Background-Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D insufficiency has been linked to a number of extraskeletal disorders, including diabetes, cancer, and cardiovascular disease. Determinants of circulating 25-hydroxyvitamin D (25-OH D) include sun exposure and dietary intake, but its high heritability suggests that genetic determinants may also play a role.

(Figure 2c), and less than 1% of variation for postprandial triglyceride and postprandial C-peptide (Figure 2b and 2d). Gut microbiome (16S rRNA). We estimated the contribution of gut microbiome composition using relative bacterial taxonomic abundances and measures of community diversity and richness, derived from 16S rRNA high-throughput sequencing of baseline stool specimens (Supplemental Table 4). We found that without adjusting for any other individual characteristics the gut microbiome composition explained 7.5% of postprandial triglyceride6h-rise, 6.4% of postprandial glucoseiAUC0-2h and 5.8% of postprandial C-peptide1h-rise. Meal composition, habitual diet and meal context. To determine the impact of the macronutrient composition of meals, we measured triglyceride6h-rise and C-peptide1h-rise for two standardized home phase meals of contrasting macronutrient compositions (for triglyceride, comparison of meals 1 and 7: 85 vs 28g of carbohydrate and 50 vs 40 g of fat at breakfast, both followed by a lunch of 71g carbohydrate and 22g fat; for C-peptide, comparison of meal 2 and 3: 71 vs 41 g of carbohydrate and 22 vs 35 g of fat; Supplement Table 2) in subsets of participants (n=712 and n=186, respectively). GlucoseiAUC0-2h was measured for seven standardized meals (comparison of meals 1, 2, 4, 5, 6, 7 and 8: 28 -95 g carbohydrate; 0 -53 g fat) totalling 9,102 meals in 920 individuals. The proportions of variance explained by meal composition, habitual diet, and by meal context are shown for triglyceride6h-risein Figure 2b, for glucoseiAUC0-2hin Figure 2c, and for C-peptide1h-risein Figure 2d. A multivariate regression model (meals 1, 2, 4, 5, 6, 7 and 8) revealed that the Glucosei AUC0-2h (mmol/L*s) was significantly (P<0.001) reduced by 79, 142 and 185 for every 1g fat, fiber and protein respectively, after adjustment for carbohydrate consumption. Machine learning model. To estimate the unbiased predictive utility of the factors analysed, we used a machine learning approach robust to overfitting 22 . Random Forest regression models 23 were fitted using all the informative features (meal composition, habitual diet, meal context, anthropometry, genetics, microbiome, clinical and biochemical parameters) to predict triglyceride6h10 described in the Methods, we considered not only the effect of the meal macronutrient and energy content in the response (meal composition), but also considered how each individual responded on average to all their set meals relative to the population (individual glucose scaling), as well as the effect of the individual's meal-specific response, the error attributable to the glucose measurement and other sources of variation (including modifiable sources of variation such as sleep, circadian rhythm and exercise). We found that, consistent with the linear models described earlier, the ANOVA models show that there are three meal-related factors explaining individual glycemic responses. Meal macronutrient composition alters iAUC by 16.73% (95%CI 15.37 -18.92%), but the individual glucose...

Objectives-To assess the relative contribution of genetic and environmental factors to common forms ofosteoarthritis ofthe hands and knees.Design-Classic twin study with unselected twins who were screened radiologically for osteoarthritis.Subjects-130 identical and 120 non-identical female twins aged recruited from a London based twin register and through a national media campaign.Main outcome measures-Similarity in identical compared with non-identical twin pairs for radiographic changes at the interphalangeal and first carpometacarpal joints of the hands and the tibiofemoral joint and patellofemoral joint of the knee expressed as intraclass correlations.Results-The intraclass correlations of radiographic osteophytes and narrowing at most sites and the presence of Heberden's nodes and knee pain were higher in the identical pairs. The intraclass correlation of the total radiographic osteoarthritis score in identical pairs (rMZ) was 0-64 (SE 0.05) compared with 0-38 (0.08) in non-identical pairs.The proportion of genetic variance of total osteoarthritis score (osteophytes and narrowing) with modelling techniques was estimated at 0*54 (95% confidence interval 0 43 to 0 65) and ranged from 0 39 to 0-65 for different sites and features (P< 0.001) after adjustment for age and weight.Conclusions-These results demonstrate for the first time a clear genetic effect for radiographic osteoarthritis of the hand and knee in women, with a genetic influence ranging from 39-65%, independent of known environmental or demographic confounders. The results of this study should lead to further work on isolating the gene or genes involved in the pathogenesis ofthis common disabling disease.

The classic twin study is sometimes described as "the perfect natural experiment" for the investigation of the aetiology of complex disease, but assumptions of the twin design need to be empirically tested if their results are to be considered unbiased and representative of singleton populations. In this study comparisons of disease and prevalence of lifestyle characteristics have been made between twin participants in the St Thomas' Hospital UK adult twin registry, the largest twin volunteer register in the UK for the study of diseases of ageing, and a parallel population-based study of singleton women. The only differences found were for weight, where monozygotic (MZ) twins were lighter and had a smaller variance than dizygotic (DZ) twins and singletons. For the other variables studied, volunteer twins were not found to differ from age-matched singleton women in distribution or prevalence of: bone mineral density, osteoarthritis, blood pressure, hypertensive drug use, height, history of hysterectomy and ovariectomy, menopausal status and current alcohol and overall tobacco consumption. We conclude that the results of twin studies can be generalised to singleton populations for these measures and disease outcomes.

Background-Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D insufficiency has been linked to a number of extraskeletal disorders, including diabetes, cancer, and cardiovascular disease. Determinants of circulating 25-hydroxyvitamin D (25-OH D) include sun exposure and dietary intake, but its high heritability suggests that genetic determinants may also play a role.Methods-We performed a genome-wide association study of 25-OH D among ∼30,000 individuals of European descent from 15 cohorts. Five cohorts were designated as discovery cohorts (n=16,125), five as in silico replication cohorts (n=9,366), and five as de novo replication * rs2282679 in Framingham, rs4588 in 1958 Birth Cohort (r 2 between SNPs >0.99).

ObjectiveThere is a great need for identification of biomarkers that could improve the prediction of early osteoarthritis (OA). We undertook this study to determine whether circulating levels of interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and C-reactive protein (CRP) can serve as useful markers of radiographic knee OA (RKOA) in a normal human population.MethodsRKOA data were obtained from the cohort of the Chingford Study, a prospective population-based study of healthy, middle-aged British women. The RKOA-affected status of the subjects was assessed using the Kellgren/Lawrence (K/L) grade as determined on radiographs obtained at baseline (n = 908) and at 10 years and 15 years thereafter. Serum levels of CRP, IL-6, and TNFα were assayed at 5, 8, and 15 years, using high-sensitivity commercial assays. A K/L grade of ≥2 in either knee was used as the outcome measure. Statistical analyses included analysis of variance for repeated measurements and logistic regression models, together with longitudinal modeling of dichotomous responses.ResultsDuring 15 years of followup, the prevalence of RKOA (K/L grade ≥2) increased from 14.7% to 48.7% (P < 0.00001 versus baseline). The body mass index (BMI) and circulating levels of CRP and IL-6 were consistently and significantly higher in subjects diagnosed as having RKOA. When multiple logistic regression was applied to the data, the variables of older age (P = 3.93 × 10−5), higher BMI at baseline (P = 0.0003), and increased levels of IL-6 at year 5 (P = 0.0129) were determined to be independent predictors of the appearance of RKOA at year 10. The results were fully confirmed using longitudinal modeling of repeated measurements of the data obtained at 3 visits. The odds ratio for RKOA in subjects whose IL-6 levels were in the fourth quartile of increasing levels (versus the first quartile) was 2.74 (95% confidence interval 1.94–3.87).ConclusionThis followup study showed that individuals were more likely to be diagnosed as having RKOA if they had a higher BMI and increased circulating levels of IL-6. These results should stimulate more work on IL-6 as a potential therapeutic target.

Objective. To examine the natural history, role of risk factors, and incidence of knee osteoarthritis (OA) in a prospective study of women from a population cohort.Methods. Women from the Chingford Study who had been recruited in 1989 were followed up with knee radiographs 4 years later. A total of 715 paired radiographs (71% of the original sample) were graded for osteophytes and 644 for joint space narrowing (JSN). Women whose radiographs had been graded as 0 in 1989 and as >14 years later were classified as having incident disease. Incident cases were compared with controls for associations with a number of risk factors.Results. Eighty-one women (12.6%) developed JSN of the knee, equating to an incidence of 3.

Objective. To estimate the risk of osteoarthritis (OA) of the hip and knee due to long-term weightbearing sports activity in ex-elite athletes and the general population.Methods. A retrospective cohort study was conducted of 81 female ex-elite athletes (67 middle-and long-distance runners, and 14 tennis players), currently ages 40-65, recruited from original playing records, and 977 age-matched female controls, taken from the age-sex register of the offices of a group general practice in Chingford, Northeast London, England. The definition of OA included radiologic changes (joint space narrowing and osteophytosis) in the hip joints, patellofemoral (PF) joints, and tibiofemoral (TF) joints.Results. Compared with controls of similar age, the ex-athletes had greater rates of radiologic OA at all sites. This association increased further after adjustment for height and weight differences, and was strongest for the presence of osteophytes at the TF joints (odds ratio [OR] 3.48), and was weakest for narrowing at the TF joints (OR 1.17, 95% CI 0.71-1.94). No clear risk factors were seen within the ex-athlete groups, although the tennis players tended to have more osteophytes at the TFjoints and hip, but the runners had more PF joint disease. Within the control group, a small subgroup of 22 women who reported long-term vigorous weight-bearing exercise had risks of OA similar to those of the ex-athletes. Ex-athletes had similar rates of symptom reporting but higher pain thresholds than controls, as measured by calibrated dolorimeter.Conclusion. Weight-bearing sports activity in women is associated with a 2-3-fold increased risk of radiologic OA (particularly the presence of osteophytes) of the knees and hips. The risk was similar in ex-elite athletes and in a subgroup from the general population who reported long-term sports activity, suggesting that duration rather than frequency of training is important.Osteoarthritis (OA) is one of the most common causes of disability in developed countries. An increase in the level of recreational physical activity is being widely encouraged as a major public health initiative to reduce cardiovascular disease and osteoporosis, yet the risks associated with excessive sports activity are unclear. To date, results of studies that have investigated the effects of weight-bearing exercise on the skeleton of athletes have been conflicting. Reports of negative effects have included studies of knee or hip O A in former cross country runners (1) and track athletes (2), a study of veteran Californian runners (3), and a study of knees and ankles of veteran military parachutists (4). Reports of positive effects have included a study from Finland of male ex-runners with OA (5), a recent record linkage study of male Finnish athletes showing a 2-fold risk of