Osteoarthritis Susceptibility Locus Research Articles

Lack of support for the presence of an osteoarthritis susceptibility locus on chromosome 6p

To replicate, in a Northern Irish population, the previously reported association between a locus on chromosome 6 and hip osteoarthritis (OA). Patients with hip OA were identified from a registry of patients who had undergone total hip replacement surgery over an 8-year period at a single large orthopedic unit in Northern Ireland. Patients identified as index cases were contacted by mail and asked to reply only if another family member also had undergone total hip replacement surgery. Using this approach, we identified 288 sibling pairs concordant for primary hip OA. DNA was extracted from peripheral blood, and microsatellite markers were amplified by polymerase chain reaction and subsequently genotyped. No evidence of linkage to this region was demonstrated by either 2-point analysis or multipoint analysis of 17 microsatellites. The reported association between a locus on chromosome 6 and hip OA could not be confirmed in this population. Different methods of ascertainment and phenotyping of OA may contribute to the current inability to replicate genetic associations for hip OA.

A genome scan for joint-specific hand osteoarthritis susceptibility: The Framingham Study.

Studies investigating hand osteoarthritis (OA) as a single entity have not shown strong linkage of the disease with any chromosomal sites. We undertook this study to test our hypothesis that phenotypes of hand OA may show stronger linkage than has been shown for overall hand OA. We performed a factor analysis on measures of hand OA to determine patterns of disease. Using the joint regions identified by this analysis, we performed a genome-wide linkage analysis for OA susceptibility loci using 426 original cohort members and 790 offspring cohort members in 267 pedigrees. Radiographic OA features evaluated included the Kellgren/Lawrence score, osteophytes, and joint space narrowing. Prior to linkage analysis, standardized residuals were computed from regression analysis of each phenotype on age. This was performed separately for each sex and cohort. The variance component model (GeneHunter) was then applied to the normalized scores of the residuals of both sexes and cohorts. There was evidence suggestive of linkage (logarithm of odds [LOD] score >1.5) at 16 sites. Four of these sites had LOD scores >3.0. Two of these sites (identified in the full sample) included a linkage region for OA of the distal interphalangeal (DIP) joint on chromosome 7 (155 cM; LOD score 3.06) and a linkage region for OA of the first carpometacarpal (CMC) joint on chromosome 15 (81 cM; LOD score 6.25). The other 2 sites (identified in women) included a linkage region for OA of the DIP joint on chromosome 1 (202 cM; LOD score 3.03) and a linkage region for OA of the first CMC joint on chromosome 20 (4 cM; LOD score 3.74). These data suggest that several chromosomes contain hand OA susceptibility genes and that a joint-specific approach may be more rewarding than a global approach to the genetics of hand OA. Further investigation of these regions is warranted using finer maps and other populations.

Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females.

Osteoarthritis (OA) is a leading cause of disability in Western society with multiple risk factors, including a complex genetic pattern. Identifying loci involved in the heredity of OA might lead to insights into the molecular pathogenesis of this common disorder. A previous genome scan mapped a primary hip OA susceptibility locus to chromosome 2q with a maximum multipoint logarithm of odds score of 1.6 in 378 affected sibling pair families. Here, microsatellite targeting of eight candidate genes in this region from 2q23-2q32 demonstrated significant associations with the tumor necrosis factor alpha-induced protein 6 gene in all probands and the integrin alpha 6 and frizzled motif associated with bone development (FRZB) genes in female probands. However, genotyping showed lack of association for a nonsynonymous single-nucleotide polymorphism in tumor necrosis factor alpha-induced protein 6, whereas a single-nucleotide polymorphism in FRZB resulting in an Arg324Gly substitution at the carboxyl terminus was associated with hip OA in the female probands (P = 0.04). This association was confirmed in an independent cohort of female hip cases (n = 338; P = 0.04). In addition, a haplotype coding for substitutions of two highly conserved arginine residues (Arg200Trp and Arg324Gly) in FRZB was a strong risk factor for primary hip OA, with an odds ratio of 4.1 (P = 0.004). FRZB encodes secreted frizzled-related protein 3, which is a soluble antagonist of wingless (wnt) signaling. Variant secreted frizzled-related protein 3 with the Arg324Gly substitution had diminished ability to antagonize wnt signaling in vitro. Hence, functional polymorphisms within FRZB confer susceptibility for hip OA in females and implicate the wnt signaling pathway in the pathogenesis of this disease.

Common variants within the interleukin 4 receptor alpha gene (IL4R) are associated with susceptibility to osteoarthritis.

Primary osteoarthritis (OA) is a common late-onset arthritis that demonstrates a complex mode of transmittance with both joint-site and gender-specific heterogeneity. We have previously linkage-mapped an OA susceptibility locus to a 12-cM interval at chromosome 16p12.3-p12.1 in a cohort of 146 affected female sibling-pair families ascertained by total hip replacement (female-THR families), with a maximum multipoint LOD score of 1.7. Despite the low LOD score, we were encouraged to investigate this interval further following the report of a linkage to the same interval in an Icelandic pedigree with an early-onset form of hip OA. Using public databases, we searched the interval for plausible candidates and concluded that the gene encoding the interleukin 4 receptor alpha chain (IL4R) was a particularly strong candidate based on its known role in cartilage homeostasis. We genotyped nine common single nucleotide polymorphisms (SNPs) from within IL4R, including six non-synonymous SNPs, in the 146 probands from our female-THR families (stage 1) and in an independent cohort of 310 female-THR cases (stage 2). We compared allele frequencies with those of 399 age-matched female controls. All individuals were UK Caucasians. The minor alleles of two SNPs demonstrated association in both stages, with the most significant association having a P-value of 0.004 with an odds ratio (OR) of 2.1. These two SNPs defined two associated SNP groups. Inheriting a minor SNP allele from both groups was a particular risk factor (OR=2.4, P=0.0008). Our data suggest that functional variants within the IL4R gene predispose to hip OA in Caucasian females.

Finer linkage mapping of primary osteoarthritis susceptibility loci on chromosomes 4 and 16 in families with affected women.

To more finely linkage-map primary osteoarthritis (OA) susceptibility loci on chromosomes 4 and 16. Two hundred eighteen families, each with 2 or more women concordant for primary OA (ascertained by total hip replacement [THR] or total knee replacement), were genotyped using highly polymorphic microsatellite markers from chromosomes 4 and 16, at an average density of 1 marker every 4 cM. Two-point and multipoint linkage analyses were performed for all 218 families and for the 146 families from the 218 that included women concordant for THR (female-THR families). A single region of linkage was identified on chromosome 4q, with a maximum multipoint logarithm of odds (LOD) score (MLS) of 3.1 in the 146 female-THR families. This locus was centered 79 cM from the 4p telomere and had a 1-LOD support interval of 4 cM. Two regions of linkage were identified on chromosome 16, the first on 16p with an MLS of 1.7 in the female-THR families and the second on 16q with an MLS of 1.9 in all 218 families. The first locus was centered 46 cM and the second 89 cM from the p-telomere. The 1-LOD support intervals were 12 cM and 10 cM, respectively. Finer linkage mapping using a high density of microsatellite markers has narrowed female OA susceptibility loci on chromosomes 4 and 16. The regions have been narrowed sufficiently for association analysis.

Genetics of osteoarthritis and potential for drug development

Genome-wide linkage scans for the mapping of osteoarthritis susceptibility loci have come to the fore in recent years, driven by the failure of candidate gene association studies. Four scans have been published, with several strong linkages reported. These do not encompass the major cartilage structural genes that many consider the most likely susceptibility loci. This has increased the probability that the biological pathways responsible for susceptibility are modifiable by drug treatment, which one would not reasonably expect for a structural protein. This in itself has stimulated the interest of several pharmaceutical companies. Such interest will be to the benefit of patients, but will require candid co-operation between academics and industry if the delay in transferring research findings from the laboratory to the clinic is to be minimised.

Finer linkage mapping of a primary hip osteoarthritis susceptibility locus on chromosome 6.

Primary osteoarthritis (OA) is a common late-onset disease that exhibits complex genetic transmittance. A previous genome-wide linkage scan of OA affected sibling pair families (ascertained by total joint replacement surgery) identified a region of suggestive linkage on chromosome 6, with a maximum multipoint-LOD score (MLS) of 2.9 in 194 families containing sibling pairs concordant for total hip replacement (THR-families). However, up to 50 cM of the chromosome had a multipoint-LOD score >2.0, indicating that the susceptibility locus was poorly mapped. We have now genotyped chromosome 6 to a higher density in an expanded cohort of 378 THR-families. We obtained an MLS of 2.8 to 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. Stratification by gender revealed that this linkage was completely accounted for by female THR-families (n=146), with an MLS of 4.0 and with the highest two-point LOD score being 4.6 for marker D6S1573 (75.9 cM). The 11.4 cM interval just encompasses the candidate gene COL9A1 (81.9 cM). We identified and then genotyped twenty common single nucleotide polymorphisms (SNPs) from within COL9A1 in the 146 probands from our female THR-families and in 215 age-matched female controls. No SNP allele, genotype or haplotype demonstrated association to disease. Overall, we have narrowed the chromosome 6 OA susceptibility locus to a point at which linkage disequilibrium/association analysis is feasible, we have demonstrated that this locus is female specific, and found no evidence that COL9A1 encodes for the susceptibility.

Finer linkage mapping of primary hip osteoarthritis susceptibility on chromosome 11q in a cohort of affected female sibling pairs.

To finer linkage-map a primary osteoarthritis (OA) susceptibility locus as a prerequisite to linkage disequilibrium/association analysis. A 50-cM interval of chromosome 11q that we had previously identified as harboring susceptibility to hip OA in a female sibling-pair cohort was subjected to finer linkage mapping. Thirty-five microsatellite markers with a mean marker interval of 1.4 cM were genotyped in 146 families containing female sibling pairs who were concordant for hip OA, as ascertained by total hip replacement. Two-point and multipoint linkage analysis revealed 2 distinct regions of linkage within the 50-cM interval. The first locus had a linkage interval of 11.9 cM and was centered at 81.5 cM from the 11p telomere, with a maximum multipoint logarithm of odds (LOD) score of 2.4. The second region had a linkage interval of 6.5 cM and was centered at 93.1 cM from the 11p telomere, with a maximum multipoint LOD score of 1.8. Dense linkage mapping has highlighted the presence of 2 loci on chromosome 11q, each conferring susceptibility to hip OA. Both loci are sufficiently narrow for association analysis to be undertaken.

Identification of sequence polymorphisms in two sulfation-related genes, PAPSS2 and SLC26A2, and an association analysis with knee osteoarthritis.

Osteoarthritis (OA) is one of the most common musculoskeletal disorders and is characterized by degeneration of articular cartilage. Sulfation of extracellular matrix proteins in articular cartilage is an important step in maintaining normal cartilage metabolism. Two sulfation-related genes have been reported as the causal genes of severe chondrodysplasias: mutations in PAPSS2 (3'-phosphoadenosine 5'-phosphosulfate synthase 2) cause spondylo-epimetaphyseal dysplasia (SEMD), and mutations in SLC26A2 (solute carrier family 26, member 2) cause diastrophic dysplasia. Given their critical roles in cartilage metabolism and the severe phenotypes that result from mutations in these genes, we examined PAPSS2 and SLC26A2 as candidate susceptibility loci for OA. We identified sequence polymorphisms in the coding and core promoter regions of these genes and analyzed their potential association with knee OA within the Japanese population. Ten sequence polymorphisms were detected in PAPSS2 and five in SLC26A2. An association analysis showed suggestive association of one minor polymorphism in the promoter region of SLC26A2. This 4-bp adenine deletion allele, del4A, was over-represented in knee OA (P = 0.043, odds ratio = 3.43) and is thought to confer a minor susceptibility to knee OA within the Japanese population. Haplotype analysis showed no evidence of association with the two genes, however, excluding them as major susceptibility loci for knee OA.

Prevalence and inheritance of hip osteoarthritis in Iceland

The purpose of this study was to: (I) assess the prevalence of hip osteoarthritis (OA) in Iceland and compare it with that in Southern Scandinavia, (II) determine the incidence of total hip replacement (THR) for primary OA in Iceland, (III) compare two different methods for defining radiographic hip OA, (IV) assess in a population-wide study in Iceland the genetic contribution t hip OA leading to THR, and (V) perform a genome-wide scan of a large Icelandic family to identify a chromosomal susceptibility locus for hip OA leading to THR. many Icelandic patients with hip OA have been well aware that this disease "goes in the family". by examining a large proportion of all Icelandic colon radiographs taken 1990-1996 the prevalence of radiographic hip OA in Iceland was found to be at least five-fold higher compared to Swedish and Danish studies that have used the same methods. A comparison of two methods for estimating hip OA from colon radiographs showed that a simple quantitative method of measuring joint space was more reliable than a qualitative method. The age-standardized incidence of THR for primary hip OA in Iceland between 1982 and 1996 was estimated and found to be about 50 percent higher than for Sweden. The higher Icelandic prevalence of hip OA may explain most of this difference. To investigate the contribution of heritability to hip OA leading to THR, information from two population-wide database in Iceland was combined: A national registry of THR between 1972 and 1996, and a genealogy database of all Icelandic genealogy records for the last 11 centuries made available by deCode Genetics. The genetic contribution to THR for OA was assessed by (a) identifying familial clusters of THR for OA, (b) applying the minimum founder test (MFT) to estimate the minimum number of ancestors to account for all patients with THR for OA, compared to the average number of founders for control lists, (c) calculating an average pairwise kinship coefficient (KC) for the patient and control lists, (d) estimating the relative risk (RR) for relatives of patients with THR for OA. A large number of familial clusters of patients with THR for OA were identified. MFT showed that OA patients descended from fewer founders than the control groups. The average pairwise KC among patients with OA was greater than in the population. RR for siblings of THR for OA patients was 3.05 (2.52, 3.10). Icelandic patients with THR for OA are thus significantly more related to each other than are matched controls. These findings support a significant genetic contribution to a common form of OA and encourages the search for genes conferring an increased susceptibility to OA. New techniques now make it possible to search the whole human genome for chromosomal susceptibility loci associating with OA. A genome wide scan was done to identify susceptibility loci for hip OA leading to THR, using DNA from a large Icelandic family with a very high prevalence of primary hip OA. A genome locus with a lod score of 2.58 was identified on chromosome 16p. A similar locus has been reported on from England. This is the first instance where what may be the same susceptibility locus for OA is independently described in two different populations with hip OA. We have identified other families with hip OA which link to the studied family and are continuing an expanded genome-wide scan. Continued studies of the kind outlined here will clarify the complex genetic background of OA and identify genetic variation associated with the disease. In addition to improving our understanding of the pathogenesis of OA and identifying new molecular targets for treatment, this will allow a better insight into the interactions between genetic background and environmental factors that initiate and drive OA.

Prevalence and inheritance of hip osteoarthritis in Iceland

The purpose of this study was to: (I) assess the prevalence of hip osteoarthritis (OA) in Iceland and compare it with that in Southern Scandinavia, (II) determine the incidence of total hip replacement (THR) for primary OA in Iceland, (III) compare two different methods for defining radiographic hip OA, (IV) assess in a population-wide study in Iceland the genetic contribution t hip OA leading to THR, and (V) perform a genome-wide scan of a large Icelandic family to identify a chromosomal susceptibility locus for hip OA leading to THR. many Icelandic patients with hip OA have been well aware that this disease "goes in the family". by examining a large proportion of all Icelandic colon radiographs taken 1990-1996 the prevalence of radiographic hip OA in Iceland was found to be at least five-fold higher compared to Swedish and Danish studies that have used the same methods. A comparison of two methods for estimating hip OA from colon radiographs showed that a simple quantitative method of measuring joint space was more reliable than a qualitative method. The age-standardized incidence of THR for primary hip OA in Iceland between 1982 and 1996 was estimated and found to be about 50 percent higher than for Sweden. The higher Icelandic prevalence of hip OA may explain most of this difference. To investigate the contribution of heritability to hip OA leading to THR, information from two population-wide database in Iceland was combined: A national registry of THR between 1972 and 1996, and a genealogy database of all Icelandic genealogy records for the last 11 centuries made available by deCode Genetics. The genetic contribution to THR for OA was assessed by (a) identifying familial clusters of THR for OA, (b) applying the minimum founder test (MFT) to estimate the minimum number of ancestors to account for all patients with THR for OA, compared to the average number of founders for control lists, (c) calculating an average pairwise kinship coefficient (KC) for the patient and control lists, (d) estimating the relative risk (RR) for relatives of patients with THR for OA. A large number of familial clusters of patients with THR for OA were identified. MFT showed that OA patients descended from fewer founders than the control groups. The average pairwise KC among patients with OA was greater than in the population. RR for siblings of THR for OA patients was 3.05 (2.52, 3.10). Icelandic patients with THR for OA are thus significantly more related to each other than are matched controls. These findings support a significant genetic contribution to a common form of OA and encourages the search for genes conferring an increased susceptibility to OA. New techniques now make it possible to search the whole human genome for chromosomal susceptibility loci associating with OA. A genome wide scan was done to identify susceptibility loci for hip OA leading to THR, using DNA from a large Icelandic family with a very high prevalence of primary hip OA. A genome locus with a lod score of 2.58 was identified on chromosome 16p. A similar locus has been reported on from England. This is the first instance where what may be the same susceptibility locus for OA is independently described in two different populations with hip OA. We have identified other families with hip OA which link to the studied family and are continuing an expanded genome-wide scan. Continued studies of the kind outlined here will clarify the complex genetic background of OA and identify genetic variation associated with the disease. In addition to improving our understanding of the pathogenesis of OA and identifying new molecular targets for treatment, this will allow a better insight into the interactions between genetic background and environmental factors that initiate and drive OA.

Linkage analysis of chromosome 2q in osteoarthritis.

In independent linkage studies chromosome 2q11-q24 and chromosome 2q23-35 have previously been implicated as regions potentially harbouring susceptibility loci for osteoarthritis (OA). To test chromosome 2q for linkage to idiopathic osteoarthritis. Using a cohort of 481 OA families that each contained at least one affected sibling pair with severe end-stage disease (ascertained by hip or knee joint replacement surgery), we conducted a linkage analysis of chromosome 2q using 16 polymorphic microsatellite markers at an average spacing of one marker every 8.5 cM. Our results provide suggestive evidence for a locus at 2q31 with a maximum multipoint logarithm of the odds score (MLS) of 1.22 which increased to 2.19 in those families concordant for hip-only disease (n = 311). This suggestive linkage was greater in male-hip families (MLS = 1.57, n = 71) than in female-hip families (MLS = 0.71, n = 132). Chromosome 2q is likely to contain at least one susceptibility locus for OA.

Linkage analysis of candidate genes as susceptibility loci for osteoarthritis-suggestive linkage of COL9A1 to female hip osteoarthritis.

To examine 11 candidate genes as susceptibility loci for osteoarthritis (OA). A total of 481 families have been ascertained in which at least two siblings have had joint replacement surgery of the hip, or knee, or hip and knee for idiopathic OA. Each candidate gene was targeted using one or more intragenic or closely linked microsatellite marker. The linkage data were analysed unstratified and following stratification by sex and by joint replaced (hip or knee). The analyses revealed suggestive linkage of the type IX collagen gene COL9A1 (6q12-q13) to a subset of 132 families that contained affected females who were concordant for hip OA (female-hip) with a P-value of 0.00053 and logarithm of the odds (LOD) score of 2.33 [corrected P-value of 0. 0016, corrected LOD score of 1.85]. COL9A1 may therefore be a susceptibility locus for female hip OA. In addition, there was weak evidence of linkage to HLA/COL11A2 (6p21.3) in female hip OA with a corrected P-value of 0.016.