title: Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females.
abstract: Osteoarthritis (OA) is a leading cause of disability in Western society with multiple risk factors, including a complex genetic pattern. Identifying loci involved in the heredity of OA might lead to insights into the molecular pathogenesis of this common disorder. A previous genome scan mapped a primary hip OA susceptibility locus to chromosome 2q with a maximum multipoint logarithm of odds score of 1.6 in 378 affected sibling pair families. Here, microsatellite targeting of eight candidate genes in this region from 2q23-2q32 demonstrated significant associations with the tumor necrosis factor alpha-induced protein 6 gene in all probands and the integrin alpha 6 and frizzled motif associated with bone development (FRZB) genes in female probands. However, genotyping showed lack of association for a nonsynonymous single-nucleotide polymorphism in tumor necrosis factor alpha-induced protein 6, whereas a single-nucleotide polymorphism in FRZB resulting in an Arg324Gly substitution at the carboxyl terminus was associated with hip OA in the female probands (P = 0.04). This association was confirmed in an independent cohort of female hip cases (n = 338; P = 0.04). In addition, a haplotype coding for substitutions of two highly conserved arginine residues (Arg200Trp and Arg324Gly) in FRZB was a strong risk factor for primary hip OA, with an odds ratio of 4.1 (P = 0.004). FRZB encodes secreted frizzled-related protein 3, which is a soluble antagonist of wingless (wnt) signaling. Variant secreted frizzled-related protein 3 with the Arg324Gly substitution had diminished ability to antagonize wnt signaling in vitro. Hence, functional polymorphisms within FRZB confer susceptibility for hip OA in females and implicate the wnt signaling pathway in the pathogenesis of this disease.
authors.affiliation: Institute of Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, University of Oxford, Oxford OX1 7LD, United Kingdom. john.laughlin@ndcls.ox.ac.uk
authors.forename: John
authors.initials: J
authors.lastname: Loughlin
authors.forename: Barbara
authors.initials: B
authors.lastname: Dowling
authors.forename: Kay
authors.initials: K
authors.lastname: Chapman
authors.forename: Lucy
authors.initials: L
authors.lastname: Marcelline
authors.forename: Zehra
authors.initials: Z
authors.lastname: Mustafa
authors.forename: Lorraine
authors.initials: L
authors.lastname: Southam
authors.forename: Athena
authors.initials: A
authors.lastname: Ferreira
authors.forename: Cathleen
authors.initials: C
authors.lastname: Ciesielski
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Carson
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
mesh_terms: D001120:Arginine / Q000235:genetics / Q000378:metabolism; D002356:Cartilage / Q000378:metabolism; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D015331:Cohort Studies; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D016017:Odds Ratio; D015207:Osteoarthritis, Hip / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011506:Proteins / Q000032:analysis / Q000737:chemistry / Q000235:genetics*; D012727:Sex Characteristics; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D001120:Arginine; D011506:Proteins; D000094742:Secreted Frizzled-Related Proteins