Association study of candidate genes for the prevalence and progression of knee osteoarthritis

Valdes, Ana M.; Hart, Deborah; Jones, Karen A.; Surdulescu, Gabriela L.; Swarbrick, P. A.; Doyle, D V; Schafer, Alan J.; Spector, Tim D.

doi:10.1002/art.20443

Cited by 169 publications

(162 citation statements)

References 41 publications

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“…The association we observed was not particularly strong but was consistent with expression data comparing normal and OA-affected cartilage (20), the fact that serum levels of COMP are increased in OA (22), and the fact that COMP levels are heritable (34). A meta-analysis including both sets of data, however, showed no evidence of association between knee OA and COMP.…”

Section: Discussionsupporting

confidence: 80%

“…The cartilage oligomeric matrix protein gene (COMP) is a member of the thrombospondin gene family, which is known to be expressed more abundantly in OA cartilage than in normal cartilage (20). Prospective studies have shown that elevated serum levels of COMP are observed early in patients in whom chronic knee pain without radiographic OA progresses to radiographic disease (21).…”

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confidence: 99%

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

Valdes

Loughlin

Oene

et al. 2007

Arthritis & Rheumatism

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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.

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Section: Discussionsupporting

confidence: 80%

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confidence: 99%

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

Valdes

Loughlin

Oene

et al. 2007

Arthritis & Rheumatism

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179

118

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“…Moreover, we did not observe a sex-dependent allele frequency difference for the LRCH1 marker SNP, which suggests that some gene effects may be relevant for both sexes; this is consistent with the recent findings reported by Kizawa et al (16). It is also possible that this gene may influence the progression of disease as much as prevalent OA changes (36).…”

Section: Discussionmentioning

confidence: 99%

Association between a variation in LRCH1 and knee osteoarthritis: A genome‐wide single‐nucleotide polymorphism association study using DNA pooling

Spector¹,

Reneland²,

Mah³

et al. 2006

Arthritis & Rheumatism

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Objective. To perform a large-scale association analysis of single-nucleotide polymorphisms (SNPs) in patients with radiographically defined osteoarthritis (OA) of the knee.Methods. We examined >25,000 SNPs located within ϳ14,000 genes for associations with radiographically defined knee OA, using polymerase chain reaction and MassExtend amplification techniques. Allele frequencies were estimated initially in DNA pools from 335 female patients with knee OA and 335 asymptomatic and radiographically negative female control subjects. All were of northern European ancestry. Significant allele frequency differences were validated by genotyping of individual DNA samples. Confirmed significant findings were verified in 2 additional case-control samples from the UK (443 cases and 303 controls) and Newfoundland (346 cases and 264 controls). Chondrosarcoma cell lines were used to test for potential differences in gene expression.Results. The marker most strongly associated with the risk of knee OA was rs912428, a C/T polymorphism in intron 1 of LRCH1, a gene on chromosome 13q14 that encodes a novel protein of as-yet-unknown function. The frequency of the T allele compared with controls was consistently increased by 40% across all 3 case-control groups. Additional subanalyses in casecontrol samples with hip OA and hand OA suggested similar trends, but did not reach statistical significance. Association fine-mapping using 10 additional SNPs in LRCH1 confirmed intron 1 as the region of highest association but failed to reveal variations with significance stronger than the marker SNP, as did the haplotype analysis. LRCH1 was not up-regulated or overexpressed in chondrosarcoma cell lines exposed to inflammatory stimuli, suggesting a possible structural role.Conclusion. A genetic variant in LRCH1 was consistently associated with knee OA in 3 samples from 2 populations. Our results also suggest that the same association with OA may exist at other sites. Additional genetic and experimental work is needed to elucidate the precise mechanism by which the LRCH1 gene influences OA risk.Osteoarthritis (OA) is a degenerative joint disease that primarily affects the knees, hips, hands, and spine (1). The biology and epidemiology of OA seem to differ between sites, with a different balance of risk factors and age at onset for different sites. For genetic purposes, site-specific classification is likely to be important, with differential linkage and association results for the hip and the spine (2).

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“…CILP-1 levels have been shown to increase with age (6, 10) and in patients with early stage osteoarthritis (11). The association of single nucleotide polymorphisms in the CILP1 gene with musculoskeletal disorders including osteoarthritis (12)(13)(14), and lumbar disc disease in a Japanese population (8) …”

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confidence: 99%

Cartilage Intermediate Layer Protein 2 (CILP-2) Is Expressed in Articular and Meniscal Cartilage and Down-regulated in Experimental Osteoarthritis

Bernardo

Belluoccio

Rowley

et al. 2011

Journal of Biological Chemistry

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Using transcriptome profiling to determine differential gene expression between the permanent mouse articular cartilage and the transient growth plate cartilage, we identified a highly expressed gene, Cilp2, which is expressed differentially by articular chondrocytes. CILP-2 is highly homologous to CILP-1 (cartilage intermediate layer protein 1), which is expressed in the intermediate zone of articular cartilage and has been linked to cartilage degenerative diseases. We demonstrated that Cilp2 has a restricted mRNA distribution at the surface of the mouse articular cartilage during development, becoming localized to the intermediate zone of articular cartilage and meniscal cartilage with maturity. Although the extracellular CILP-2 protein localization is broadly similar to CILP-1, CILP-2 appears to be more localized in the deeper intermediate zone of the articular cartilage extracellular matrix at maturity. CILP-2 was shown to be proteolytically processed, N-glycosylated, and present in human articular cartilage. In surgically induced osteoarthritis in mice, Cilp1 and Cilp2 gene expression was dysregulated. However, whereas Cilp1 expression was increased, Cilp2 gene expression was down-regulated demonstrating a differential response to mechanically induced joint destabilization. CILP-2 protein was reduced in the mouse osteoarthritic cartilage. Ultrastructural analysis also suggested that CILP-2 may be associated with collagen VI microfibrils and thus may mediate interactions between matrix components in the territorial and inter-territorial articular cartilage matrix. mRNA expression analysis indicated that whereas Cilp1 and Cilp2 are expressed most abundantly in cartilaginous tissues, expression can be detected in muscle and heart. During limb development, chondrocytes follow alternative developmental pathways. Chondrocytes that form at the epiphyseal surface of long bones develop into permanent articular chondrocytes and form the smooth articular cartilage necessary for effective weight-bearing and joint movement. The other group of chondrocytes, the transient epiphyseal chondrocytes, are organized into growth plates, and undergo a sequential maturation program from resting cells to proliferative, prehypertrophic, and ultimately hypertrophic end-stage chondrocytes that are replaced with bone during endochondral ossification. Both populations of chondrocytes are critical for the formation of the skeleton and disturbances to normal chondrocyte development and function results in chondrodysplasias (reviewed by Refs. 1-3).One of the important determinants of cartilage function is extracellular matrix (ECM) 3 structure and composition. To identify new ECM determinants of the articular cartilage, we compared the gene expression profile of mouse articular cartilage with growth plate cartilage. These studies revealed that the most highly differentially expressed cDNA on the array was a Riken clone that corresponded to Cilp2 (cartilage intermediatelayer protein, isoform 2), recently reported as a product of cartilage c...

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Association study of candidate genes for the prevalence and progression of knee osteoarthritis

Cited by 169 publications

References 41 publications

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

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

Association between a variation in LRCH1 and knee osteoarthritis: A genome‐wide single‐nucleotide polymorphism association study using DNA pooling

Cartilage Intermediate Layer Protein 2 (CILP-2) Is Expressed in Articular and Meniscal Cartilage and Down-regulated in Experimental Osteoarthritis

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