the presence of a putative susceptibility locus on chromosome 14q21-23. This large population-based genetic association study was undertaken to examine this region.
  
  
  METHODS
  A 2-stage case-control association study of 950 unrelated Japanese patients with RA and 950 healthy controls was performed using >400 gene-based common single-nucleotide polymorphisms (SNPs).
  
  
  RESULTS
  Multiple SNPs in the PRKCH gene encoding the eta isozyme of protein kinase C (PKCeta) showed significant single-locus disease associations, the most significant being SNP c.427+8134C>T (odds ratio 0.72, 95% confidence interval 0.62-0.83, P = 5.9 x 10(-5)). Each RA-associated SNP was consistently mapped to 3 distinct regions of strong linkage disequilibrium (i.e., linkage disequilibrium or haplotype blocks) in the PRKCH gene locus, suggesting that multiple causal variants influence disease susceptibility. Significant SNPs included a novel common missense polymorphism of the PRKCH gene, V374I (rs2230500), which lies within the ATP-binding site that is highly conserved among PKC superfamily members. In circulating lymphocytes, PRKCH messenger RNA was expressed at higher levels in resting T cells (CD4(+) or CD8(+)) than in B cells (CD19(+)) or monocytes (CD14(+)) and was significantly down-regulated through immune responses.
  
  
  CONCLUSIONS
  Our results provide evidence of the involvement of PRKCH as a susceptibility gene for RA in the Japanese population. Dysregulation of PKCeta signal transduction pathway(s) may confer increased risk of RA through aberrant T cell-mediated autoimmune responses.
authors.affiliation: The University of Tokushima, Tokushima, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Takata
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hamada
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Miyatake
authors.forename: Shunji
authors.initials: S
authors.lastname: Nakano
authors.forename: Fumio
authors.initials: F
authors.lastname: Shinomiya
authors.forename: Charles R
authors.initials: CR
authors.lastname: Scafe
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Reeve
authors.forename: Dai
authors.initials: D
authors.lastname: Osabe
authors.forename: Maki
authors.initials: M
authors.lastname: Moritani
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kunika
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Natsuo
authors.initials: N
authors.lastname: Yasui
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Itakura
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D002883:Chromosomes, Human, Pair 14; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism; D000099293:Protein Kinase C-lambda
chemical_list: D007527:Isoenzymes; D011493:Protein Kinase C; D012333:RNA, Messenger; D029961:Zebrafish Proteins; D000099293:Protein Kinase C-lambda