Risk Of Hand Osteoarthritis Research Articles

Common variants in GNL3 gene contributed the susceptibility of hand osteoarthritis in Han Chinese population

Osteoarthritis (OA) is one of the most popular degenerative joint diseases. The nucleolar GTP binding protein 3 (GNL3) gene encodes guanine nucleotide binding protein-like 3, which is related in cell proliferation, differentiation, and cell cycle regulation. Our study aimed to examine the contribution of GNL3 gene polymorphisms to the risk of hand OA and its related clinical features. A total of 3387 study participants including 1160 patients with hand OA and 2227 controls were recruited in this study. Eleven SNPs in GNL3 gene were selected for genotyping. Genetic association signals were examined using Plink. Relationships between significant SNPs and clinical features of hand OA were also explored. SNP rs11177 was found to be strongly associated with susceptibility of hand OA (P = 4.32 × 10–5). The minor allele of rs11177 was associated with increased susceptibility of hand OA. In addition, significant associations were also identified between genotypes of rs11177 and clinical features of hand OA patients including K-L grade (P < 0.01) and categorized pain scores (P < 0.01). Significant eQTL signals for rs11177 on GNL3 in multiple types of human tissues were also identified in GTEx database. Our results have established the link between GNL3 gene and susceptibility of hand OA.

Association Between Race and Radiographic, Symptomatic, and Clinical Hand Osteoarthritis: A Propensity Score-Matched Study Using Osteoarthritis Initiative Data.

To determine the associations between Black race and the presence of radiographic, symptomatic, and clinical hand osteoarthritis (OA). Using available hand radiographs from the Osteoarthritis Initiative cohort (total 4,699; n=849 Black subjects [18.1%], n=3,850 non-Black subjects [81.9%]), a propensity score-matching method was used to match Black subjects with non-Black subjects for known potential risk factors of hand OA (age, sex, body mass index, smoking status, cardiovascular disease, osteoporosis, excessive occupation- or recreation-related hand use, and knee OA). Posteroanterior radiographs of subjects' dominant hands were reviewed by a musculoskeletal radiologist in a blinded manner. To assess the severity of hand OA, the modified Kellgren/Lawrence (K/L) radiographic OA scoring scale (grades 0-4) was used, and the presence of erosive OA in the hand joints was recorded. Associations between race and the severity of hand OA (measured as the summed modified K/L grade), presence of radiographic hand OA (modified K/L grade ≥2), presence of erosive hand OA, presence of symptomatic hand OA (radiographic OA with hand pain), and presence of clinical hand OA (indicated by clinical findings of Heberden's nodes in the hands) were studied using regression models. In these models, beta coefficients or odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated for the associations between Black race and any of these radiographic and symptomatic hand OA phenotypes. Black subjects had less severe hand OA (β=-1.93 [95% CI -2.53, -1.34]), as well as a lower risk of developing radiographic hand OA (OR 0.79 [95% CI 0.66, 0.94]), erosive hand OA (OR 0.23 [95% CI 0.11, 0.47]), symptomatic hand OA (OR 0.63 [95% CI 0.49, 0.82]), and clinical hand OA (OR 0.49 [95% CI 0.41, 0.60]), as compared to non-Black subjects. In contrast to the well-established association between Black race and knee or hip OA, the findings of this study suggest that the risk of hand OA is lower in Black subjects compared to non-Black subjects, which is not mediated by known hand OA risk factors. Future studies are warranted to determine the mediating protective factors for hand OA among Black subjects.

The association of hand osteoarthritis with systemic metabolic and inflammatory factors – a population-based study

Purpose: There is increasing interest in the role of metabolic factors in the pathogenesis and progression of osteoarthritis (OA). This interest was stimulated in part by the observations of an increased risk of hand OA, a non-weight bearing joint, in obese patients. Consequently, studies focusing on hand OA have been conducted to help separate out the systemic effects of obesity from the over-shadowing effects of the biomechanical and biological effect of obesity in weight-bearing joints. A number of studies have demonstrated a relationship between hand OA and a range of systemic factors such as low and high density lipoproteins, triglycerides, hypertension, impaired glucose tolerance, as well as other factors such as C-reactive protein and atherosclerosis.

Familial Clustering of Erosive Hand Osteoarthritis in a Large Statewide Cohort.

Erosive hand osteoarthritis (OA) is a severe and rapidly progressing subset of hand OA. Its etiology remains largely unknown, which has hindered development of successful treatments. This study was undertaken to test the hypothesis that erosive hand OA demonstrates familial clustering in a large statewide population linked to genealogical records, and to determine the association of potential risk factors with erosive hand OA. Patients diagnosed as having erosive hand OA were identified by searching 4,741,840 unique medical records from a comprehensive statewide database, the Utah Population Database (UPDB). Affected individuals were mapped to pedigrees to identify high-risk families with excess clustering of erosive hand OA as defined by a familial standardized incidence ratio (FSIR) of ≥2.0. The magnitude of familial risk of erosive hand OA in related individuals was calculated using Cox regression models. Association of potential erosive hand OA risk factors was analyzed using multivariate conditional logistic regression and logistic regression models. We identified 703 affected individuals linked to 240 unrelated high-risk pedigrees with excess clustering of erosive hand OA (FSIR ≥2.0, P < 0.05). The relative risk of developing erosive hand OA was significantly elevated in first-degree relatives (P < 0.001). There were significant associations between a diagnosis of erosive hand OA and age, sex, diabetes, and obesity (all P < 0.05). Familial clustering of erosive hand OA observed in a statewide database indicates a potential genetic contribution to the etiology of the disease. Age, sex, diabetes, and obesity are risk factors for erosive hand OA. Identification of causal gene variants in these high-risk families may provide insight into the genes and pathways that contribute to erosive hand OA onset and progression.

Mendelian randomization identifies a causal role for serum insulin-like growth factor-1 in hip osteoarthritis

Purpose: Individuals with acromegaly (characterised by elevated circulating IGF-1) are at an increased risk of secondary osteoarthritis (OA), but epidemiological evidence for an association between serum insulin-like growth factor-1 (IGF-1) and OA in the general population is conflicting. We determined the observational associations between serum IGF-1 and hospital-diagnosed (HD) hand, hip and knee and hand OA in UK Biobank (UKBB). We performed Mendelian Randomization (MR) to determine if observed associations represent a true causal effect. Methods: Serum IGF-1 was assessed by chemiluminescent immunoassay. HD hip, knee and hand OA were determined using linked hospital inpatient records. Observational associations between serum IGF-1 and HD OA variables were determined by multivariable logistic regression, adjusting for age, sex, ethnicity, oestrogen use and BMI. We performed one-sample (1SMR) using two-stage least-squares regression, with an unweighted allele score generated from the eight single nucleotide polymorphisms (SNPs) robustly associated with IGF-1 in the largest genome-wide association study (GWAS) meta-analysis, as an instrument. MR is a form of instrumental variable regression which uses genetic variants robustly related to the exposure as instruments, providing an estimate of the causal effect which is unbiased by confounding and reverse causality. Multivariable MR (MVMR) determined the BMI-independent effect of IGF-1, by including BMI as an additional exposure, instrumented by an unweighted BMI allele score generated from 69 independent loci. MR analyses were adjusted for sex, genotyping chip and 10 principal components (PCs) to account for population stratification. Results: 421,572 individuals had complete data for the observational analyses, of whom 332,092 (79%) had genetic data, were unrelated and of European ancestry, suitable for MR. The mean (SD) ages of the observational and MR populations were 56.4 (8.1) and 56.5 (8.0) years respectively, with 54% female in both populations. Median (interquartile range) IGF-1 concentration was 21.3 (17.6, 24.9) nmol/L in both populations. In the observational population, 3.1% had HD hip OA (3.2% in the MR population); 0.7% had hand OA and 5.4% knee OA in both populations. In analyses adjusted for age, sex, ethnicity and oestrogen use, serum IGF-1 concentration was associated with a decreased odds of HD OA (ORhand=0.82 [0.77, 0.88] p=3x10-9, ORhip=0.94 [0.91, 0.97] p=4x10-4, ORknee=0.81 [0.80, 0.83] p=1x10-64; OR per doubling in IGF-1 concentration). After additional adjustment for BMI, serum IGF-1 remained associated with a reduced odds of hand OA; however, it was then associated with an increased odds of hip OA (ORhip=1.04 [1.01, 1.07] p=0.014), with little evidence of an association with knee OA. Using 1SMR, we found strong evidence for increased risk of hip OA with higher IGF-1 concentrations (risk difference per SD increase in IGF-1=0.009 [0.004, 0.015] p=0.001, corresponding to an approximate ORhip 1.36 [1.13, 1.63]), and also evidence for an increased risk of knee OA (risk difference=0.009 [0.001, 0.016] p=0.019). In contrast, point estimates suggested a decreased risk of hand OA, although confidence intervals were wide, reflecting the low prevalence of HD hand OA. When testing the assumptions of MR, we found evidence for an association between the IGF-1 allele score and BMI, which violates the assumption that an instrument is unrelated to any confounders of the exposure-outcome relationship. We therefore performed MVMR analyses to determine the BMI-independent effect; the effect size for IGF-1 on hip OA was unchanged (risk difference=0.009 [0.003, 0.014] p=0.003); whereas, the effect of IGF-1 on knee OA was attenuated by one-third (risk difference=0.006 [-0.001, 0.014] p=0.076). Conclusions: Our MR analyses provide strong evidence that higher concentrations of serum IGF-1 are a causal risk factor for hip OA in a very large UK population, with weaker evidence for a causal role in knee OA and very little evidence for an effect on hand OA. Our MVMR analyses estimate the direct effect of IGF-1 on OA conditional on BMI, these results suggest that this causal role of IGF-1 is independent of BMI, consistent with our observational analyses. Further study is justified to determine the mechanism underlying this association.

Vascular Pathology and Osteoarthritis: A Systematic Review.

Vascular pathology (changes in blood vessels) and osteoarthritis (OA) are both common chronic conditions associated with aging and obesity, but whether vascular pathology is a risk factor for OA is unclear. The aim of this study was to systematically review the evidence for an association between vascular pathology and risk of joint-specific OA. Scopus, Ovid Medline, and EMBASE were searched from inception to February 2019. MeSH terms and keywords were used to identify studies examining the association between vascular pathology and OA. Two reviewers independently extracted the data and assessed the methodological quality. Qualitative evidence synthesis was performed. Fifteen studies with high (n = 3), fair (n = 3), or low (n = 9) quality were included. Features of vascular pathology included atherosclerosis, vascular stiffness, and endothelial dysfunction in different vascular beds. There was evidence for an association between vascular pathology and risk of hand OA in women but not men, and between vascular pathology and risk of knee OA in both men and women. Only 2 studies examined hip OA showing no association between vascular pathology and risk of hip OA. There is evidence suggesting an association between vascular pathology and risk of hand and knee OA, with a potential causal relationship for knee OA. Based on the limited evidence, it is hard to conclude an association for hip OA. Further stronger evidence is needed to determine whether there is a causal relationship.

Functional Characterization of the Osteoarthritis Genetic Risk Residing at ALDH1A2 Identifies rs12915901 as a Key Target Variant

ObjectiveTo identify the functional single‐nucleotide polymorphisms (SNPs) and mechanisms conferring increased risk of hand osteoarthritis (OA) at the ALDH1A2 locus, which is a retinoic acid regulatory gene.MethodsTissue samples from 247 patients with knee, hip, or hand OA who had undergone joint surgery were included. RNA‐sequencing analysis was used to investigate differential expression of ALDH1A2 and other retinoic acid signaling pathway genes in cartilage. Expression of ALDH1A2 in joint tissues obtained from multiple sites was quantified using quantitative reverse transcription–polymerase chain reaction. Allelic expression imbalance (AEI) was measured by pyrosequencing. The consequences of ALDH1A2 depletion by RNA interference were assessed in primary human chondrocytes. In silico and in vitro analyses were used to pinpoint which, among 62 highly correlated SNPs, could account for the association at the locus.Results ALDH1A2 expression was observed across multiple joint tissue samples, including osteochondral tissue from the hand. The expression of ALDH1A2 and of several retinoic acid signaling genes was different in diseased cartilage compared to non‐diseased cartilage, with ALDH1A2 showing lower levels in OA cartilage. Experimental depletion of ALDH1A2 resulted in changes in the expression levels of a number of chondrogenic markers, including SOX9. In addition, reduced expression of the OA risk–conferring allele was witnessed in a number of joint tissues, with the strongest effect in cartilage. The intronic SNP rs12915901 recapitulated the AEI observed in patient tissues, while the Ets transcription factors were identified as potential mediators of this effect.ConclusionThe ALDH1A2 locus seems to increase the risk of hand OA through decreased expression of ALDH1A2 in joint tissues, with the effect dependent on rs12915901. These findings indicate a mechanism that may now be targeted to modulate OA risk.

Lifetime Risk of Symptomatic Hand Osteoarthritis: The Johnston County Osteoarthritis Project.

Symptomatic hand osteoarthritis (OA) is a common condition that affects hand strength and function, and causes disability in activities of daily living. Prior studies have estimated that the lifetime risk of symptomatic knee OA is 45% and that of hip OA is 25%. The objective of the present study was to estimate the overall lifetime risk of symptomatic hand OA, and the stratified lifetime risk according to potential risk factors. Data were obtained from 2,218 adult subjects (ages ≥45 years) in the Johnston County Osteoarthritis Project, a population-based prospective cohort study among residents of Johnston County, North Carolina. Data for the present study were collected from 2 of the follow-up cycles (1999-2004 and 2005-2010). Symptomatic hand OA was defined as the presence of both self-reported symptoms and radiographic OA in the same hand. Lifetime risk, defined as the proportion of the population who will develop symptomatic hand OA in at least 1 hand by age 85 years, was estimated from models using generalized estimating equations. Overall, the lifetime risk of symptomatic hand OA was 39.8% (95% confidence interval [95% CI] 34.4-45.3%). In this population, nearly 1 in 2 women (47.2%, 95% CI 40.6-53.9%) had an estimated lifetime risk of developing symptomatic hand OA by age 85 years, compared with 1 in 4 men (24.6%, 95% CI 19.5-30.5%). Race-specific symptomatic hand OA risk estimates were 41.4% (95% CI 35.5-47.6%) among whites and 29.2% (95% CI 20.5-39.7%) among African Americans. The lifetime risk of symptomatic hand OA among individuals with obesity (47.1%, 95% CI 37.8-56.7%) was 11 percentage points higher than that in individuals without obesity (36.1%, 95% CI 29.7-42.9%). These findings demonstrate the substantial burden of symptomatic hand OA overall and in sociodemographic and clinical subgroups. Increased use of public health and clinical interventions is needed to address its impact.

Prevalence and risk factors for hand osteoarthritis

IntroductionHand osteoarthritis (OA) is a highly prevalent disease with a significant physical and social burden. Thus we decided to find out prevalence of hand OA in the patients above 40 year of age who presented to us with either hand symptoms or knee OA. MethodsPostero-anterior hand radiographs were taken of both hands to confirm the diagnosis of hand OA. Fifteen joints were evaluated for the presence of osteophytes, joint space narrowing, sclerosis, and cysts. 358 patients attending Rheumatology OPD of two tertiary care centers in Eastern India in one year participated in study. ResultsNinety nine (27.65%) of 358 subjects had radiological hand OA. Among the 222 patients with knee OA 90 (40.5%) patients had hand OA. Nine (6.6%) of 136 patients with hand symptoms alone had hand OA. Overall 212 (59.21%) of 358 patients had symptoms in hand joints and of them 49 (23.2%) patients had hand OA positive. Female sex, older age, BMI >25, family history of OA or diabetes mellitus increased the risk of radiological hand OA. Knee OA increased the risk of hand OA both symptomatic and asymptomatic. ConclusionHand OA is common and a good quality X ray of hand is an initial investigation to diagnose hand OA. Presence of Knee OA increases risk of hand OA.

Variations in the TNFα gene and their interactions with the IL4R and IL10 genes in relation to hand osteoarthritis.

BackgroundThe development of osteoarthritis (OA) involves inflammation, but the evidence for participation of genes propagating or inhibiting inflammation in the OA process is inconsistent. We investigated the associations of common variants in the TNFα gene, and their interactions with other cytokine genes, with hand OA among Finnish women.MethodsThis cross-sectional study was based on bilateral hand radiographs of 542 female dentists and teachers which were classified according to the presence of OA (radiographic K-L score ≥ 2 in ≥ 3 joints) using reference images. The genotypes were determined by PCR-based methods. The degree of pairwise linkage disequilibrium (LD) and haplotypes were constructed and analyzed by the SNPStats software. The associations between four TNFα SNPs and hand OA were tested using logistic regression adjusting for age, occupation, and BMI, and fitting a log-additive model of inheritance. Gene-gene interactions of TNFα SNPs with IL4R and IL10 SNPs were examined by stratified logistic regression analyses. Possible interactions of the TNFα SNPs with variants in the previously reported IL1β and IL6 genes in influencing hand OA were also explored.ResultsTwo TNFα polymorphisms (“-1031” and “-863”) were associated with hand OA (OR = 1.45, 95% CI 1.01-2.07 and 1.55, 1.06-2.25, respectively). These associations retained when adjusting further for IL1β “3954” and IL6 “174”. The TNFα G-A-G haplotype was associated with an increased risk of hand OA (1.61, 1.10-2.37, p = 0.01). Interactions were observed between TNFα “-1031” and IL4R Ser503Pro, TNFα “-1031” and IL10 “-1082”, and TNFα “-863” and IL10 “-1082” SNPs with regard to hand OA (p = 0.012, p = 0.0068, and p = 0.02, respectively). The carriage of the TNFα “-1031” minor allele doubled the risk (2.01, 1.26 - 3.22) only in women with the IL4R Ser/Ser genotype. Similarly, the TNFα “-1031” and “-863” minor alleles were associated with an increased risk of hand OA only in IL10 G/G or A/A homozygotes (2.54, 1.45-4.47 and 2.60, 1.46-4.62, respectively) but not in heterozygotes (G/A).ConclusionsOur results suggest that the TNF α gene variants play a role in the etiology of hand OA. In addition, the findings are suggestive of a gene-gene interaction of the TNF α with IL4R and IL10 genes.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2474-15-311) contains supplementary material, which is available to authorized users.

Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints

ObjectivesData on the incidence of symptomatic osteoarthritis (OA) are scarce. We estimated incidence of clinical hip, knee and hand OA, and studied the effect of prevalent OA on joint-specific incident...

MATN3 Gene Polymorphism Is Associated with Osteoarthritis in Chinese Han Population: A Community-Based Case-Control Study

Background. The matrilin, especially matrilin-3 (MATN3), are reported to play important roles in the pathophysiology of osteoarthritis (OA). To explore the relationship between MATN3 SNP6 (rs8176070) and primary OA, we conducted a community-based case-control study. Methods. A total of 732 community residents aged 40–84 years participated in the community-based study in Northeast China. After taking physical and radiographic examinations, 420 of the residents were diagnosed OA (216 women and 204 men). The other 312 individuals without any symptoms of osteoarthritis or signs in the radiographs (156 women and 156 men) were considered as healthy controls. After obtaining the DNA of case and control groups, genotypes of the MATN3 SNP6 were determined by polymerase chain reaction followed by restriction enzyme digestion. The numbers of patients with different OA subtypes were also calculated. Results. The distribution of genotypes and alleles of the MATN3 SNP6 between OA patients and controls was different significantly. The BB carrier tends to be associated with the increased osteoarthritis (P = 0.025, OR = 1.724, 95% CI = 1.071–2.77), especially the knee osteoarthritis (P = 0.021, OR = 2.402, 95% CI = 1.141–5.060) and lumber osteoarthritis (P = 0.020, OR = 1.880, 95% CI = 1.103–3.204). Bb carrier increased hand osteoarthritis risk (P = 0.002, OR = 5.380, 95% CI = 1.828–15.835). The B allele might have an effect on the increased knee osteoarthritis (P = 0.000, OR = 3.143, 95% CI = 2.283–4.328). Conclusion. These findings suggest that the MATN3 gene polymorphism might be associated with osteoarthritis in the Chinese Han population.

Pharmacological Therapies for Osteoarthritis of the Hand

Osteoarthritis (OA) of the hand is highly prevalent in US senior citizens, developing in >50% of individuals aged >60 years. Hormonal, genetic and inflammatory mechanisms are known to increase the risk of hand OA and influence the course of the disease. However, the underlying processes in the development of hand OA are not well understood, and there is no known disease-modifying drug. Likewise, surgical interventions for affected hand joints have not proven as successful as joint replacement for the knee or hip. Current treatment of hand OA focuses on reducing pain and improving patient function to improve quality of life. Pharmacological approaches have included several oral therapies, such as paracetamol (acetaminophen), oral nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, all of which carry a risk of adverse events that typically increases with age. Topical NSAIDs, recently approved in the US, appear to provide efficacy similar to that of oral NSAIDs for hand OA, with less systemic NSAID exposure. Intra-articular corticosteroids and hyaluronic acid have also shown modest symptomatic efficacy with generally good tolerability. Two proposed disease-modifying therapies, chondroitin sulfate and hydroxychloroquine, have had unclear effects on disease modification in clinical trials. This review of pharmacotherapies for the treatment of hand OA focuses on their efficacy and safety in elderly patients. Articles cited herein were identified via a search of PubMed from January 2005 to November 2009. The bibliographies of articles identified through this search were searched manually for additional references of interest.

COL2A1 gene polymorphisms and susceptibility to osteoarthritis of the hand in Finnish women

Objectives:To study the role of two COL2A1 single nucleotide polymorphisms (rs3737548 and rs2276455) and their haplotypes in individual susceptibility to osteoarthritis (OA) of the hand in Finnish women.Methods:Bilateral hand radiographs...

Potential influence of IL1B haplotype and IL1A–IL1B–IL1RN extended haplotype on hand osteoarthritis risk

To assess osteoarthritis (OA) association with the human interleukin-1 (IL-1) region. Sixty-four European-descent cases with radiographic hand OA and 48 European-descent controls were genotyped at nine single nucleotide polymorphism (SNP), one variable-number-of-tandem-repeat (VNTR), and one microsatellite marker extending across loci for IL-1alpha (IL1A), IL-1beta (IL1B), and IL-1 receptor antagonist (IL1RN). The genotype data were used to reconstruct individual locus haplotypes, and then locus haplotypes were used as superalleles for extended haplotype reconstruction. Nine different extended IL1A-IL1B-IL1RN haplotypes occurred at a frequency 0.05 or greater in either cases or controls. Only two IL1A-IL1B-IL1RN extended haplotypes were consistent with previously described extended risk haplotypes and totaled n=9 in cases and n=3 in controls [odds ratio (OR) 2.1, Haldane's chi(2) 1.67, one-sided P 0.1]. Our prior report showed hand OA association with homozygous IL1B rs1143633 minor allele genotype. All except one extended risk haplotype copy also had the IL1B rs1143633 minor allele. The rs1143633 genotype association was explained by one common six-SNP IL1B haplotype bearing rs1143633 minor allele and also risk alleles at rs1143634, rs1143627, and rs16944, component markers of the previously described extended risk haplotypes. The IL1B haplotype bearing all three risk alleles was found in 16 haplotype-homozygous hand OA cases and in four haplotype-homozygous controls and conferred OR 3.4 among homozygotes (nominal P value 0.006). Our evidence broadly supports the genetic association of OA phenotypes with an IL-1 region extended risk haplotype and specifically IL1B genotype. The extended risk haplotype previously associated with hip OA appears to be less frequent and has weaker genetic effect in hand OA. Hand OA risk is conferred by homozygous state for the IL1B haplotype characteristic of the extended risk haplotype.

Aggrecan core protein of a certain length is protective against hand osteoarthritis

To study the contribution of aggrecan VNTR (variable number of tandem repeats) polymorphism to clinically differing manifestations of hand osteoarthritis (OA). Five hundred thirty Finnish females representing two academically similar occupations with completely diverse exposure to hand load were included. Radiographs of hands were analysed, the OA findings were graded and the subjects were divided into categories. Aggrecan VNTR alleles were identified by Southern hybridization. Statistical analyses were used to compare joint involvement and pathological findings with the prevalences of the alleles and genotypes. Subjects homozygous for the most common aggrecan VNTR allele, A27 with 27 repeats, had a significantly lower risk of hand OA, with OR 0.46 (95% CI 0.27-0.78) for OA of grade 2 or more. Our results suggest that carrying two copies of the alleles with less than 27 repeats could predispose a subject to a severe hand OA (OR 2.45, 95% CI 1.17-5.12) and carrying two copies of the alleles with more than 27 repeats also increases the risk of the disease (OR 1.73, 95% CI 1.03-2.89). These findings indicate that allele A27 provides protection from hand OA and that alleles shorter or longer than this may predispose subjects to the disease. Furthermore, they suggest that a certain number of tandem repeats provide for optimal functioning of the aggrecan molecule and that the contribution of genetic factors to the development of hand OA may be even more important than that of environmental factors.

Genetics of hand osteoarthritis

There is convincing epidemiological evidence for a strong hereditary component to hand osteoarthritis (OA). For example: (1) greater concordance for hand OA in monozygotic than in dizygotic twins, the estimated proportion of variance explained by genetic factors being as high as 0.59; and (2) a substantially increased risk of hand OA in first-degree relatives (siblings, parents, offspring) of subjects with hand OA. Such evidence clearly justifies a search for the genes involved. However, gene association studies in genetically complex polygenic conditions such as OA present many problems, including case definition, late age of phenotype expression and adjustment for other constitutional and environmental risk factors. Nevertheless, association studies of affected sibling pairs and nuclear families, using candidate gene and genome wide screening and transmission disequilibrium testing, suggest no association with candidates such as COL2A1 (responsible for some rare monogenic syndromes of premature generalized OA) but possible associations, currently not isolated, on chromosome 2q. Such ongoing work and subsequent gene-gene and gene-environment interaction studies are likely to give important, perhaps unexpected, insights into the pathogenesis of hand OA.