Margaret Wheeler

The GDF5 rs143383 polymorphism is associated with osteoarthritis of the knee with genome-wide statistical significance

Osteoarthritis of the knee is a major cause of pain, disability and the use of healthcare resources among middle-aged and older people.1 Although osteoarthritis is multifactorial, it is known to have a significant genetic contribution and a number of studies have attempted to dissect such a contribution (see Valdes and Spector2 for review). The GDF5 gene encodes the growth differentiation factor 5, a bone morphogenetic protein involved in joint formation, expressed in different joint structures, which has been shown to ameliorate tendon, ligament and bone healing after trauma in mice.3 4 A promoter polymorphism (rs143383) in GDF5 has been found to be strongly associated with both hip and knee osteoarthritis in Asian individuals,4 and is the most widely replicated genetic association with knee osteoarthritis, although much less so for hip and hand osteoarthritis.5 This variant is functional, with the lower gene expression variant having increased genetic risk.4 A large-scale meta-analysis reported the association of the major (T) allele with knee osteoarthritis achieved OR 1.15 p=9.7×10−7 and achieved p=9×10−5 (OR 1.13, 95% CI 1.06 to 1.20) when Asian subjects were excluded.5 The genome-wide statistical significance level of p<5×10−8 is increasingly …

The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis

Objective To assess if a coding variant in the gene encoding transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is associated with genetic risk of painful knee osteoarthritis (OA). Methods The Ile585Val TRPV1 variant encoded by rs8065080 was genotyped in 3270 cases of symptomatic knee OA, 1098 cases of asymptomatic knee OA and 3852 controls from seven cohorts from the UK, the USA and Australia. The genetic association between the low-pain genotype Ile–Ile and risk of symptomatic and asymptomatic knee OA was assessed. Results The TRPV1 585 Ile–Ile genotype, reported to be associated with lower thermal pain sensitivity, was associated with a lower risk of symptomatic knee OA in a comparison of symptomatic cases with healthy controls, with an odds ratio (OR) of 0.75 (95% CI 0.64 to 0.88; p=0.00039 by meta-analysis) after adjustment for age, sex and body mass index. No difference was seen between asymptomatic OA cases and controls (OR=1.02, 95% CI 0.82 to 1.27 p=0.86) but the Ile–Ile genotype was associated with lower risk of symptomatic versus asymptomatic knee OA adjusting for covariates and radiographic severity (OR=0.73, 95% CI 0.57 to 0.94 p=0.0136). TRPV1 expression in articular cartilage was increased by inflammatory cytokines (tumour necrosis factor α and interleukin 1). However, there were no differences in TRPV1 expression in healthy and arthritic synovial tissue. Conclusions A genotype involved in lower peripheral pain sensitivity is significantly associated with a decreased risk of painful knee OA. This indicates a role for the pro-nociceptive gene TRPV1 in genetic susceptibility to symptomatic knee OA, which may also be influenced by a role for this molecule in cartilage function.

Association of the DVWA and GDF5 polymorphisms with osteoarthritis in UK populations

Background: Variants in the growth differentiation factor 5 (GDF5) and in the double von Willebrand factor A (DVWA) have recently been reported to be associated with osteoarthritis (OA) in Asian populations. Objective: To assess the role of such variants in OA susceptibility in two independent UK samples of Caucasian origin. Methods: Polymorphisms rs11718863 and rs7639618 (DVWA) and rs143383 (GDF5) were genotyped in 999 patients with knee OA, 843 patients with hip OA and 1166 controls from two UK studies from Nottingham and Chingford. Results: In agreement with previous reports, the major allele at rs143383 (GDF5) was associated with a higher risk of knee OA in our samples (ORMH = 1.29, 95% CI 1.14 to 1.47 p = 8×10−5). Conversely, the major allele at the DVWA SNP rs7639618, which increased risk in Asians, was not associated with a risk of knee OA, (ORMH = 0.88, 95% CI 0.74 to 1.04; p = 0.12). A meta-analysis of Asian and UK knee OA data indicated highly significant heterogeneity (I2 = 92%, Q = 48.5, p = 7×10−10) and no significant association with knee OA using a random effects meta-analysis (ORDL = 1.18, 95% CI 0.86 to 1.63; p = 0.309). Conclusions: These data confirm that the GDF5 variant is consistently associated with the risk of knee OA. Considerable ethnic variation in allele frequencies at the DVWA gene was found and no significant association was found in UK samples or by combining UK and Asian samples. The results suggest that the effect of DVWA amino acid changes on tubulin binding is unlikely to influence the risk of OA in Caucasians.

LARGE SCALE META-ANALYSIS OF INTERLEUKIN-1 BETA AND INTERLEUKIN-1 RECEPTOR ANTAGONIST POLYMORPHISMS ON RISK OF RADIOGRAPHIC HIP AND KNEE OSTEOARTHRITIS AND SEVERITY OF KNEE OSTEOARTHRITIS

OBJECTIVE To clarify the role of common genetic variation in the Interleukin-1β (IL1B) and Interleukin-1R antagonist (IL1RN) genes on risk of knee and hip osteoarthritis (OA) and severity of knee OA by means of large-scale meta-analyses. METHODS We searched PubMed for articles assessing the role of IL1B and IL1RN polymorphisms/haplotypes on the risk of hip and/or knee OA. Novel data were included from eight unpublished studies. Meta-analyses were performed using fixed- and random-effects models with a total of 3595 hip OA and 5013 knee OA cases, and 6559 and 9132 controls respectively. The role of ILRN haplotypes on radiographic severity of knee OA was tested in 1918 cases with Kellgren-Lawrence (K/L) 1 or 2 compared to 199 cases with K/L 3 or 4. RESULTS The meta-analysis of six published studies retrieved from the literature search and eight unpublished studies showed no evidence of association between common genetic variation in the IL1B or IL1RN genes and risk of hip OA or knee OA (P>0.05 for rs16944, rs1143634, rs419598 and haplotype C-G-C (rs1143634, rs16944 and rs419598) previously implicated in risk of hip OA). The C-T-A haplotype formed by rs419598, rs315952 and rs9005, previously implicated in radiographic severity of knee OA, was associated with reduced severity of knee OA (odds ratio (OR)=0.71 95%CI 0.56-0.91; P=0.006, I(2)=74%), and achieved borderline statistical significance in a random-effects model (OR=0.61 95%CI 0.35-1.06 P=0.08). CONCLUSION Common genetic variation in the Interleukin-1 region is not associated with prevalence of hip or knee OA but our data suggest that IL1RN might have a role in severity of knee OA.

Involvement of different risk factors in clinically severe large joint osteoarthritis according to the presence of hand interphalangeal nodes.

OBJECTIVE To quantify the differences in risk factors influencing total hip replacement (THR) and total knee replacement (TKR) based on the presence versus absence of multiple interphalangeal nodes in 2 or more rays of the fingers of each hand in patients with large joint osteoarthritis (OA). METHODS A group of 3,800 patients with large joint OA who underwent total joint replacement (1,201 of whom had the nodal phenotype) and 1,906 control subjects from 2 case-control studies and a population-based cohort in the UK were studied. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for the risk of total joint replacement in association with age, sex, body mass index (BMI), height, and prevalence of the T allele in the GDF5 rs143383 polymorphism. ORs for total joint replacement were compared between cases of nodal OA and cases of non-nodal OA and between patients who underwent TKR and those who underwent THR. RESULTS Age, sex, and BMI had significantly higher ORs for an association with total joint replacement in nodal OA cases than in non-nodal OA cases. The GDF5 polymorphism was significantly associated with THR in cases of nodal OA, but not in cases of non-nodal OA, and increased height was a risk factor for THR in non-nodal OA cases only. Female sex was a protective risk factor for TKR in non-nodal OA cases (OR 0.60, 95% CI 0.52-0.70) but was predisposing for TKR in the nodal form of OA (OR 1.83, 95% CI 1.49-2.26). The nodal phenotype was associated with a significantly higher risk of undergoing both THR and TKR (OR 1.46, 95% CI 1.09-1.94) and also a significantly higher risk of bilateral TKR (OR 1.70, 95% CI 1.37-2.11), but, paradoxically, was associated with a lower risk of bilateral THR (OR 0.72, 95% CI 0.56-0.91). CONCLUSION Nodal and non-nodal forms of large joint OA have significantly different risk factors and outcomes, indicating a different etiology for the 2 forms of OA. With regard to the likelihood of undergoing THR, this appears to be, at least in part, genetically determined.

The DOT1L rs12982744 polymorphism is associated with osteoarthritis of the hip with genome-wide statistical significance in males

Osteoarthritis (OA) of the hip is a major cause of pain, disability and use of healthcare resources.1 Although OA is multifactorial, it is known to have significant genetic contribution and a number of studies have attempted to dissect such contribution (see2 for review). The DOT1L gene encodes the DOT1-like histone H3 methyltransferaseis, a potentially dedicated enzyme for Wnt target gene activation in leukaemia recently shown to be associated with endochondral bone formation.3 A polymorphism (rs12982744) in DOT1L has been found to be strongly associated with minimum joint space width (minJSW) at the hip. This exact same single nucleotide polymorphism (SNP) was previously identified to be associated with increased height.4 ,5 The C allele associated with lower minJSW and lower height was associated with hip OA, although this association did not reach genome-wide significance (GWS) (OR 1.14, CI 1.06 to 1.22; p=1.5  ×  10−4).3 The GWS level of p<5×10−8 is the threshold at which genetic associations are considered credible.6 The aim of our study was to prove that common genetic variation in the DOT1L gene is important …

Large Scale Replication Study of the Association between HLA Class II/BTNL2 Variants and Osteoarthritis of the Knee in European-Descent Populations

Osteoarthritis (OA) is the most common form of arthritis and a major cause of disability. This study evaluates the association in Caucasian populations of two single nucleotide polymorphisms (SNPs) mapping to the Human Leukocyte Antigen (HLA) region and deriving from a genome wide association scan (GWAS) of knee OA in Japanese populations. The frequencies for rs10947262 were compared in 36,408 controls and 5,749 knee OA cases from European-descent populations. rs7775228 was tested in 32,823 controls and 1,837 knee OA cases of European descent. The risk (major) allele at rs10947262 in Caucasian samples was not significantly associated with an odds ratio (OR)  = 1.07 (95%CI 0.94 -1.21; p = 0.28). For rs7775228 the meta-analysis resulted in OR = 0.94 (95%CI 0.81-1.09; p = 0.42) for the allele associated with risk in the Japanese GWAS. In Japanese individuals these two SNPs are in strong linkage disequilibrium (LD) (r2 = 0.86) with the HLA class II haplotype DRB1*1502 DQA1*0103 DQB1*0601 (frequency 8%). In Caucasian and Chinese samples, using imputed data, these SNPs appear not to be in LD with that haplotype (r2<0.07). The rs10947262 and rs7775228 variants are not associated with risk of knee OA in European descent populations and they do not appear tag the same HLA class II haplotype as they do in Japanese individuals.

The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a mendelian randomisation study

Objective Variation in the fat mass and obesity-associated (FTO) gene influences susceptibility to obesity. A variant in the FTO gene has been implicated in genetic risk to osteoarthritis (OA). We examined the role of the FTO polymorphism rs8044769 in risk of knee and hip OA in cases and controls incorporating body mass index (BMI) information. Methods 5409 knee OA patients, 4355 hip OA patients and up to 5362 healthy controls from 7 independent cohorts from the UK and Australia were genotyped for rs8044769. The association of the FTO variant with OA was investigated in case/control analyses with and without BMI adjustment and in analyses matched for BMI category. A mendelian randomisation approach was employed using the FTO variant as the instrumental variable to evaluate the role of overweight on OA. Results In the meta-analysis of all overweight (BMI≥25) samples versus normal-weight controls irrespective of OA status the association of rs8044769 with overweight is highly significant (OR[CIs] for allele G=1.14 [01.08 to 1.19], p=7.5×10−7). A significant association with knee OA is present in the analysis without BMI adjustment (OR[CIs]=1.08[1.02 to 1.14], p=0.009) but the signal fully attenuates after BMI adjustment (OR[CIs]=0.99[0.93 to 1.05], p=0.666). We observe no evidence for association in the BMI-matched meta-analyses. Using mendelian randomisation approaches we confirm the causal role of overweight on OA. Conclusions Our data highlight the contribution of genetic risk to overweight in defining risk to OA but the association is exclusively mediated by the effect on BMI. This is consistent with what is known of the biology of the FTO gene and supports the causative role of high BMI in OA.

Genetic contribution to radiographic severity in osteoarthritis of the knee

Objective Knee osteoarthritis (OA) has a significant genetic component. The authors have assessed the role of three variants reported to influence risk of knee OA with p<5×10–8 in determining patellofemoral and tibiofemoral Kellgren Lawrence (K/L) grade in knee OA cases. Methods 3474 knee OA cases with sky-line and weight-bearing antero-posterior x-rays of the knee were selected based on the presentation of K/L grade ≥2 at either the tibiofemoral or patellofemoral compartments for one or both knees. Patients belonging to three UK cohorts, were genotyped for rs143383, rs4730250 and rs11842874 mapping to the GDF5, COG5 and MCF2L genes, respectively. The association between tibiofemoral K/L grade and patellofemoral K/L grade was assessed after adjusting for age, gender and body mass index. Results No significant association was found between the rs4730250 and radiographic severity. The rs11842874 mapping to MCF2L was found to be nominally significantly associated with patellofemoral K/L grade as a quantitative trait (p=0.027) but not as a binary trait. The GDF5 single nucleotide polymorphism rs143383 was associated with tibiofemoral K/L grade (β=0.05 (95% CI 0.02 to 0.08) p=0.0011). Conclusions Our data indicate that within individuals affected by radiographic knee OA, OAGDF5 has a modest but significant effect on radiographic severity after adjustment for the major risk factors.

The genetic contribution to severe post-traumatic osteoarthritis

Objective to compare the combined role of genetic variants loci associated with risk of knee or hip osteoarthritis (OA) in post-traumatic (PT) and non-traumatic (NT) cases of clinically severe OA leading to total joint replacement. Methods A total of 1590 controls, 2168 total knee replacement (TKR) cases (33.2% PT) and 1567 total hip replacement (THR) cases (8.7% PT) from 2 UK cohorts were genotyped for 12 variants previously reported to be reproducibly associated with risk of knee or hip OA. A genetic risk score was generated and the association with PT and NT TKR and THR was assessed adjusting for covariates. Results For THR, each additional genetic risk variant conferred lower risk among PT cases (OR=1.07, 95% CI 0.96 to 1.19; p=0.24) than NT cases (OR 1.11, 95% CI 1.06 to 1.17; p=1.55×10−5). In contrast, for TKR, each risk variant conferred slightly higher risk among PT cases (OR 1.12, 95% CI 1.07 to 1.19; p=1.82×10−5) than among NT cases (OR 1.08, 95% CI 1.03 to 1.1; p=0.00063). Conclusions Based on the variants reported to date PT TKR cases have at least as high a genetic contribution as NT cases.