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 ␣-induced protein 6 gene in all probands and the integrin ␣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 ␣-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.

Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee

“…However, the present study is, to our knowledge, the first to show a genetic association with knee OA. We must note that some of the subjects used in the current study (the 185 female control subjects from Oxford) are shared between this study and the original study by Loughlin et al (8). For this reason, the 2 studies are not totally independent.…”

“…Accelerated cartilage breakdown has been shown to develop in knockout mice deficient in this gene (7). The original study in which an association of FRZB with hip OA was reported involved a cohort of women (8); that study showed that the associated alleles at FRZB reduced the activity of the protein encoded. In particular, the haplotype composed of substitutions at 2 highly conserved aspartic acid residues in FRZB (R200W and R324G) was highlighted as a strong risk factor for primary hip OA.…”

Wnt signaling antagonists are potential prognostic biomarkers for the progression of radiographic hip osteoarthritis in elderly Caucasian women

“…Recently, the Wnt/␤-catenin signaling cascade, which is involved in skeletal and joint development, has received attention in OA (3,4). The potential role of the Wnt signaling pathway in the development of OA has been suggested by the increase in susceptibility for hip OA in women that is associated with 2 functional genetic variants in FRZB, which encodes Frizzled-related protein (FRP) (5)(6)(7)(8). Secreted FRP (sFRP) is a naturally occurring soluble antagonist that competitively binds Wnt to antagonize its ability to signal through Frizzled receptors (9,10).…”

“…Secreted FRP (sFRP) is a naturally occurring soluble antagonist that competitively binds Wnt to antagonize its ability to signal through Frizzled receptors (9,10). FRP is expressed in adult human cartilage, and its messenger RNA expression is altered in response to cartilage injury in vitro and in vivo (8,11), suggesting that FRP might protect against the development or progression of OA.…”

Recent advances in association studies of osteoarthritis susceptibility genes

“…35 The associations reported in the original paper were marginal. 36 When multiple testing is considered, only a negative association has been reported in replication studies, even in the European Caucasians. 13,37,38 We also did not find an association of the FRZB variants in the Japanese and Han Chinese populations (D Shi et al, unpublished data).…”