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

Abstract

Objective. To assess whether the association of genetic polymorphisms with osteoarthritis (OA) in other populations could be replicated in a large, multicenter, mixed-sex, case-control study of clinical knee OA.Methods. Genetic polymorphisms in OA candidate genes were genotyped in 298 men and 305 women, ages 50-86 years, all of whom had a diagnosis of knee OA as assessed clinically and radiographically, and in 300 male and 299 female control subjects matched for age and ethnicity. Allele and haplotype frequencies for 5 genes (ASPN, CALM1, COL2A1, COMP, and FRZB) previously tested for association with hip and/or knee OA in other populations were compared between patients and control subjects, analyzing men and women separately.Results. The same FRZB 2-marker single-nucleotide polymorphism (SNP) haplotype associated with hip OA in other populations of Caucasian women was shown to increase the risk of knee OA among the women (but not the men) in the current study (odds ratio [OR] 2.87, P < 0.04). The CALM1 SNP, which affects the risk of hip OA in Japanese individuals, was not shown to be associated with susceptibility to OA in men or women. COL2A1 haplotypes were demonstrated to be associated with a decreased risk of knee OA in men (OR 0.68, P < 0.005) but not in women. COMP haplotypes that were associated with susceptibility to knee OA were different in men and women (P < 0.014 and P < 0.032, respectively). A meta-analysis of these data and those from previously published reports indicated a strong association between the FRZB G324 allele (P < 0.0003) and suggested that an ASPN allele is protective against the risk of knee OA in Caucasians (P < 0.02).Conclusion. Our results indicate that genetic polymorphisms affecting knee OA vary between populations (Japanese versus Caucasian) and sexes and indicate a role for ASPN, COMP, FRZB, and COL2A1 in Caucasians.

Variation at the ANP32A gene is associated with risk of hip osteoarthritis in women

“…Our data apply only to women of European descent. Differences in the strength or even the presence of genetic associations with OA between sexes have previously been reported, as have those between Asian and Caucasian patients (27,28); therefore, it is possible that this gene may not be associated with OA in men or in other ethnic groups.…”

Osteoarthritis susceptibility genes influence the association between hip morphology and osteoarthritis

“…The identification of such genes should be considered essential to obtain a better understanding of OA and the underlying biologic events preceding its onset (3). One path leading to OA in which genes might play a role starts with the causal effect of hip morphology on the development of OA and may explain part of the heritability of hip OA.…”

Recent advances in association studies of osteoarthritis susceptibility genes

“…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). Taken together with the lack of functional characterization of the FRZB polymorphisms and evidence of causality in OA, the previously reported FRZB association 36 seems to be just another example of a false-positive association.…”

“…However, replication studies in the European Caucasian and Chinese populations reported negative associations for this SNP (rs12885713). [12][13][14][15] Using the same system, Miyamoto et al 16 identified association of DVWA (double von Willebrand factor type A domain) with knee OA. DVWA was a previously unknown gene, not in the gene database.…”