Alternative titles; symbols
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q32.1 | {Osteoarthritis susceptibility 1} | 165720 | Multifactorial | 3 | FRZB | 605083 |
A number sign (#) is used with this entry because of evidence that susceptibility to osteoarthritis-1 (OS1) is conferred by variation in the FRZB gene (605083) on chromosome 2q32.
Osteoarthritis (OA) is a degenerative disease of the joints characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone with sclerosis (Meulenbelt et al., 2006). Clinical problems include pain and joint stiffness often leading to significant disability and joint replacement. Osteoarthritis exhibits a clear predilection for specific joints; it appears most commonly in the hip and knee joints and lumbar and cervical spine, as well as in the distal interphalangeal and the first carpometacarpal (base of thumb) and proximal interphalangeal joints of the hand; however, patients with osteoarthritis may have 1, a few, or all of these sites affected (Stefansson et al., 2003). According to a conservative estimate, greater than 70% of the population of the United States at age 65 years is affected by the disease, reflecting its age dependence.
Genetic Heterogeneity of Susceptibility to Osteoarthritis
Susceptibility to osteoarthritis has been associated with variation in other genes: OS2 (140600) with variation in the MATN3 gene (602109) on chromosome 2p24; OS3 (607850) with variation in the ASPN gene (608135) on chromosome 9q22; and OS5 (612400) with variation in the GDF5 gene (601146) on chromosome 20q11.
Other susceptibility loci for osteoarthritis have been mapped to chromosomes 2q33 (OS4; 610839) and 3p24 (OS6; 612401).
It has long been suggested that osteoarthritis, the most common form of arthritis, is inherited. For example, Stecher (1955) suggested the inheritance of Heberden nodes (140600), a common manifestation of OA, and Kellgren et al. (1963) and Lawrence et al. (1983) reported studies. Kellgren et al. (1963) found an apparently significant role of genetic factors in generalized osteoarthrosis in combination with Heberden nodes before the age of 65 years.
In a study of the genetics of osteoarthritis, Spector et al. (1996) compared radiographs of the hands and knees, presence of Heberden nodes, and pain assessment among 130 identical and 120 nonidentical female twins, aged 48 to 70 years, in Great Britain. The authors calculated the genetic influence for this disorder to be from 39 to 65% in this group of women. Kaprio et al. (1996) corroborated the results of Spector et al. (1996) for women but not for men.
To investigate the inheritance of the common variety of OA, with onset in middle age and the elderly years, Felson et al. (1998) studied hand and knee radiographs obtained from members of the Framingham (Massachusetts) Study cohort (the parents) in 1967 to 1970 and 1992 to 1993, and from the adult children in the Framingham Offspring Study in 1993 to 1994. All hand and knee radiographs evaluated for OA were graded using the Kellgren and Lawrence scale. A total of 337 nuclear families with 2 parents and at least 1 biologic offspring were studied. In parents, the mean age was 61.2 years at the time of hand radiographs and 72.8 years at the time of knee radiographs, which were mostly obtained at a later examination. The mean age at the time of radiographs in offspring was 53.9 years. Using standardized residuals, parent-offspring and sib-sib correlations ranged from 0.115 to 0.306. In segregation analyses, models testing the hypotheses of no familial aggregation, no familial transmission, or a mendelian gene alone were all rejected (P less than 0.001 for each of these models). The best fitting models were mixed models with a mendelian mode of inheritance and a residual multifactorial component. The mendelian recessive model provided the best fit.
Noting that IHH (600726) is the major hedgehog (HH) ligand in chondrocytes, Lin et al. (2009) examined the expression of the HH target genes GLI1 (165220), PTCH (601309), and HHIP (606178) in human osteoarthritic samples and in articular cartilage from mice with surgically induced osteoarthritis and found significant increases in expression of the HH target genes. In genetically modified mice, higher levels of HH signaling in chondrocytes caused a more severe osteoarthritic phenotype. Pharmacologic or genetic inhibition of HH signaling in mice and in human cartilage explants reduced the severity of osteoarthritis; this process appeared to be mediated by RUNX2 (600211) via regulation of ADAMTS5 (605007) expression. Lin et al. (2009) concluded that hedgehog signaling is activated in osteoarthritis and that its modulation can attenuate the severity of disease.
Loughlin et al. (2002) found evidence for linkage of hip osteoarthritis to chromosome 2q: the linkage centered at marker D2S2284 on chromosome 2q31.1, which had a maximum MLS of 1.6 in 378 affected sib pair families.
Heterogeneity
Chapman et al. (1999) performed a 2-stage genomewide scan for osteoarthritis susceptibility loci, using 481 families that each contained at least 1 affected sib pair. The first stage, with 272 microsatellite markers and 297 families, involved a sparse map covering 23 chromosomes at intervals of approximately 15 cM. Sixteen markers that showed evidence of linkage at nominal P equal to or less than 0.5 were taken through to the second stage, with an additional 184 families. This second stage confirmed evidence of linkage for markers on 11q. Additional markers from this region were then typed to create a denser map. They obtained a maximum single-point lod score of 2.40 (p = 0.0004) at D11S901 and a maximum multipoint lod score of 3.15, between markers D11S1358 and D11S35. A subset of 196 of the 481 families, comprising affected female sib pairs, generated a corrected lod score of 2.54 (p = 0.0003) for marker D11S901, with evidence for linkage extending 12 cM proximal to this marker. When they stratified for affected male sib pairs, there was no evidence of linkage to chromosome 11. The data suggested that a female-specific susceptibility gene for idiopathic osteoarthritis is located on 11q.
Loughlin et al. (2002) performed finer linkage mapping of a primary hip osteoarthritis susceptibility locus previously suggested on chromosome 6 by a genomewide linkage scan (Loughlin et al., 1999). Loughlin et al. (2002) genotyped 26 chromosome 6 markers in a cohort of 378 UK Caucasian families that each contained 2 or more sib who had undergone 1 or more replacements of the total hip for primary OA. The highest 2-point lod score was 2.3 for marker D6S1573, while the maximum multipoint lod score (MLS) was 2.8, located at an 11.4 cM interval defined by markers D6S452 and 509-8B2, which map between 70.5 to 81.9 cM from the 6p telomere at 6p12.3-q13. Stratification by gender revealed that this linkage was completely accounted for by the 146 female total hip replacement families, with the highest 2-point lod score being 4.6 for marker D6S1573 and an MLS of 4.0 in the 11.4 cM interval, whereas the 83 male total hip replacement families were unlinked to this interval. As the COL9A1 gene (120210) resides just within the linked interval, Loughlin et al. (2002) identified and genotyped 20 common single-nucleotide polymorphisms (SNPs) from within COL9A1 in the 146 probands from the female total hip replacement families and in 215 age-matched unrelated female controls. None of the SNP alleles or genotypes were associated with OA and there was no significant difference in the frequency of common SNP haplotypes between the probands and the controls. This comprehensive association analysis did not produce any evidence supporting COL9A1 as the primary OA susceptibility locus.
Mabuchi et al. (2006) characterized a large Japanese family with familial osteoarthritis of the hip associated with acetabular dysplasia (142700). They mapped the phenotype to chromosome 13q22.
Using microsatellite targeting of 8 candidate genes spanning the 2q23-q32 region with known roles in skeletal development or homeostasis, Loughlin et al. (2004) found association of hip osteoarthritis with the TNFAIP6 (600410) gene in all probands and with the integrin alpha-6 (ITGA6; 147556) gene and the FRZB gene in female probands. However, genotyping showed lack of association for a nonsynonymous SNP in TNFAIP6, whereas a SNP in FRZB resulting in an arg324-to-gly substitution (R324G; 605083.0001) at the C terminus was associated with hip osteoarthritis in the female probands (p = 0.04). The association was confirmed in an independent cohort of female hip cases. In addition, a haplotype coding for substitutions of 2 highly conserved arginine residues in FRZB, R324G and arg200 to trp (R200W; 605083.0002), was a strong risk factor for primary hip OA, with an odds ratio of 4.1 (p = 0.004). The FRZB protein is a soluble antagonist of wingless (WNT) signaling. Variant FRZB protein with the R324G substitution had diminished ability to antagonize WNT signaling in vitro. Loughlin et al. (2004) concluded that functional polymorphisms within FRZB confer susceptibility for hip OA in females and implicate the WNT signaling pathway in the pathogenesis of this disease.
Associations Pending Confirmation
Hirsch et al. (1998) cited familial aggregation of osteoarthritis on the basis of the Baltimore Longitudinal Study on Aging. The cohort studied was a group of volunteers drawn from a community setting and ascertained without regard to osteoarthritis status. An arg519-to-cys mutation of the type II collagen gene (120140.0003) was found in 4 apparently unrelated families with a distinctive pattern of dominantly inherited generalized osteoarthrosis associated with a mild chondrodysplasia (604864). This led to the suggestion by Prockop et al. (1990) that defects in the COL2A1 gene with a milder effect may be involved in sporadic generalized osteoarthrosis. As a preliminary to association studies of the COL2A1 gene in relation to osteoarthrosis, Meulenbelt et al. (1996) determined the allele frequencies and pairwise linkage disequilibria of RFLPs distributed over the entire COL2A1 gene (spanning 23.6 kb) in a population of unrelated Dutch Caucasians. Their data suggested that disease-related population studies involving the COL2A1 gene should include a minimum of 4 RFLPs to obtain 98% of possible haplotypes occurring.
In a population-based cohort study in Rotterdam (Meulenbelt et al., 1999), radiographic osteoarthritis (ROA) was studied in relation to specific haplotypes of the COL2A1 gene (120140). Radiographs of knees, hips, hands, and spine were scored for the presence of ROA in subjects 55 to 70 years of age. Cases had ROA in 3 or more joint groups; controls, from the same population, had ROA in less than 3 joint groups. Meulenbelt et al. (1999) found that a specific COL2A1 haplotype seemed to predispose to generalized ROA.
Bergink et al. (2003) studied the association between ESR1 (133430) haplotypes as defined by the RFLPs PvuII and XbaI and radiographic osteoarthritis of the knee in a large population-based cohort of 1,483 individuals aged 55 years and older from the Rotterdam Study. Three different haplotype alleles, px, PX and Px, were identified. The PX allele was associated with an increased prevalence of radiographic knee osteoarthritis with an adjusted odds ratio of 1.3 for heterozygotes and 2.2 for homozygotes. Separate analyses for men and women showed similar risk estimates.
In a case-control cohort of 158 Greek patients with idiopathic osteoarthritis of the knees and 193 controls, Fytili et al. (2005) studied long (L) and short (S) alleles of the -1174(TA)n, 1092+3607(CA)n, and 172(CAG)n repeat polymorphisms of the ESR1, ESR2 (601663), and androgen receptor (313700) genes, respectively. When odds ratios were adjusted for various risk factors, it was observed that women with LL genotypes for the ESR2 and AR genes showed significantly increased risk for development of osteoarthritis (p = 0.002 and 0.001, respectively).
In 2 independent Japanese populations totaling 428 osteoarthritis (OA; 165720) patients and 1,008 controls, Mototani et al. (2005) identified significant association between hip OA and a -16C-T promoter SNP (rs12885713) in the CALM1 gene. Functional analysis indicated that the -16T allele decreased CALM1 transcription in vitro and in vivo. CALM1 was expressed in cultured chondrocytes and articular cartilage, and its expression was increased in OA. Inhibition of CALM1 in chondrogenic cells reduced expression of the major cartilage matrix genes COL2A1 (120140) and AGC1 (155760). Mototani et al. (2005) suggested that the transcriptional level of CALM1 may be associated with susceptibility for hip OA through modulation of chondrogenic activity.
Mahr et al. (2006) sought to identify novel regulatory gene polymorphisms associated with OA. Their strategy included an initial transcriptome analysis of the peripheral blood mononuclear cells of 6 patients with OA and 6 age-matched healthy controls. These were screened for allelic expression imbalances and potential regulatory SNPs in the 5-prime regions of the genes. To establish disease association, disparate promoter SNP distributions correlating with the differential expression were tested on larger cohorts. The approach yielded 26 candidate genes differentially expressed between patients and controls. Whereas BLP2 (610014) and CIAS1 (606416) seem to be trans-regulated, as the absence of allelic expression imbalances suggested, the presence of allelic imbalances confirmed cis-regulatory mechanisms for RHOB (165370) and TXNDC3 (607421). On/off-switching suggested additional trans-regulation for TXNDC3. For RHOB and TXNDC3, Mahr et al. (2006) demonstrated statistically significant associations between 5-prime SNPs and OA that hinted at regulatory functions.
In OA, regulatory gene polymorphisms within the IL1 locus (147760) were described by Moos et al. (2000) and Meulenbelt et al. (2004) to be associated with the disease.
Spector et al. (2006) performed a genomewide association analysis of more than 25,000 SNPs in 335 female patients with knee osteoarthritis and 335 asymptomatic and radiographically negative female controls. The marker most strongly associated (p less than 10(-3)) with the risk of knee osteoarthritis was a C/T polymorphism (rs912428) in intron 1 of the LRCH1 gene (610368). The frequency of the T allele compared with controls was consistently increased by 40% in the original group and in 2 independent case-control sample groups of males and females. Combining all 3 data sets, the overall OR for knee osteoarthritis was 1.45 (p less than 0.0005).
Jiang et al. (2008) genotyped the LRCH1 SNP rs912428 in a total of 1,145 patients with knee osteoarthritis and 1,266 controls from Chinese, Japanese, and Greek populations and found no significant difference in genotype or allele frequencies between knee osteoarthritis and control groups in the 3 populations. Metaanalysis of 6 previously published studies found no significant association between LRCH1 and osteoarthritis of the knee.
Mototani et al. (2008) analyzed SNPs in 44 G protein-coupled receptor (GPCR) candidate genes in 368 individuals with knee osteoarthritis and 323 controls and identified a SNP (rs10980705; -2820G-A) in the promoter region of the LPAR1 gene (602282) that showed significant association with disease (uncorrected p = 2.6 x 10(-5); odds ratio, 2.3). Transfection studies in a synovial cell line showed that the LPAR1 promoter with the A allele resulted in increased LPAR1 expression due to stronger binding affinity for AP1 (JUN; 165160).
Saito et al. (2010) analyzed allele frequencies of a common +18C-T SNP (rs17039192) in the EPAS1 gene (603349) between 397 Japanese individuals with knee osteoarthritis and 437 controls, and found significant association of rs17039192 with knee osteoarthritis (p = 0.013; odds ratio = 1.44). Studies in chondrogenic and nonchondrogenic cells demonstrated that the susceptibility allele (+18C) showed higher promoter activity in chondrogenic cells but not in nonchondrogenic cells, confirming that enhanced transactivation of EPAS1 in chondrocytes is associated with osteoarthritis in humans.
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