A mendelian randomization study based on data from multiple cohorts conducted by Karani Santhanakrishnan Vimaleswaran and colleagues re-examines the causal nature of the relationship between vitamin D levels and obesity.

Background

Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis.

Methods and Findings

We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects.

Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m2 higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10−27). The BMI allele score was associated both with BMI (p = 6.30×10−62) and 25(OH)D (−0.06% [95% CI −0.10 to −0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10−57 for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: −4.2 [95% CI −7.1 to −1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores).

Conclusions

On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

Obesity—having an unhealthy amount of body fat—is increasing worldwide. In the US, for example, a third of the adult population is now obese. Obesity is defined as having a body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) of more than 30.0 kg/m2. Although there is a genetic contribution to obesity, people generally become obese by consuming food and drink that contains more energy than they need for their daily activities. Thus, obesity can be prevented by having a healthy diet and exercising regularly. Compared to people with a healthy weight, obese individuals have an increased risk of developing diabetes, heart disease and stroke, and tend to die younger. They also have a higher risk of vitamin D deficiency, another increasingly common public health concern. Vitamin D, which is essential for healthy bones as well as other functions, is made in the skin after exposure to sunlight but can also be obtained through the diet and through supplements.

Why Was This Study Done?

Observational studies cannot prove that obesity causes vitamin D deficiency because obese individuals may share other characteristics that reduce their circulating 25-hydroxy vitamin D [25(OH)D] levels (referred to as confounding). Moreover, observational studies cannot indicate whether the larger vitamin D storage capacity of obese individuals (vitamin D is stored in fatty tissues) lowers their 25(OH)D levels or whether 25(OH)D levels influence fat accumulation (reverse causation). If obesity causes vitamin D deficiency, monitoring and treating vitamin D deficiency might alleviate some of the adverse health effects of obesity. Conversely, if low vitamin D levels cause obesity, encouraging people to take vitamin D supplements might help to control the obesity epidemic. Here, the researchers use bi-directional “Mendelian randomization” to examine the direction and causality of the relationship between BMI and 25(OH)D. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the influence of a modifiable environmental exposure and the outcome of interest. Because gene variants do not change over time and are inherited randomly, they are not prone to confounding and are free from reverse causation. Thus, if a lower vitamin D status leads to obesity, genetic variants associated with lower 25(OH)D concentrations should be associated with higher BMI, and if obesity leads to a lower vitamin D status, then genetic variants associated with higher BMI should be associated with lower 25(OH)D concentrations.

What Did the Researchers Do and Find?

The researchers created a “BMI allele score” based on 12 BMI-related gene variants and two “25(OH)D allele scores,” which are based on gene variants that affect either 25(OH)D synthesis or breakdown. Using information on up to 42,024 participants from 21 studies, the researchers showed that the BMI allele score was associated with both BMI and with 25(OH)D levels among the study participants. Based on this information, they calculated that each 10% increase in BMI will lead to a 4.2% decrease in 25(OH)D concentrations. By contrast, although both 25(OH)D allele scores were strongly associated with 25(OH)D levels, neither score was associated with BMI. This lack of an association between 25(OH)D allele scores and obesity was confirmed using data from more than 100,000 individuals involved in 46 studies that has been collected by the GIANT (Genetic Investigation of Anthropometric Traits) consortium.

What Do These Findings Mean?

These findings suggest that a higher BMI leads to a lower vitamin D status whereas any effects of low vitamin D status on BMI are likely to be small. That is, these findings provide evidence for obesity as a causal factor in the development of vitamin D deficiency but not for vitamin D deficiency as a causal factor in the development of obesity. These findings suggest that population-level interventions to reduce obesity should lead to a reduction in the prevalence of vitamin D deficiency and highlight the importance of monitoring and treating vitamin D deficiency as a means of alleviating the adverse influences of obesity on health.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001383.

The US Centers for Disease Control and Prevention provides information on all aspects of overweight and obesity (in English and Spanish); a data brief provides information about the vitamin D status of the US population

The World Health Organization provides information on obesity (in several languages)

The UK National Health Service Choices website provides detailed information about obesity and a link to a personal story about losing weight; it also provides information about vitamin D

The International Obesity Taskforce provides information about the global obesity epidemic

The US Department of Agriculture's ChooseMyPlate.gov website provides a personal healthy eating plan; the Weight-control Information Network is an information service provided for the general public and health professionals by the US National Institute of Diabetes and Digestive and Kidney Diseases (in English and Spanish)

The US Office of Dietary Supplements provides information about vitamin D (in English and Spanish)

MedlinePlus has links to further information about obesity and about vitamin D (in English and Spanish)

Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

Overview and details of the collaborative large-scale genetic association study (D-CarDia) provide information about vitamin D and the risk of cardiovascular disease, diabetes and related traits

Objectives

To describe current disease-modifying antirheumatic drugs (DMARDs) prescription in rheumatoid arthritis (RA) with reference to best practice and to identify temporal and regional trends in the UK.

Design

Descriptive, register-based cohort study.

Participants

Permanently registered patients aged ≥18 years with a recorded diagnosis of RA between 1 January 1995 and 31 March 2010 and matched controls. Participants with RA were identified through screening of all patients in the General Practice Research Database (GPRD) with a clinical or referral record for RA and at least 1 day of follow-up.

Setting

639 general practices in the UK supplying data to the GPRD.

Main outcome measures

Medication prescribing between 3 and 12 months of RA diagnosis by region and time period (1995–1999, 2000–2005 and 2006–April 2010).

Results

Of the 35 911 patients in the full RA cohort, 15 259 patients (42%) had incident RA. Analysis of prescribing in incident RA patients demonstrated that between 1995 (baseline) and 2010 there was a substantial increase in DMARD, and specifically methotrexate, prescribing across all regions with a less marked increase in combination DMARD prescribing. Taking 12-month prescribing as a snapshot: DMARD prescribing was 19–49% at baseline increasing to 45–74% by 2006–April 2010; methotrexate prescribing was 4–16% at baseline increasing to 32–60%; combination DMARD prescribing was 0–8% at baseline increasing to 3–17%. However, there was marked regional variation in the proportion of RA patients receiving DMARD regardless of time period.

Conclusions

There has been a substantial increase in prescribing of DMARDs for RA since 1995; however, regional variation persists across the UK with relative undertreatment, according to established best practice. Improved implementation of evidence-based best clinical practice to facilitate removal of treatment variation is warranted. This may occur as a result of the implementation of published national guidance.

The majority of knee arthroplasties (KAs) are performed in patients with osteoarthritis (OA). Although bone mass may be increased in these patients, subjects with knee OA may have an increased risk of hip fracture, possibly due to an increased severity of falls. However, in patients with KAs, risk of hip fracture has not been studied extensively. We evaluated the association between KAs and hip fracture risk in a population-based case–control study using the Dutch PHARMO Record Linkage System (1991–2002, n = 33,104). Cases were patients with a first admission for hip fracture; controls were matched by age, gender, and geographic location. Neither group had a previous history of fracture. Time since first KA was calculated. Analyses were adjusted for disease and drug history. A 54% increased hip fracture risk was found in patients who underwent KA (adjusted [adj.] OR = 1.54, 95% CI 1.19–2.00). We found a strong effect modification by age in these patients: the youngest patients (aged 18–70 years) were at more increased risk for hip fracture (adj. OR = 2.76, 95% CI 1.16–6.59), while we could not detect a statistical increase in patients aged >80 years. Furthermore, the association tended to be greater during the first few years after surgery, although it did not reach statistical significance. We found that KAs are associated with a 54% increased risk of hip fracture, in particular among adult patients aged <71 years old. Fracture risk assessment could be considered in patients who are about to undergo a KA.

Objective

To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes.

Methods

Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. To investigate whether different OA definitions result in different association results, we created hip OA definitions used within the consortium in the Rotterdam Study-I and tested the association of hip OA with gender, age and BMI using one-way ANOVA. For radiographic OA, we standardized the hip, knee and hand ROA definitions and calculated prevalence's of ROA before and after standardization in 9 cohort studies. This procedure could only be performed in cohort studies and standardization of SOA definitions was not feasible at this moment.

Results

In this consortium, all studies with symptomatic OA phenotypes (knee, hip and hand) used a different definition and/or assessment of OA status. For knee, hip and hand radiographic OA 5, 4 and 7 different definitions were used, respectively. Different hip OA definitions do lead to different association results. For example, we showed in the Rotterdam Study-I that hip OA defined as “at least definite JSN and one definite osteophyte” was not associated with gender (p=0.22), but defined as “at least one definite osteophyte” was significantly associated with gender (p=3×10−9). Therefore, a standardization process was undertaken for radiographic OA definitions. Before standardization a wide range of ROA prevalence's was observed in the 9 cohorts studied. After standardization the range in prevalence of knee and hip ROA was small. Standardization of SOA phenotypes was not possible due to the case-control design of the studies.

Conclusion

Phenotype definitions influence the prevalence of OA and association with clinical variables. ROA phenotypes within the TREAT-OA consortium were standardized to reduce heterogeneity and improve power in future genetics studies.

Background

Plantar pressures are commonly used as clinical measures, especially to determine optimum foot orthotic design. In rheumatoid arthritis (RA) high plantar foot pressures have been linked to metatarsophalangeal (MTP) joint radiological erosion scores. However, the sensitivity of foot pressure measurement to soft tissue pathology within the foot is unknown. The aim of this study was to observe plantar foot pressures and forefoot soft tissue pathology in patients who have RA.

Methods

A total of 114 patients with established RA (1987 ACR criteria) and 50 healthy volunteers were assessed at baseline. All RA participants returned for reassessment at twelve months. Interface foot-shoe plantar pressures were recorded using an F-Scan® system. The presence of forefoot soft tissue pathology was assessed using a DIASUS musculoskeletal ultrasound (US) system. Chi-square analyses and independent t-tests were used to determine statistical differences between baseline and twelve months. Pearson's correlation coefficient was used to determine interrelationships between soft tissue pathology and foot pressures.

Results

At baseline, RA patients had a significantly higher peak foot pressures compared to healthy participants and peak pressures were located in the medial aspect of the forefoot in both groups. In contrast, RA participants had US detectable soft tissue pathology in the lateral aspect of the forefoot. Analysis of person specific data suggests that there are considerable variations over time with more than half the RA cohort having unstable presence of US detectable forefoot soft tissue pathology. Findings also indicated that, over time, changes in US detectable soft tissue pathology are out of phase with changes in foot-shoe interface pressures both temporally and spatially.

Conclusions

We found that US detectable forefoot soft tissue pathology may be unrelated to peak forefoot pressures and suggest that patients with RA may biomechanically adapt to soft tissue forefoot pathology. In addition, we have observed that, in patients with RA, interface foot-shoe pressures and the presence of US detectable forefoot pathology may vary substantially over time. This has implications for clinical strategies that aim to offload peak plantar pressures.

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.

Our aim was to examine the association between serum dehydroepiandrosterone sulfate (DHEAS) at baseline and BMD change at the femoral neck (FN) and lumbar spine (LS) in postmenopausal women during a 15-year follow-up. All participants were from the Chingford Study. BMD at the FN and LS were measured eight times during the 15-year follow-up by dual-energy X-ray absorptiometry. DHEAS at baseline was measured using radioimmunoassay. Data on height, weight, and hormone-replacement therapy (HRT) status were obtained at each visit. Multilevel linear regression modeling was used to examine the association between longitudinal BMD change at the FN and LS and DHEAS at baseline. Postmenopausal women (n = 1,003) aged 45–68 years (mean 54.7) at baseline were included in the study. After adjustment for baseline age, estradiol, HRT, and BMI, BMD at the FN decreased on average 0.49% (95% CI 0.31–0.71%) per year; and the decline was slowed down by 0.028% per squared year. Increase of DHEAS (each micromole per liter) was associated with 0.49% less bone loss at the FN (95% CI 0.21–0.71%, P = 0.001). However, this strong association became slightly weaker over time. Similar but weaker results were obtained for LS BMD. Our data suggest that high serum DHEAS at baseline is associated with less bone loss at both FN and LS and this association diminishes over time. The nature of the association is unclear, but such an association implies that, in managing BMD loss, women might benefit from maintaining a high level of DHEAS.

Imputation is an extremely valuable tool in conducting and synthesising genome-wide association studies (GWASs). Directly typed SNP quality control (QC) is thought to affect imputation quality. It is, therefore, common practise to use quality-controlled (QCed) data as an input for imputing genotypes. This study aims to determine the effect of commonly applied QC steps on imputation outcomes. We performed several iterations of imputing SNPs across chromosome 22 in a dataset consisting of 3177 samples with Illumina 610k (Illumina, San Diego, CA, USA) GWAS data, applying different QC steps each time. The imputed genotypes were compared with the directly typed genotypes. In addition, we investigated the correlation between alternatively QCed data. We also applied a series of post-imputation QC steps balancing elimination of poorly imputed SNPs and information loss. We found that the difference between the unQCed data and the fully QCed data on imputation outcome was minimal. Our study shows that imputation of common variants is generally very accurate and robust to GWAS QC, which is not a major factor affecting imputation outcome. A minority of common-frequency SNPs with particular properties cannot be accurately imputed regardless of QC stringency. These findings may not generalise to the imputation of low frequency and rare variants.

Background

Inhibition of tumour necrosis factor (TNF) is an effective way of reducing synovitis and preventing joint damage in rheumatoid arthritis (RA), yet very little is known about its specific effect on foot pain and disability. The aim of this study was to evaluate whether anti-TNF therapy alters the presence of forefoot pathology and/or reduces foot pain and disability.

Methods

Consecutive RA patients starting anti-TNF therapy (infliximab, etanercept, adalimumab) were assessed for presence of synovial hypertrophy and synovitis in the 2nd and 5th metatarso-phalangeal (MTP) joints and plantar forefoot bursal hypertrophy before and 12 weeks after therapy. Tender MTP joints and swollen bursae were established clinically by an experienced podiatrist and ultrasound (US) images were acquired and interpreted by a radiologist. Assessment of patient reported disease impact on the foot was performed using the Manchester Foot Pain and Disability Index (MFPDI).

Results

31 patients (24 female, 7 male) with RA (12 seronegative, 19 seropositive) completed the study: mean age 59.6 (SD 10.1) years, disease duration 11.1 (SD 10.5) years, and previous number of Disease Modifying Anti Rheumatic Drugs 3.0 (1.6). Significant differences after therapy were found for Erythrocyte Sedimentation Rate (t = 4.014, p < 0.001), C-reactive protein (t = 3.889, p = 0.001), 28 joint Disease Activity Score (t = 3.712, p = 0.0001), Visual Analog Scale (t = 2.735, p = 0.011) and Manchester Foot Pain and Disability Index (t = 3.712, p = 0.001).

Presence of MTP joint synovial hypertrophy on US was noted in 67.5% of joints at baseline and 54.8% of joints at twelve weeks. Presence of plantar forefoot bursal hypertrophy on US was noted in 83.3% of feet at baseline and 75% at twelve weeks. Although there was a trend for reduction in observed presence of person specific forefoot pathology, when the frequencies were analysed (McNemar) this was not significant.

Conclusions

Significant improvements were seen in patient reported foot pain and disability 12 weeks after commencing TNF inhibition in RA, but this may not be enough time to detect changes in forefoot pathology.

Background

The use of musculoskeletal ultrasound (MSUS) in the diagnosis and management of foot and ankle musculoskeletal pathology is increasing. Due to the wide use of MSUS and the depth and breadth of training required new proposals advocate tailored learning of the technique to discrete fields of practice. The aims of the study were to evaluate the inter-observer agreement between a MSUS radiologist and a podiatrist, who had completed basic skills training in MSUS, in the MSUS assessment of the forefoot of patients with Rheumatoid Arthritis.

Methods

A consecutive sample of thirty-two patients with rheumatoid arthritis was assessed for presence of synovitis, erosions and bursitis within the forefoot using MSUS. All MSUS assessments were performed independently on the same day by a podiatrist and one of two Consultant Radiologists experienced in MSUS.

Results

Moderate agreement on image acquisition and interpretation was achieved for bursitis (kappa 0.522; p < 0.01) and erosions (kappa 0.636; p < 0.01) and fair agreement for synovitis (kappa 0.216; p < 0.05) during the primary assessments. Following a further training session, substantial agreement (kappa 0.702) between the two investigators was recorded. The sensitivity of the podiatrist using MSUS was 82.4% for detection of bursitis, 83.0% for detection of erosion and 84.0% for detection of synovitis. Specificity of the podiatrist using MSUS was 88.9% for detection of bursitis, 80.7% for detection of erosion and 35.9% for detection of synovitis.

Conclusion

This study demonstrated good inter-observer agreement between a podiatrist and radiologist on MSUS assessment of the forefoot, particularly for bursitis and erosions, in patients with rheumatoid arthritis. There is scope to further evaluate and consider the role of podiatrists in the MSUS imaging of the foot following appropriate training and also in the development of reliable protocols for MSUS assessment of the foot.

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.

Objectives To test whether bisphosphonate use is related to improved implant survival after total arthroplasty of the knee or hip.

Design Population based retrospective cohort study.

Setting Primary care data from the United Kingdom.

Participants All patients undergoing primary total arthroplasty of the knee (n=18 726) or hip (n=23 269) in 1986-2006 within the United Kingdom’s General Practice Research Database. We excluded patients with a history of hip fracture before surgery or rheumatoid arthritis, and individuals younger than 40 years at surgery.

Intervention Bisphosphonate users were classified as patients with at least six prescriptions of bisphosphonates or at least six months of prescribed bisphosphonate treatment with more than 80% adherence before revision surgery.

Outcome measures Revision arthroplasties occurring after surgery, identified by READ and OXMIS codes. Parametric survival models were used to determine effects on implant survival with propensity score adjustment to account for confounding by indication.

Results Of 41 995 patients undergoing primary hip or knee arthroplasty, we identified 1912 bisphosphonate users, who had a lower rate of revision at five years than non-users (0.93% (95% confidence interval 0.52% to 1.68%) v 1.96% (1.80% to 2.14%)). Implant survival was significantly longer in bisphosphonate users than in non-users in propensity adjusted models (hazard ratio 0.54 (0.29 to 0.99); P=0.047) and had an almost twofold increase in time to revision after hip or knee arthroplasty (time ratio 1.96 (1.01 to 3.82)). Assuming 2% failure over five years, we estimated that the number to treat to avoid one revision was 107 for oral bisphosphonates.

Conclusions In patients undergoing lower limb arthroplasty, bisphosphonate use was associated with an almost twofold increase in implant survival time. These findings require replication and testing in experimental studies for confirmation.

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.

Objective

Subtle deformities of the hip joint are implicated in the etiology of osteoarthritis (OA) of the hip. Parameters that quantify these deformities may aid understanding of these associations. We undertook this study to examine relationships between such parameters and the 19-year risk of total hip arthroplasty (THA) for end-stage OA.

Methods

A new software program designed for measuring morphologic parameters around the hip was developed and validated in a reliability study. THA was the outcome measure for end-stage OA. A nested case–control study was used with individuals from a cohort of 1,003 women who were recruited at year 1 in 1989 and followed up to year 20 (the Chingford Study). All hips with THA by year 20 and 243 randomly selected control hips were studied. Pelvis radiographs obtained at year 2 were analyzed for variations in hip morphology. Measurements were compared between the THA case group and the control group.

Results

Patients with THA had a higher prevalence of cam deformity than did their respective controls (median alpha angle 62.4° versus 45.8° [P = 0.001]; mean modified triangular index height 28.5 mm versus 26.9 mm [P = 0.001]) as well as a higher prevalence of acetabular dysplasia (mean lateral center edge angle 29.5° versus 34.3° [P = 0.001]; median extrusion index 0.25 versus 0.185 [P = 0.009]). Logistic regression analyses clustering by subject and adjusting for radiographic hip OA at year 2 showed that these morphologic parameters were still significantly associated with THA by year 20. The alpha angle and lateral center edge angle predicted the risk of THA independently when included in the same model.

Conclusion

This investigation describes measurements that predict the risk of THA for end-stage OA by year 20, independently of the presence of radiographic hip OA at year 2. These measurements can be made on an anteroposterior pelvis radiograph, which is an inexpensive and commonly used clinical method of investigation.

Objectives

Osteoarthritis (OA) has a complex aetiology with a strong genetic component. Genome-wide association studies implicate several nuclear genes in the aetiology, but a major component of the heritability has yet to be defined at the molecular level. Initial studies implicate maternally inherited variants of mitochondrial DNA (mtDNA) in subgroups of patients with OA based on gender and specific joint involvement, but these findings have not been replicated.

Methods

The authors studied 138 maternally inherited mtDNA variants genotyped in a two cohort genetic association study across a total of 7393 OA cases from the arcOGEN consortium and 5122 controls genotyped in the Wellcome Trust Case Control consortium 2 study.

Results

Following data quality control we examined 48 mtDNA variants that were common in cohort 1 and cohort 2, and found no association with OA. None of the phenotypic subgroups previously associated with mtDNA haplogroups were associated in this study.

Conclusions

We were not able to replicate previously published findings in the largest mtDNA association study to date. The evidence linking OA to mtDNA is not compelling at present.