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.

(Gut 2000;46:656-660)

Tumor necrosis factor-stimulated gene-6 (TSG-6) encodes a 35-kDa protein, which is comprised of contiguous Link and CUB modules. TSG-6 protein has been detected in the articular joints of osteoarthritis (OA) patients, with little or no constitutive expression in normal adult tissues. It interacts with components of cartilage matrix (e.g. hyaluronan and aggrecan) and thus may be involved in extracellular remodeling during joint disease. In addition, TSG-6 has been found to have anti-inflammatory properties in models of acute and chronic inflammation. Here we have mapped the human TSG-6 gene to 2q23.3, a region of chromosome 2 linked with OA. A single nucleotide polymorphism was identified that involves a non-synonymous G 3 A transition at nucleotide 431 of the TSG-6 coding sequence, resulting in an Arg to Gln alteration in the CUB module (at residue 144 in the preprotein). Molecular modeling of the CUB domain indicated that this amino acid change might lead to functional differences. Typing of 400 OA cases and 400 controls revealed that the A 431 variant identified here is the major TSG-6 allele in Caucasians (with over 75% being A 431 homozygotes) but that this polymorphism is not a marker for OA susceptibility in the patients we have studied. Expression of the Arg 144 and Gln 144 allotypes in Drosophila Schneider 2 cells, and functional characterization, showed that there were no significant differences in the ability of these full-length proteins to bind hyaluronan or form a stable complex with inter-␣-inhibitor.

Objective. To investigate whether the interleukin-1 (IL-1) ligand gene cluster at 2q13 encodes for genetic susceptibility to primary osteoarthritis (OA).Methods. Seven single-nucleotide polymorphisms (SNPs) and a variable-number tandem repeat (VNTR) polymorphism from within the IL-1 ligand genes IL1A, IL1B, and IL1RN were genotyped in a cohort of 557 OA cases and 557 age-matched controls.Results. None of the variants demonstrated association in the unstratified data set. However, when cases were stratified according to sex and site of disease (hip or knee), 4 SNPs showed marginal evidence for association (P < 0.1) in knee cases (n ‫؍‬ 136) and male knee cases (n ‫؍‬ 58). For 2 of these SNPs, evidence for association was enhanced when probands from 60 kneeonly affected sibling pair families were genotyped and combined with the original knee cases (P < 0.05). Further analysis revealed that the associated alleles at 2 of these SNPs were markers for the same haplotype, the frequency of which was significantly elevated when knee cases and knee probands were combined (P ‫؍‬ 0.01, odds ratio [OR] 1.4) and when male knee cases and male knee probands were combined (P ‫؍‬ 0.009, OR 1.7). Furthermore, linkage analysis of 2q revealed suggestive evidence for linkage to the IL-1 gene clusters in affected sibling pairs concordant for knee OA but no evidence for linkage in affected sibling pairs concordant for hip OA.Conclusion. The IL-1 ligand cluster encodes for susceptibility to knee OA but not to hip OA, highlighting the genetic heterogeneity of this common, complex disease.

Objective. A compelling genetic association with osteoarthritis (OA) of 2 functional alleles in the aspartic acid (D) repeat of the asporin gene was recently reported in a Japanese population. Allele D13 of the repeat encoded OA protection, whereas allele D14 encoded OA susceptibility. The 2 alleles mediate differences in the capacity of asporin to inhibit the cartilage growth factor transforming growth factor ␤, with the D14 allele being a particularly potent inhibitor. Our objective was to assess whether the D repeat is associated with OA in UK Caucasians.Methods. The repeat was genotyped in 1,247 patients who had undergone elective joint replacement of the hip or the knee due to end-stage primary OA and in 748 age-matched controls.Results. The D13 allele was more common in controls, and the D14 allele was more common in patients. However, this trend was significant only for men who had undergone hip replacement (P ‫؍‬ 0.016, odds ratio 1.48, 95% confidence interval 1.09-2.01).Conclusion. Our data suggest that the asporin polymorphism is not a major influence on OA etiology in Caucasians. The results of our study do not question the veracity of the Japanese report. Instead, our study highlights the complex, heterogeneous nature of OA genetic susceptibility.A genetic association of 2 alleles of a functional polymorphism in the aspartic acid (D) repeat of the gene encoding asporin (ASPN) with primary osteoarthritis (OA) was recently reported in a Japanese population (1). Asporin is an extracellular protein belonging to the small leucine-rich proteoglycan family (2,3). These proteins can bind to and regulate the activity of the cartilage growth factor transforming growth factor ␤ (TGF␤). In the Japanese study, 10 alleles of the ASPN D repeat, containing 10-19 D residues, were detected. Allele D14 was significantly more common in 530 patients with knee OA than in 608 controls, with frequencies of 8.6% and 4.8%, respectively (P ϭ 0.00024, odds ratio [OR] 1.87, 95% confidence interval [95% CI] 1.3-2.6). This allele was also significantly more common in 593 patients with hip OA, with a frequency of 7.9% (P ϭ 0.0078, OR 1.70, 95% CI 1.1-2.5). The D13 allele was significantly less common in patients compared with controls. The associations were consistent in both men and women. No other alleles showed significant frequency differences. Subsequent function studies demonstrated that the D14 allele was particularly potent at inhibiting the TGF␤-mediated expression of the genes encoding the cartilage structural proteins aggrecan and type II collagen. The investigators had therefore identified OA-protective (D13) and OA-susceptible (D14) forms of asporin in the Japanese population. Our objective was to assess the role of this repeat polymorphism in OA development in a Caucasian population. PATIENTS AND METHODSCase-control cohort. The patients (n ϭ 1,247; 737 women and 510 men) were ascertained through the Nuffield Orthopaedic Centre in Oxford. Patients had primary OA and had undergone total joint replacement of a hip (n ϭ 9...