title: Genome-wide association scan identifies a prostaglandin-endoperoxide synthase 2 variant involved in risk of knee osteoarthritis.
abstract: Osteoarthritis (OA), the most prevalent form of arthritis in the elderly, is characterized by the degradation of articular cartilage and has a strong genetic component. Our aim was to identify genetic variants involved in risk of knee OA in women. A pooled genome-wide association scan with the Illumina550 Duo array was performed in 255 controls and 387 cases. Twenty-eight variants with p < 1 x 10(-5) were estimated to have probabilities of being false positives <or=0.5 and were genotyped individually in the original samples and in replication cohorts from the UK and the U.S. (599 and 272 cases, 1530 and 258 controls, respectively). The top seven associations were subsequently tested in samples from the Netherlands (306 cases and 584 controls). rs4140564 on chromosome 1 mapping 5' to both the PTGS2 and PLA2G4A genes was associated with risk of knee OA in all the cohorts studied (overall odds ratio OR(mh) = 1.55 95% C.I. 1.30-1.85, p < 6.9 x 10(-7)). Differential allelic expression analysis of PTGS2 with mRNA extracted from the cartilage of joint-replacement surgery OA patients revealed a significant difference in allelic expression (p < 1.0 x 10(-6)). These results suggest the existence of cis-acting regulatory polymorphisms that are in, or near to, PTGS2 and in modest linkage disequilibrium with rs4140564. Our results and previous studies on the role of the cyclooxygenase 2 enzyme encoded by PTGS2 underscore the importance of this signaling pathway in the pathogenesis of knee OA.
authors.affiliation: Twin Research Unit, St. Thomas' Hospital Campus, Kings College London School of Medicine, London SE1 7EH, UK. ana.valdes@kcl.ac.uk
authors.forename: Ana M
authors.initials: AM
authors.lastname: Valdes
authors.forename: John
authors.initials: J
authors.lastname: Loughlin
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Timms
authors.forename: Joyce J B
authors.initials: JJ
authors.lastname: van Meurs
authors.forename: Lorraine
authors.initials: L
authors.lastname: Southam
authors.forename: Scott G
authors.initials: SG
authors.lastname: Wilson
authors.forename: Sally
authors.initials: S
authors.lastname: Doherty
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Lories
authors.forename: Frank P
authors.initials: FP
authors.lastname: Luyten
authors.forename: Alexander
authors.initials: A
authors.lastname: Gutin
authors.forename: Victor
authors.initials: V
authors.lastname: Abkevich
authors.forename: Dongliang
authors.initials: D
authors.lastname: Ge
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Hart
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Guangju
authors.initials: G
authors.lastname: Zhai
authors.forename: Rainer J
authors.initials: RJ
authors.lastname: Egli
authors.forename: Michael
authors.initials: M
authors.lastname: Doherty
authors.forename: Jerry
authors.initials: J
authors.lastname: Lanchbury
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D019902:Chondrocytes / Q000201:enzymology; D015331:Cohort Studies; D051546:Cyclooxygenase 2 / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D023281:Genomics; D054513:Group IV Phospholipases A2 / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020370:Osteoarthritis, Knee / Q000201:enzymology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics; D012307:Risk Factors
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D054513:Group IV Phospholipases A2; C516389:PLA2G4A protein, human