Investigating the aspartic acid (D) repeat of asporin as a risk factor for osteoarthritis in a UK Caucasian population

Abstract

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...

Mechanisms for Asporin Function and Regulation in Articular Cartilage

“…Asporin belongs to the group of class I SLRPs that also includes decorin and biglycan (9,27); unlike other family members, however, asporin lacks a glycosaminoglycan attachment site and hence is not a proteoglycan. Also unique to asporin is a polymorphic aspartic acid repeat in the N-terminal region, which ranges in length from 8 to 19 residues (7,8,28). This repeat shows a significant genetic association with knee and hip OA, with the D14 allele being over-represented in OA (7,8).…”

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

“…The effect on TGF␤ activity is allele specific, with the D14 allele resulting in greater inhibition than that associated with other alleles. An association of the same polymorphism with OA was later reported among patients of Greek origin with knee OA (14), but no such association was observed among female patients with hip or knee OA in a Caucasian UK population (although a weaker association was observed among male patients) (15), and no association was observed among Spanish patients of either sex (16).…”

“…Three hundred eighty-six of the control subjects in this study had also participated in a genetics association study by Mustafa and coworkers (15); the genotype for the aspartic acid repeat was available for this subset, thus enabling us to determine that the specific 5-SNP haplotypes were in positive linkage disequilibrium with particular aspartic acid repeat alleles (Figure 1). The product-moment correlation pairwise measure of linkage disequilibrium between 5-SNP haplotypes and microsatellite alleles was computed by isolating a specific allele or SNP haplotype and clumping all other alleles together.…”

Strong linkage on 2q33.3 to familial early-onset generalized osteoarthritis and a consideration of two positional candidate genes

“…6 -8 Investigations of these variants within other OA populations revealed confirmation in some studies; 9 however, were excluded in others. 10,11 Together, these studies highlight the complex and heterogeneous nature of OA genetic susceptibility. Additional genes and/or pathways may therefore be discovered to explain the genetic susceptibility to OA further.…”