Genomewide Scan for Hand Osteoarthritis: A Novel Mutation in Matrilin-3

Objective. Rheumatoid arthritis (RA) is a heterogeneous disease that exhibits a complex genetic component. Previous RA genome scans confirmed the involvement of the HLA region and generated data on suggestive signals at non-HLA regions, albeit with few overlaps in findings between studies. The present study was undertaken to detect potential RA gene regions and to estimate the number of true RA gene regions, taking into account the heterogeneity of RA, through performance of a dense genome scan.Methods. In a study of 88 French Caucasian families (105 RA sibpairs), 1,088 microsatellite markers were genotyped (3.3-cM genome scan), and a multipoint model-free linkage analysis was performed. The statistical assessment of the results relied on 10,000 computer simulations. A covariate-based multipoint model-free linkage analysis was performed on the locations of regions with suggestive evidence for linkage.Results. Involvement of the HLA region was strongly confirmed (P ‫؍‬ 6 ؋ 10 ؊5 ), and 19 non-HLA regions showed suggestive evidence for linkage (P < 0.05); 9 of these overlapped with regions suggested in other published RA genome scans. A routine 12-cM genome scan with the same families would have detected only 7 of the 19 regions, including only 4 of the 9 overlapping regions. From the 10,000 computer simulations, we estimated that 8 ؎ 4 regions (mean ؎ SD) were true-positives. RA covariate-based analysis provided additional linkage evidence for 3 regions, with age at disease onset, erosions, and HLA-DRB1 shared epitope as covariates.Conclusion. The results of this study provide evidence of 19 non-HLA RA gene regions, with an estimate of 8 ؎ 4 as true-positives, and provide additional evidence for 3 regions from covariate-based analysis.

Section: Discussionmentioning

confidence: 53%

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confidence: 99%

Dense genome‐wide linkage analysis of rheumatoid arthritis, including covariates

Fortéa¹,

Bükülmez²,

Petit-Teixeira³

et al. 2004

“…Several groups of investigators have performed genome-wide screens of sibling pairs or nuclear families with OA and reported multiple chromosome areas (e.g., 2q13-14, 2q24-32, 2p24, 3p12, 4q32, 11q12, 9q33-34, 4q27, Xp11.3, and 7p22) that show positive linkage to specific OA phenotypes, such as radiographic OA (ROA) in the distal interphalangeal (DIP) joints, severe end-stage disease (based on hip replacement surgery), and nodal OA (7)(8)(9)(10)(11)(12)(13). When investigating end-stage disease (joint replacement surgery) (8), nodal OA (7), or DIP joint OA (11), the most consistent linkage was reported for a broad region on human chromosome 2q13-32.…”

Section: Discussionmentioning

confidence: 99%

Association of the interleukin‐1 gene cluster with radiographic signs of osteoarthritis of the hip

Meulenbelt

Seymour

Nieuwland

et al. 2004

Objective. To study the role of the interleukin-1␤ gene (IL1B) and the IL-1 receptor antagonist gene (IL1RN) in relation to the occurrence of radiographic osteoarthritis (ROA) in the hip, knee, and hand and disc degeneration of the spine.Methods. The study population consisted of a random sample of 886 subjects (ages 55-65 years) from a population-based cohort (the Rotterdam study). Two polymorphisms within IL1B (3953C>T and ؊511C>T) and one within IL1RN (the variable-number tandem repeat [VNTR]) were analyzed and used in an association study of the occurrence of ROA. Haplotyping and simultaneous logistic regression analysis were performed to investigate whether the associations observed were independent.Results. Associations with a predisposition for hip ROA were observed for heterozygous and homozygous carriers of the rare IL1B allele ؊511T (crude odds ratio [OR] 1.8, 95% confidence interval [95% CI] 1.0-3.4 and OR 2.9, 95% CI 1.4-6.3, respectively) and of the IL1RN VNTR allele 2 (crude OR 2.0, 95% CI 1.1-3.4 and OR 3.3, 95% CI 1.4-7.8, respectively). An additive effect was observed for carriers of risk alleles of both polymorphisms, with a significant linear-by-linear association (P ‫؍‬ 0.00022). Conclusion.Our findings suggest that the IL-1 gene cluster polymorphisms may play a significant role in the pathogenesis of OA of the hip.Osteoarthritis (OA) is a joint disease characterized by degeneration of articular cartilage and remodeling of the subchondral bone with sclerosis. It has been demonstrated that genetic factors also play an important role in late-onset OA. Familial aggregation of OA (especially hand, knee, and hip OA) was observed in population-based studies (1-4). Candidate genes that may exert this genetic influence have been investigated by means of population-based association studies and genetic linkage studies in OA families. A large number of association studies using various definitions of OA have been performed, mainly investigating genes encoding structural proteins of the extracellular matrix of cartilage (e.g., COL2A1, CRTM, and AGN) or genes playing a role in the regulation of bone density and mass (e.g., VDR, IGF1, and ER), and have shown both positive and negative results for each of the genes (for review, see ref. 5). These differences in study results may indicate either false-positive or false-negative results, could be the result of differences in the OA phenotype investigated, or could be attributable to different linkage disequilibrium (LD) between the associated polymorphism and the causal mutation in various populations. Moreover, it is becoming increasingly clear that the genetic risk factors for OA at different joint sites may be distinct (6).Several groups of investigators have performed genome-wide screens of sibling pairs or nuclear families with OA and reported multiple chromosome areas (e.g., 2p24, 3p12, 4q32, 11q12, 4q27, Xp11.3, and 7p22) that show positive linkage to specific OA phenotypes, such as radiographic OA (ROA) in the distal interphalangeal (DIP) joints, s...

“…Several MATN3 mutations are involved in multiple epiphyseal dysplasia (MED) (6,7), and another mutation of MATN3 is statistically significantly associated with hand osteoarthritis (8). Furthermore, osteoarthritis in humans is accompanied by increased MATN3 accumulation in the extracellular matrix (9).…”

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confidence: 99%

Increased expression of matrilin‐3 not only in osteoarthritic articular cartilage but also in cartilage‐forming tumors, and down‐regulation of SOX9 via epidermal growth factor domain 1–dependent signaling

Vincourt¹,

Vignaud²,

Lionneton³

et al. 2008

Conclusion. Aberrant expression and processing of MATN3 are hallmarks of conventional cartilaginous neoplasms. A particular step in the maturation of MATN3 limits its processing through the secretion machinery, resulting in its intracellular accumulation upon increased expression. Soluble, secreted MATN3, however, down-regulates SOX9 at the messenger RNA and protein levels. The first EGF-like domain of MATN3 is a critical determinant of its regulatory activity toward SOX9. These activities of MATN3 suggest that its increased expression in osteoarthritis might contribute to the degeneration of articular cartilage.Articular cartilage is mostly made of extracellular specialized collagens and proteoglycans, with physical properties that support frictionless movements and the load-bearing capacity of the joints. Homeostasis of carti-