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s / Osteoarthritis and Cartilage 22 (2014) S57–S489 S398 matrix remodeling process induced by an inflammatory microenvironment suggested by the presence of synovial hypervascularization. Figure 1. Prolidase protein expression: A) Hipertrophy synovial of patient with OA B) Normal synovium 710 MANUAL LABOR OCCUPATIONS INCREASE THE SHORT-TERM INCIDENCE OF KNEE OSTEOARTHRITIS IN JAPANESE, BUT NOT CAUCASIAN SUBJECTS K.M. Leyland y, M.T. Sanchez-Santos y, S. Muraki z, A. Judge y, T.D. Spector x, D.J. Hart x, J. Newton y, C. Cooper ky, N. Yoshimura z, N.K. Arden yk. yUniv. of Oxford, Oxford, United Kingdom; zUniv. of Tokyo, Tokyo, Japan; x St. Thomas’ Hosp., London, United Kingdom; kUniv. of Southampton, Southampton, United Kingdom Purpose: To determine the interacting role of occupation and obesity on the risk of incident knee osteoarthritis (OA) among Caucasian and Japanese women. Methods: We used data from women in two prospective communitybased cohorts, the UK based Chingford study and the Japanese Research on Osteoarthritis/osteoporosis Against Disability (ROAD) study. Incident radiographic knee osteoarthritis (RKOA) was defined as having Kellgren and Lawrence (K/L) grade 0 or 1 in both knees at baseline and a K/L grade 2 or greater at follow up. Follow-up x-rays were taken after a median of 4 years after baseline for Chingford and 3 years in ROAD. The cut-off for a normal BMI was 25 kg/m2 for the Caucasian subjects and 23 kg/m2 for the Japanese subjects. Occupation was divided into manual versus non-manual (i.e. sedentary/moderate activity) for both populations based on self-assessment. Multivariable logistic regression models assessed of risk of obesity, occupation and their interaction on incident RKOA, controlling for age, hand grip strength, walking distance, smoking and alcohol intake. Results: 12.4% of Caucasian and 14.5% of Japanese women developed incident RKOA in at least one knee. Being overweight/obese was associated with an increased risk of incident RKOA in both populations (Caucasian OR 1.7 [95% CI 1.0, 2.8]; Japanese OR 2.5 [95% CI 1.3, 4.9]), however having a manual labour occupation was only significantly associated with incident RKOA in the Japanese subjects (OR 2.8 [95% CI 1.3, 5.8]). No significant interaction between BMI category and occupation was found for either population (Chingford p1⁄40.070; ROAD p1⁄40.291), however the Japanese population showed a slight increase in risk for manual labour occupations in the overweight/obese category Table 1 Profile of Participants by presence or absence of back pain

Objective(s): Strontium ranelate (SrRan) has potential beneficial effects on cartilage degradation in osteoarthritis (OA), stimulating human cartilage matrix formation in vitro and decreasing urinary CTX-II. SrRan has also been shown to reduce radiographic spinal OA progression and back pain in osteoporotic women with prevalent spinal OA. We compared the efficacy and safety of SrRan with placebo in the treatment of knee OA in a double-blind, placebo-controlled, randomised, international 3-year study (registration number: ISRCTN41323372).Material & Methods: 1683 patients with symptomatic primary knee osteoarthritis and with a Kellgren-Lawrencescore II or III were included and randomly allocated to SrRan 1 or 2 g/day, or placebo. The primary endpoint was radiographic joint space narrowing measured as the mean change from baseline to End in Joint Space Width (JSW) of the knee medial tibiofemoral compartment using a semiautomated centralised reading method. JSW was measured at selection, 12, 24, and 36 months on radiographs acquired using a postero-anterior, weight-bearing, fixed-flexion acquisition technique (described elsewhere1). Symptoms were primarily assessed by algofunctional WOMAC score and subscores and safety by adverse events and biological parameters.Results: The intention-to-treat population included 1371 (82%) patients (mean follow-up 29.810.5 months). Mean age was 62.8±7.2 years and 69% were female. Mean BMI was 30±5 kg/m2, mean JSWwas 3.50±0.83 mm, and 61% of randomised patients were Kellgren and Lawrence stage II. Treatment with SrRan was associated with less progression of cartilage degradation, decrease in JSW was -0.230.56 mm with 1 g/day; -0.270.63 mm with 2 g/day and -0.370.59 mm with placebo; treatment-placebo estimated differences (SE) were 0.14 (0.04), p

Background. The General Health Questionnaire (GHQ) is the most popular screening instrument for detecting psychiatric disorders in community samples. Using longitudinal data of a large sample of UK twin pairs, we explored (i) heritabilities of the four scales and the total score; (ii) the genetic stability over time; and (iii) the existence of differential heritable influences at the high (ill) and low (healthy) tail of the distribution.Method. At baseline we assessed the GHQ in 627 MZ and 1323 DZ female pairs and at a second occasion (3·5 years later) for a small subsample (90 MZ and 270 DZ pairs). Liability threshold models and raw ordinal maximum likelihood were used to estimate twin correlations and to fit longitudinal genetic models. We estimated extreme group heritabilities of the GHQ distribution by using a model-fitting implementation of the DeFries–Fulker regression method for selected twin data.Results. Heritabilities for Somatic Symptoms, Anxiety, Social Dysfunction, Depression and total score were 0·37, 0·40, 0·20, 0·42 and 0·44, respectively. The contribution of shared genetic factors to the correlations between time points is substantial for the total score (73%). Group heritabilities of 0·48 and 0·43 were estimated for the top and bottom 10% of the total GHQ score distribution, respectively.Conclusion. The overall heritability of the GHQ as a measure of psychosocial distress was substantial (44%), with all scales having significant additive genetic influences that persisted across time periods. Extreme group analyses suggest that the genetic control of resilience is as important as the genetic control of vulnerability.

The menopause has a large effect on bone density, and hormone replacement therapy (HRT) has been shown to be an effective treatment for preventing postmenopausal bone loss. The aim of this study was to compare the effects of HRT use on speed of sound (SOS) measurements at the radius, tibia, phalanx, and metatarsal with bone mineral density (BMD) measurements of the lumbar spine and proximal femur. The study population consisted of 278 healthy premenopausal women, 194 healthy postmenopausal women, and 126 healthy postmenopausal women currently receiving HRT for one or more years. SOS measurements were taken at the radius, tibia, phalanx, and metatarsal using the Sunlight Omnisense, and BMD measurements at the lumbar spine and proximal femur using Hologic QDR-4500 densitometers. Z-scores were calculated using the postmenopausal control group. Z-score differences between the postmenopausal controls and HRT group, for the entire group and with the HRT group subdivided into three groups based on duration of HRT usage, were calculated. Significant postmenopausal bone loss was found for all SOS and BMD measurements. A positive effect of HRT usage was found for all SOS measurement sites and lumbar spine BMD, although only the radius and tibia SOS and lumbar spine BMD reached statistical significance. The Z-score differences between the two groups were 0.44, 0.37, 0.15, and 0.26 for the radius, tibia, phalanx, and metatarsal SOS respectively, and 0.28, 0.00, and -0.03 for the lumbar spine, femoral neck, and total hip BMD respectively. A clear effect of the duration of HRT use was seen for the radius measurements, the differences being less marked elsewhere. In conclusion, these results demonstrate a positive effect of HRT on SOS measurements at the radius and tibia and BMD measurements of the lumbar spine.

In this confirmatory candidate gene study, we investigated possible linkage and association for bone density, heel ultrasound and bone turnover with the osteocalcin gene using the nearby (50-180kb) microsatellite marker D1S3737. Non-identical twin sisters aged 18-75 years at first interview were recruited for the study from the St Thomas' UK Adult Twin Registry with 1366 women being genotyped for marker D1S3737. Linkage, allelic association and joint linkage and association tests were carried out using quantitative transmission disequilibrium tests (QTDT), along with post-hoc multivariate tests of linkage and association. Phenotypes tested were bone mineral density (BMD) at the spine, left forearm and left total hip; quantitative ultrasound measurements of the heel including velocity of ultrasound (VOS) and broadband ultrasound attenuation (BUA); and bone turnover markers, urine deoxypyridinoline (DPD), serum osteocalcin, bone specific and total alkaline phosphatase (ALP). BMD and ultrasound variables showed evidence of pleiotropic linkage ( p = 0.05) and association ( p = 0.02) with the marker in postmenopausal women. Bone markers showed little or no evidence of linkage and association for any age group. Evidence for pleiotropic linkage appeared to be strongest for BUA and spine BMD in postmenopausal women. The univariate test statistic for BUA was chi(2)(1)=12.8 ( p = 0.0003), equivalent to a LOD score of 2.8. DPD showed borderline evidence of linkage to the marker for women of all ages. Multivariate model-fitting showed allele 10 to be negatively associated with BMD, VOS and BUA via a common pathway, suggesting the putative functional polymorphism affects both bone content and structure through shared underlying metabolic pathways. It is likely that the alleles are in linkage disequilibrium with functional polymorphism(s) in or nearby the osteocalcin gene, which may contribute to the onset of osteoporosis.

We previously reported an association between high bone mass (HBM) and a bone-forming phenotype of radiographic hip osteoarthritis (OA). As knee and hip OA have distinct risk factors, in this study we aimed to determine (i) whether HBM is also associated with knee OA, and (ii) whether the HBM knee OA phenotype demonstrates a similar pattern of radiographic features to that observed at the hip. HBM cases (defined by DXA BMD Z-scores) from the UK-based HBM study were compared with unaffected family controls and general population controls from the Chingford and Hertfordshire cohort studies. A single blinded observer graded AP weight-bearing knee radiographs for features of OA (Kellgren–Lawrence score, osteophytes, joint space narrowing (JSN), sclerosis) using an atlas. Analyses used logistic regression, adjusting a priori for age and gender, and additionally for BMI as a potential mediator of the HBM–OA association, using Stata v12. 609 HBM knees in 311 cases (mean age 60.8 years, 74% female) and 1937 control knees in 991 controls (63.4 years, 81% female) were analysed. The prevalence of radiographic knee OA, defined as Kellgren–Lawrence grade ≥ 2, was increased in cases (31.5% vs. 20.9%), with age and gender adjusted OR [95% CI] 2.38 [1.81, 3.14], p, Highlights • We examined associations between high bone mass and radiographic knee osteoarthritis (OA). • High bone mass cases had an increased prevalence of knee OA compared with controls. • The OA phenotype in high bone mass is characterised by osteophytosis. • Body mass index is a partial mediator of the high bone mass–OA association.

SummaryThe hand is a common site of peripheral joint involvement in osteoarthritis (OA) and although often underestimated as a cause of disability, the effect on quality of life from limitations in performing activities of daily living such as dressing and feeding may be considerable. Hand OA may also be an important indicator of a systemic tendency to OA which may involve weight bearing joints, notably the hips and knees.1The definition of hand OA, particularly for epidemiological studies, has undergone reassessment and revision over the last few years. In this paper we examine the issues relating to this and consider the epidemiology of hand OA.

Family and twin studies demonstrate a strong genetic component to osteoporosis, suggesting that a positive family history for this disease may be an important clinical risk factor. We have therefore explored the extent to which a history of wrist fracture in a female first-degree relative was associated with an increased risk of prevalent fracture at both appendicular and vertebral sites in a cross-sectional study design. One thousand and three Caucasian women (age range 45-64 years) were studied from a UK population cohort. Bone mineral density (BMD) was measured at the lumbar spine and femoral neck using dual-energy X-ray absorptiometry. Appendicular fractures (wrist and hip) were recorded by questionnaire and validated from radiographs and hospital records. Vertebral fractures were assessed using radiologic survey of the thoracolumbar spine and semi-automated morphometric analysis. A positive family history of osteoporotic fracture (hip and/or wrist) in either a mother and/or sister was reported in 138 of the 1003 women. When compared with those with a negative family history of fracture, BMD was significantly reduced in those with a positive history at both the spine (p = 0.02) and the hip (p = 0.02). In total, there were 63 validated fragility fractures found in the 1003 women (16 wrist, 6 hip and 41 vertebral). Family history of osteoporotic fracture was associated with an increased total risk for osteoporotic fracture, with an odds ratio (95% confidence interval) of 2.02 (1.02, 3.78). Site-specific analysis showed that a positive family history of wrist fracture was associated with a considerably elevated risk of wrist fracture, with an odds ratio of 4.24 (1.44, 12.67). These increases in risk remained after adjustment for BMD, suggesting that other genetic factors account for the familial risk of osteoporosis and fracture.

Background: The second to fourth finger length ratio (2d:4d) is thought to be related to diverse traits including cognitive ability, disease susceptibility, and sexuality. Objective: To examine the relationship between 2d:4d and sports ability in women. Methods: Hand radiographs from 607 women (mean age 54 years) were used to estimate 2d:4d. Ranking of sports ability was on a scale (1–5). Results: The highest achieved level of participation in any sport was significantly negatively associated with 2d:4d (b = −4.93, p = 0.01) as was the relationship between 2d:4d and running level (b = −6.81, p = 0.034). Ability in other sports also showed a negative relationship albeit non-significant. Conclusions: These results suggest that a low 2d:4d ratio is related to increased female sports ability. It can be postulated that this ratio may predict potential sports ability. Understanding the mechanisms underpinning this relationship may give important insights into musculoskeletal fitness, health and disease.

Alendronate is a drug with considerable potential. It is likely to work best in elderly patients with moderate to severe osteoporosis. Long-term studies and comparison with other therapeutic agents are needed before its exact role is established.

Objectives: To investigate the possible association between vitamin D receptor genotype and bone mineral density in a large group of postmenopausal twins. Design: Cross sectional twin study. Setting: Twin population based in Britain. Subjects: 95 dizygotic (non-identical) pairs of twins and 87 monozygotic (identical) pairs of twins aged 50-69 years, postmenopausal, and free of diseases affecting bone, recruited from a national register of twins and with a media campaign. Main outcome measures: Bone mineral density measured at the hip, lumbar spine, forearm, and for the whole body by dual energy x ray absorptiometry in relation to differences in the vitamin D receptor genotype. Results: At all sites the values of bone density among dizygotic twins were more similar in those of the same vitamin D receptor genotype than in those of differing genotype, and the values in the former were closer to the correlations seen in monozygotic twins. Women with the genotype that made them at risk of osteoporotic fracture had an adjusted bone mineral density that was significantly lower by SD 0.5 to 0.6 at the hip, lumbar spine, and for the whole body. The results could not be explained by differences in age, weight, years since menopause, or use of hormone replacement therapy. Conclusions: The findings that in postmenopausal women in Britain bone density—particularly at the hip and spine—is genetically linked and specifically associated with the vitamin D receptor genotypes should lead to novel approaches to the prevention and treatment of osteoporosis. Key messages Key messages Vitamin D has an important role in the metabolism of calcium and bone, mediated through its receptor Common variants of the vitamin D receptor gene are responsible for 7-10% of the difference in bone density between women after the menopause This genetic marker is important because of its potential role in identifying individual women at increased risk of fracture before menopause and in selecting optimal treatment

Quantitative sensory testing (QST) and questionnaire-based assessments have been used to demonstrate features of neuropathic pain in subjects with musculoskeletal pain. However, their direct relationship has not been investigated in the community. The purpose of this study was to conduct an observational study to describe the characteristics of joint pain and to examine the relationship between QST measures and the PainDETECT Questionnaire (PD-Q).Warm detection, heat pain, and mechanical pain thresholds as well as mechanical pain sensitivity over the sternum were determined and the PD-Q scores were calculated in a cross-sectional study of 462 participants in the Chingford Study. Comparisons were made between subjects with and those without joint pain. Logistic regression modeling was used to describe the association between neuropathic pain features, as determined by the PD-Q score, and each of the QST measures individually, adjusting for age, body mass index, and use of pain-modifying medications.A total of 66.2% of the subjects reported recent joint pain, with a median average pain severity of 5 of 10. There was increased sensitivity to painful stimuli in the group with pain as compared to the pain-free group, and this persisted after stratification by pain-modifying medication use. While only 6.7% of subjects had possible neuropathic pain features and 1.9% likely neuropathic pain features according to the standard PD-Q thresholds, features of neuropathic pain were common and were present in50% of those reporting pain of at least moderate severity. Heat pain thresholds and mechanical pain sensitivity were significantly associated with features of neuropathic pain identified using the PD-Q, with an odds ratio (OR) of 0.88 (95% confidence interval [95% CI] 0.79-0.97; P = 0.011) and an OR of 1.24 (95% CI 1.04-1.48; P = 0.018), respectively.QST measures and the PD-Q identified features of neuropathic pain in subjects in this community-based study, with significant overlap between the findings of the two techniques.

Twins have always fascinated medical research even before the discovery of DNA and the understanding of the differences between identical and non-identical twins. Dermatology with the benefit of being able to visualize phenotypes was one of the first specialities reporting on the fascinating concordance in identical (MZ) twins in the 1920's. Over the last 20 years, the heritability of skin diseases using twins has been clearly demonstrated, across a wide variety of traits including melanoma, polymorphic light eruption, psoriasis, eczema and acne. Other rarer diseases have also been shown to have a significant genetic basis such as lupus, sarcoidosis and lichen sclerosus. Following evidence of heritability for many skin disease the next step was Genome-Wide Association Studies (GWAS) which are uncovering new genes in large twin cohorts. The twin model is also ideal for the new field of epigenetics, investigating subtle differences in DNA methylation within discordant MZ pairs for a disease, as well as differences in CNVs. Twins are also valuable for examining differences in gene function via RNA expression in twins discordant for a skin trait or disease.

The natural history of hand osteoarthritis (OA) is poorly understood. The aim of the study was to ascertain the extent and pattern of radiological progression of hand OA over a 10-year period. A follow-up study was carried out on 169 consecutive patients who initially presented with OA of the hands or knees between 1975-1977. Fifty-nine subjects (45 women and 14 men) were recontacted who had paired hand radiographs, a mean of 10 years apart, and were a mean 69 (range 53-86) years old at follow-up. X-rays were scored blind, in three joint areas--distal and proximal interphalangeal joints (DIP and PIP) and first carpo-metacarpal (CMC) joints--using the method of Kellgren and Lawrence (K&L) (0-4), and for osteophytes and narrowing (0-3). Using the highest score for right and left hands (N = 118), K&L changes at the three areas were similar with 47-50% deteriorating, 45-46% unchanged, and 6-8% improving. Similar deterioration was seen when scoring the three joint areas for osteophytes (38-39%) and narrowing (39-48%). New osteophytes appeared in 48% of DIP joints during the 10 years. There was a weak correlation between progression at the DIP and PIP joints, but no relationship between DIP and CMC, or CMC and PIP. Virtually all subjects (97%) deteriorated when the total scores of all joints were calculated. No significant differences were seen between 'severe progressors' and 'minor' in terms of age or body mass index (BMI). A nonsignificant increase in the proportion of knee progressors in the severe progressor hand group was seen and there was a higher rate of baseline DIP OA in knee progressors. These results suggest that the majority of patients with OA of the hands attending a rheumatology outpatients clinic deteriorate radiologically over a 10-year period, about half developing new changes in DIP joints. There were no obvious features distinguishing those with rapid deterioration, although DIP OA appears to be a risk factor for knee progression.

We illustrate the use of a quantitative trait locus (QTL) association test with data on blood pressure and six single nucleotide polymorphisms (SNPs) within the transforming growth factor-β1(TGF-β1) gene in a large sample of dizygotic (DZ) twins. The test was specified within the framework of structural equation modelling and allows for population stratification and easily incorporates confounders. Results showed linkage in the presence of association between the TGF-β1 263 polymorphism and blood pressure levels, with carriers showing a clinically significant increase of 6 and 4 mm Hg in systolic and diastolic blood pressure, respectively. The described association test offers an easy and flexible way to analyse QTL data in sib or DZ twin pairs while controlling for population stratification by making use of within-family controls.

It has been known for over 20 years that osteoporosis is highly influenced by genetic factors. Bone mineral density (BMD) has also been shown to be highly heritable. Other known risk factors for osteoporotic fractures such as reduced bone quality, femoral neck geometry and bone turnover are now also known to be heritable. Susceptibility to osteoporosis is mediated, in all likelihood, by multiple genes each having small effect. Different approaches are being used currently to identify the many genes responsible. These include linkage studies in man and experimental animals as well as candidate gene studies and alterations in gene expression. Linkage studies have identified multiple quantitative trait loci (QTL) for regulation of BMD and, with twin studies, have indicated that the effects of these loci are partly site-dependent and sex-specific. On the whole, the genes responsible for BMD regulation at these QTL have not yet been isolated. Most studies have used the candidate gene approach. The vitamin D receptor gene (VDR), the collagen type I alpha 1 gene (COLIA1) and estrogen receptor gene (ER) alpha have been most widely investigated and found to play a role in regulating BMD, but the effects are modest and together probably account for less than 5% of the heritable contribution to BMD. Genes may vary in their influence of particular intermediate phenotypes, and we now know that not all genes influencing BMD will be important in fracture. In addition, the study of other diseases such as osteoarthritis and metabolic bone syndromes may prove fruitful in highlighting genes which overlap to osteoporosis as well. As large scale genetic testing becomes more cost-effective, recent findings have illustrated the potential of novel approaches. These include combining large multi-national populations for candidate gene analysis, meta-analyses, DNA pooling studies and gene expression studies.

To estimate the heritability of frozen shoulder (FS) and tennis elbow (TE) and to examine the two disorders for possible genetic or environmental associations.Self-reporting questionnaire data on risk factors for, and a physician diagnosis of, FS or TE were obtained from 865 monozygotic (MZ) and 963 dizygotic (DZ) unselected female twin pairs aged between 20 and 76 yr registered with the St Thomas' UK Adult Twin Registry. The heritability of each disorder was estimated in a classic twin study. The association between FS and TE was then explored by log-linear modelling comparing MZ with DZ individuals and twin pairs for the presence of both disorders.The prevalence of FS and TE were 11.6 and 16.7%, respectively. A heritability of 42% was estimated for FS and 40% for TE after adjusting for age. There was no confounding by environmental risk factors. Log-linear modelling demonstrated FS and TE, independently, to be associated within members of a twin pair and confirmed a stronger association in MZ than DZ pairs. In addition the two disorders occurred together 2-3 times more frequently in individuals than would be expected by chance. However, there was no association between FS and TE across members of a twin pair, implying no evidence for a shared genetic component to the two disorders.Genetic factors are implicated in the aetiology of both frozen shoulder and tennis elbow but are independent of each other. The two disorders occur together 2-3 times more frequently than by chance in individuals. However, the association is most likely mediated by individual-specific environmental factors common to the two conditions and not by a common genetic susceptibility.

Distal forearm fractures are the most common perimenopausal fracture and are generally associated with osteoporosis. The aim of this study was to evaluate the capability of speed of sound (SOS) measurements in cortical bone at the phalanx, radius, tibia and metatarsal to discriminate Colles' fracture cases from controls in postmenopausal women and to compare this with bone mineral density (BMD) measurements obtained by dual-energy X-ray absorptiometry (DXA). Sixty-three postmenopausal Colles' fracture cases and 191 postmenopausal controls had SOS measurements of the radius, tibia, phalanx and metatarsal using a semi-reflection ultrasound technique and BMD measurements of the lumbar spine and proximal femur using DXA. The age-adjusted odds ratios (ORs) for fracture for the SOS measurement sites were 1.50 [95% CI 1.07-2.10] for the radius, 1.23 [0.86-1.76] for the tibia, 1.85 [1.06-3.23] for the phalanx and 1.74 [1.12-2.71] for the metatarsal site. For the BMD measurements the ORs were 1.95 [1.34-2.85] for the lumbar spine, 2.21 [1.43-3.40] for the femoral neck and 2.62 [1.69-4.08] for the total hip. The benefits of combining sites either by taking their average Z-score or by using the manufacturer's ORI algorithm were evaluated. The two methods yielded similar results and the ORs for the combination of the radius and phalanx were 2.00 [1.21-3.33], for the radius and metatarsal 1.67 [1.05-2.67], for the phalanx and metatarsal 1.86 [1.11-3.08] and for the radius, phalanx and metatarsal 1.81 [1.07-3.06]. Combinations of DXA sites gave 2.22 [1.44-3.41] for the lumbar spine and femoral neck and 2.41 [1.57-3.70] for the lumbar spine and total hip. In conclusion, semi-reflection ultrasound measurements at the radius, phalanx or metatarsal demonstrated an ability to discriminate fracture cases from controls in postmenopausal Colles' fracture patients, although the odds ratios were lower than with spine and femur BMD.

HbA(1c), a measure of blood glucose regulation, reflects glucose levels in the preceding months. In diabetes, HbA(1c) levels predict the risk of microvascular complications. The aim of this study was to determine whether genetic factors could influence HbA(1c) levels in normal subjects and type 1 diabetic patients. We performed a classical twin study of HbA(1c) in healthy nondiabetic female twins and 42 monozygotic (MZ) and 47 dizygotic (DZ) pairs. Interclass correlations (r) were higher in MZ (r = 0.77) compared with DZ (r = 0.53) twin pairs, suggesting a substantial genetic effect; this was confirmed by quantitative genetic model fitting. Additive genetic effects (heritability) explained 62% (95% CI 47-75) of population variance in HbA(1c); the remainder was attributable to the influence of unique environment (23% [15-36]) and age (14% [5-28]). Multivariate modeling showed that genetic factors also have a substantial influence on fasting glucose levels (51%). However, HbA(1c) heritability could not be explained by genes in common with fasting glucose. In the patients with type 1 diabetes, HbA(1c) levels were correlated in 33 MZ twins concordant for diabetes (r = 0.68; P0.001) but also in 45 MZ twins discordant for the disease (r = 0.52; P0.001). These significant correlations for HbA(1c) in both concordant and discordant pairs indicate a diabetes-independent familial effect. Thus, HbA(1c) levels are largely genetically determined and independent of the genes influencing fasting glucose. Even in type 1 diabetes, familial (i.e., diabetes-independent) factors influence protein glycation, implying that familial factors may explain, in part, the risk for microvascular complications, as indicated by high HbA(1c) levels.

Reduced bone mineral density (BMD), the major risk factor for osteoporotic fracture, has been linked to palmoplantar pustular psoriasis, but no significant studies have examined BMD in chronic plaque psoriasis (CPP). In this study, in-patients with severe CPP had their BMD measured at the nondominant hip and lumbar spine using dual energy X-ray absorbtiometry. Ten male and 10 female Caucasian patients were recruited, with a mean age of 47 years (range 20--71 years). There were no significant differences in BMD between patients and controls. However, patients with psoriatic arthropathy in addition to CPP had a significantly lower mean lumbar spine Z-score (- 1.16) than those without arthropathy (+1.38, P = 0.015). Neither previous nor current treatment with systemic steroids, retinoids or methotrexate significantly affected BMD. We found no evidence that patients with CPP, despite risk factors, have a significantly low BMD, although the subgroup with joint involvement appear be at significantly higher risk of osteoporosis and may therefore require preventative treatment.

This study evaluated the clinical utility of a new multisite ultrasound device capable of measuring speed of sound (SOS) at the phalanx, radius, tibia and metatarsal. The in vitro and in vivo short- and long-term precision were evaluated, reference data were collected for 409 healthy white women (236 premenopausal and 173 postmenopausal), and age and menopause related changes were calculated using linear regression. Fracture discrimination was evaluated using 109 women with vertebral fractures and the age-adjusted odds ratios calculated for each standard deviation decrease in SOS measurement. Correlations between SOS measurements and spine and femur bone mineral density (BMD) were calculated. T-score equivalence with BMD was also investigated together with the prevalence of osteoporosis as defined by the WHO criteria. The in vivo short-term precision standardized in T-score units ranged from 0.14 to 0.33 and long-term standardized precision was 0.35-0.65. Postmenopausal age-related bone loss expressed as the annual change in T-score ranged from 0.040 to 0.089 for SOS and 0.053 to 0.066 for BMD, whilst menopause-related annual loss ranged from 0.036 to 0.094 for SOS and 0.050 to 0.074 for BMD. Correlations between the different SOS sites ranged from r = 0.24 to 0.55, and between SOS and BMD from r = 0.12 to 0.47. The odds ratio (and 95% confidence intervals) for fracture per 1 SD decrease in SOS were 2.0 (1.22 to 3.23) for the phalanx; 1.5 (1.01 to 2.24) for the metatarsal; 1.4 (1.03 to 1.99) for the radius and 1.2 (0.87 to 1.66) for the tibia. Odds ratios for BMD in the same population ranged from 2.6 to 4.8 (1.70 to 8.29). The prevalence of osteoporosis as defined by T =-2.5 in the age range 60-69 ranged from 7.1% to 20.6% for SOS and 6.4% to 12.1% for BMD. In conclusion, this study demonstrated that multisite ultrasound has adequate precision for investigating skeletal status, is capable of differentiating between pre- and postmenopausal women and women with vertebral fractures, has a T-score equivalence similar to that of dual-energy X-ray absorptiometry (DXA), and appears to be a promising new technique for evaluating skeletal status at clinically relevant sites.

A classical twin study was performed to examine the relative importance of genes and environment in refractive error.Refractive error was examined in 226 monozygotic (MZ) and 280 dizygotic (DZ) twin pairs aged 49 to 79 years (mean age, 62.4 years). Using a Humphrey-670 automatic refractor, continuous measures of spherical equivalent, total astigmatism, and corneal astigmatism were recorded. Univariate and bivariate maximum likelihood model fitting was used to estimate genetic and environmental variance components using information from both eyes.For the continuous spectrum of myopia/hyperopia, a model specifying additive genetic and unique environmental factors showed the best fit to the data, yielding a heritability of 84% to 86% (95% confidence interval [CI], 81%-89%). If myopia and hyperopia (or = -0.5 D andor = 0.5 D, respectively) were treated as binary traits, the heritability was 90% (95% CI, 81%-95%) for myopia and 89% (95% CI, 81%-94%) for hyperopia. For total and corneal astigmatism, modeling showed dominant genetic effects are important; dominant genetic effects accounted for 47% to 49% of the variance of total astigmatism (95% CI, 37%-55%) and 42% to 61% of corneal astigmatism variance (95% CI, 8%-71%), with additive genetic factors accounting for 1% to 4% and 4% to 18%, respectively (95% CIs, 0%-13% and 0%-60%, respectively).Genetic effects are of major importance in myopia/hyperopia; astigmatism appears to be dominantly inherited.

The objectives of this study were to investigate the effects of GH replacement therapy in hypopituitary adults with growth hormone deficiency (GHD) on activation of bone remodelling during dose titration and on BMD over a median of 58 months of continuous therapy.Open label study in adult patients with GHD. rhGH was commenced at dose of 0.8 IU subcutaneously daily (0.4 IU if hypertensive or glucose tolerance impaired) with subsequent dose titration based on 2 weekly measurement of serum IGF-I until levels reached the target range (between the median and upper end of the age related reference range). In patients previously commenced on GH using weight based regimens the dose of GH was adjusted during clinical follow-up in order to maintain serum IGF-I in the target range.Initial effects of GH on bone remodelling during dose titration were studied in 17 patients (8F). Long-term effects of GH were determined in a separate group of 13 GHD adults (6F) over a median period of 58 months (range 44-72).Osteoblastic activity was estimated by measuring serum bone specific alkaline phosphatase (S-BAP). BMD was determined at both lumbar spine (L2-L4) and femoral neck by dual energy X-ray absorptiometry (DEXA).During dose titration a significant increment in S-BAP was observed by 10 weeks in females but occurred later in males (12-26 weeks). In the long term treatment group there was a significant increment in S-BAP compared to baseline (P = 0.013) after 6 months GH treatment. After long-term GH treatment (median 58 months) S-BAP levels decreased and were no longer statistically significantly different from baseline at the end of the study period. A similar response was observed in male and female patients. There were no significant differences in baseline BMD between male and female patients at either lumbar spine or femoral neck in the long term treatment group. No significant changes were observed in BMD after 6 months GH treatment in either lumbar spine or femoral neck but BMD increased over the remainder of the study at both sites (P = 0.023 and P = 0.03 respectively). When analysed by gender male patients showed a clear positive change in BMD after longer-term replacement in both lumbar spine and femoral neck (P = 0.01 and P = 0.02 respectively) but female patients showed no significant changes. Qualitatively similar results were observed when analysing changes in BMD expressed as Z scores.This study demonstrates an earlier onset of GH activation of bone remodelling as reflected by S-BAP in females compared to males and confirms that long-term GH treatment in hypopituitary adults with GH deficiency increases or preserves BMD both at lumbar spine and femoral neck. However male patients seem to derive the greater benefits in BMD from long-term GH replacement; in females BMD appears simply to be stabilized rather than increased. This constitutes a genuine gender difference in susceptibility given that serum IGF-I was in the upper part of the reference range in all subjects.

A classical twin study was performed to establish the relative importance of genes and environment in cortical cataract.Five hundred six pairs of unselected female twin volunteers (226 monozygotic and 280 dizygotic) with a mean age of 62 years (range, 49-79 years) were examined. Cortical cataract was assessed using the slit-lamp-based Oxford Clinical Cataract Classification and Grading System (clinical grading) and the Wilmer Automated Grading System, which analyzed digital retroillumination images of subjects' lenses (digital grading). The worse eye categorized score for each individual was used in maximum likelihood path modeling of the correlations within twin pairs. These correlations were used to determine the underlying liability to cortical cataract.Prevalence of significant cortical cataract (/=5% of lens area) was similar in monozygotic and dizygotic twins, occurring in 19.4% and 20.6% with the clinical grading system and 24% and 23% using the digital grading system, respectively. Modeling suggested liability to cortical cataract is explained by additive and dominant genes, individual environment, and age. Estimates of the broad sense heritability of cortical cataract were 58% (95% confidence interval [CI], 51%-64%) for the clinical grading system and 53% (95% CI, 45%-60%) for the digital system. Dominant genes were estimated to contribute to 38% (95% CI, 1%-64%) of the genetic effect with the clinical grading and 53% (95% CI, 28%-60%) with the digital grading. Individual environment explained 26% and 37% and age 16% and 11% of cortical cataract variance in clinical and digital gradings, respectively.Genetic effects are important in the development of cortical cataract and involve the action of dominant genes.

OBJECTIVE: Bone mineral density (BMD) in later life is a major determinant of osteoporotic fracture risk and has been shown to be under strong genetic influence. Transforming growth factor beta 1 (TGF- beta 1) is an important regulatory cytokine, is found in high concentrations in the bone matrix, and is a plausible candidate for the genetic regulation of BMD. METHODS: This study investigated whether a novel polymorphism within the TGF-beta 1 gene is associated with BMD in a large normal female population of 1706 dizygotic (DZ) twins (age range 18-76 yr). RESULTS: A C--->T [corrected] polymorphism was identified in intron 5, the T [corrected] allele having a frequency of 0.25. Subjects homozygous for the presence of the TGF-beta 1 T [corrected] allele had a 4% reduction in femoral neck BMD compared with the other two genotype groups (P

The aim of this session was to identify current issues and problems relating to risk factors for hand osteoarthritis (OA). The following important factors were discussed: Genetics, Age, Gender, Obesity, HRT (hormone replacement therapy), Physical activity/trauma.

To assess the genetic contribution to radiographic hip osteoarthritis (OA) by measuring the distribution of disease features in monozygotic (MZ) and dizygotic (DZ) twins.A population-based, cross-sectional study was conducted of 135 MZ and 277 DZ healthy female twin pairs, 50 years of age and older, who were recruited into the St. Thomas' UK Adult Twin Registry. Pelvic radiographs were read by a single observer who was blinded to the pairing and zygosity of the twins. The films were assessed for overall OA grade using a modification of the Kellgren and Lawrence scheme, and assessed for individual radiographic features.There was evidence of significant familial clustering for grade I and grade II OA changes, with an excess concordance in MZ twins compared with DZ twins, suggesting a genetic effect. The MZ versus DZ excess was also apparent for those classified as having more severe disease, although the number of pairs with these disease features was small. Familial clustering attributable to genetic factors was evident for joint space narrowing of2.5 mm. Familial, but not genetic, clustering was seen for subchondral sclerosis. The number of pairs concordant for definite osteophytes in the sample was too low to assess this feature alone. These results translate into a significant heritability of 58% for OA overall and 64% for joint space narrowing. The heritability estimates decreased a little when the potential confounding influences of age, body mass index, and hip bone density were taken into account.Genetic factors have a significant contribution to OA at the hip in women and account for approximately 60% of the variation in population liability to the disease.

Previous case-control studies have shown various degrees of inverse relationship between osteoarthritis (OA) and osteoporosis (OP). The aim of this study was to examine the relationship between radiographic hip OA and bone mineral density (BMD) at the affected and contralateral hips, as well as at more distal sites. We also explored the possibility that this association might be confounded by genetic factors.Using the discordant twin model to reduce selection bias and adjust for genetic factors, plain pelvic radiographs of white female twins aged40 years, from the St. Thomas' UK Adult Twin Register, were assessed for radiographic features of hip OA. Overall OA was classified using a 6-point global grading system (Croft). Osteophytes (OPH) and joint space narrowing (JSN) were also examined separately. BMD was measured by dual x-ray absorptiometry at the left hip, lumbar spine, and total body. The association of OA with BMD was assessed using conditional logistic regression. Adjustments were made for body mass index, lifetime physical activity, menopausal status, use of estrogen, and smoking.The analysis included a total of 1,148 women comprising 160 monozygotic and 414 dizygotic twin pairs. The median age of the twins was 53 years (range 40-70). The crude and adjusted odds ratios and 95% confidence intervals for having radiographic features of hip OA were 1.63 (1.06, 2.50) and 1.80 (1.05, 3.12), respectively, per unit difference in standardized BMD of the ipsilateral femoral neck. The presence of OPH, but not JSN, was associated with higher BMD. Twins with hip OPH had 3.5% higher femoral neck BMD than their unaffected cotwins. No clear association was found between hip OA and BMD at the contralateral site, lumbar spine, or total body.This twin study confirms the existence of an inverse relationship between OA and OP at the hip. However, the relationship was localized to the OA-affected hip. The generalized and greater increase in BMD in osteoarthritic subjects seen in previous studies of unrelated populations is therefore likely to be due, in part, to genetic factors shared by hip OA and high bone mass. It also suggests that local changes in bone density may be a component of the disease process in hip OA.

To determine whether clinical outcome during pregnancy in rheumatoid arthritis (RA) is associated with changes in the levels of exposed immunoglobulin G (IgG) terminal sugars.Serum IgG glycosylation from 23 pregnant patients with RA was analyzed during the prenatal, antenatal, and post-partum periods. Patients were randomly selected on the basis of whether they achieved spontaneous remission (n = 11) or did not remit (n = 12); of the latter group 6 patients experienced a relapse in disease activity. Levels of exposed terminal IgG sugars, galactose (Gal), N-acetylglucosamine (GlcNAc), and sialic acid (SA), were estimated in a lectin binding assay using Ricinis (communis, Bandeiraea simplicifolia II, and Sambucus nigra, respectively.Exposed Gal levels increased (p0.02) and GlcNAc levels decreased (p0.05) in the antenatal period, and returned to preconception levels during post-partum. GlcNAc rebound was instantaneous (p0.005), whereas Gal remained high for a further 10 weeks. SA did not undergo any major changes. Remission was associated with an earlier and significantly greater antenatal reduction in GlcNAc (2nd and 3rd trimester; p0.02) in comparison to the groups that did not experience a decrease in disease activity. Analysis of individual IgG samples during the first trimester revealed a significant negative correlation between Gal and GlcNAc in the remission group (r = -0.80; p0.05), which was opposite to that found in the relapse group (r = +0.87; p0.03). There was no significant difference between the groups with regard to the timing and/or incidence of a post-partum flare of disease.Temporal changes in the levels of IgG terminal sugars, in particular exposed GlcNAc, are integrally associated with the clinical manifestation of RA in pregnancy. Generation of IgG sugar micro-heterogeneity is complex and understanding it may help unravel pathogenic features associated with RA.

The challenge faced by research into the genetic basis of complex disease is to identify genes of small relative effect against a background of substantial genetic and environmental variation. This has focused interest on a classical epidemiological design: the study of twins. Through their precise matching for age, the common family environment and background environmental variation, studying diseases in non-identical twins provides a means to enhance the power of conventional strategies to detect genetic influence through linkage and association. The unique matching of identical twins provides researchers with ways to isolate the function of individual genes involved in disease together with approaches to understanding how genes and the environment interact.

To assess the relative contribution of genetic factors in the variation of F cells (FC) and other hematologic variables, we conducted a classical twin study in unselected twins. The sample included 264 identical (monozygotic [MZ]) twin pairs and 511 nonidentical (dizygotic [DZ]) same-sex twin pairs (aged 20 to 80 years) from the St. Thomas' UK Adult Twin Register. The FC values were distributed continuously and positively skewed, with values ranging from 0.6% to 22%. FC values were higher in women than in men and decreased with age, with the variables accounting for 2% of the total FC variance. The intraclass correlations of FC values were higher in MZ (rMZ = 0.89) than in DZ (rDZ = 0.49) twins. The XmnI-(G)gamma polymorphism in the beta-globin gene cluster had a significant effect on FC levels, accounting for approximately 13% of the total FC variance. Variance components analysis showed that the FC values were accounted for predominantly by additive genetic and nonshared environmental influences, with an estimate of heritability of 0.89. Hemoglobin levels and red blood cell, white blood cell, and platelet numbers were also substantially heritable, with heritability estimates of 0.37, 0.42, 0.62, and 0.57, respectively. Previously, studies of sib pairs with sickle cell disease and isolated family studies showed that high levels of Hb F and FC tend to be inherited. Here, our classical twin study demonstrated that the variance of FC levels in healthy adults is largely genetically determined. (Blood. 2000;95:342-346)

Degenerative intervertebral disc disease is common; however, the importance of genetic factors is unknown. This study sought to determine the extent of genetic influences on disc degeneration by classic twin study methods using magnetic resonance imaging (MRI).We compared MRI features of degenerative disc disease in the cervical and lumbar spine of 172 monozygotic and 154 dizygotic twins (mean age 51.7 and 54.4, respectively) who were unselected for back pain or disc disease. An overall score for disc degeneration was calculated as the sum of the grades for disc height, bulge, osteophytosis, and signal intensity at each level. A "severe disease" score (excluding minor grades) and an "extent of disease" score (number of levels affected) were also calculated.For the overall score, heritability was 74% (95% confidence interval [95% CI] 64-81%) at the lumbar spine and 73% (95% CI 64-80%) at the cervical spine. For "severe disease," heritability was 64% and 79% at the lumbar and cervical spine, respectively, and for "extent of disease," heritability was 63% and 63%, respectively. These results were adjusted for age, weight, height, smoking, occupational manual work, and exercise. Examination of individual features revealed that disc height and bulge were highly heritable at both sites, and osteophytes were heritable in the lumbar spine.These results suggest an important genetic influence on variation in intervertebral disc degeneration. However, variation in disc signal is largely influenced by environmental factors shared by twins. The use of MRI scans to determine the phenotype in family and population studies should allow a better understanding of disease mechanisms and the identification of the genes involved.

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.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 asor =14 years later were classified as having incident disease. Incident cases were compared with controls for associations with a number of risk factors.Eighty-one women (12.6%) developed JSN of the knee, equating to an incidence of 3.1% per year. No clear risk factors for JSN were identified. Reproducibility of measures of joint space is poor, however, leading to inaccuracy of definition. Incident knee osteophytes developed in 95 women (133%), equating to an incidence of 3.3% per year. Compared with controls, women with incident knee osteophytes were older, heavier, and had more hand OA and knee symptoms. Women in the top tertile of obesity (body mass index26.4) had a significantly increased risk of incident knee osteophytes (odds ratio [OR] 2.38, 95% confidence interval [95% CI] 1.29-4.39). Incident knee osteophytes increased by 20% per 5-year age increase. A nonsignificant protective effect for incident knee osteophytes was seen with current estrogen replacement therapy (ERT) (OR 0.41, 95% CI 0.12-1.42). No effect was associated with smoking, physical activity, hysterectomy, or previous knee injury.Obesity and aging are associated with a high risk of new knee OA developing in women. Evidence of a protective effect of ERT was seen. No clear association was found for incident JSN, suggesting that different etiologic mechanisms are operating or that standard radiographs are an inaccurate measure of incident narrowing.

A classical twin study was performed to assess the extent to which genetic factors explain individual differences in age at menopause and (indications for) hysterectomy. It was further examined whether a genetic effect on the timing of the menopause was mediated through a genetic effect on age at menarche. The subjects were 275 monozygotic and 353 dizygotic female twin pairs. Maximum likelihood model fitting was used to estimate genetic and environmental variance components, Kaplan-Meier survival analysis was used to account for censored data, and the Cox proportional hazards model was used to adjust for potential confounders. A model specifying additive genetic and unique environmental factors showed the best fit to the data, yielding a heritability (h2) for age at menopause of 63%. The significance of the genetic effect was confirmed by the survival analysis and was not affected by adjustment for confounders. Both early and late menopause were found to be significantly influenced by genetic factors. Hysterectomy also showed considerable heritability (h2 = 59%), as did its two main indications: fibroids (h2 = 69%) and menorrhagia (h2 = 55%). The genetic contribution to the variance in age at menarche was estimated to be 45%, with the majority (37%) being due to dominant genetic effects. No correlation was found between age at menopause and age at menarche, suggesting different genetic mechanisms. This study provides convincing evidence for the importance of genetic factors in determining natural and surgical menopause. Understanding how genes control the timing of menopause and exploring whether these genes are indirectly associated with disease are important areas for future study.

Although for many years it was speculated that osteoarthritis was genetically determined, little data were available to support this contention. A major problem with early work was a lack of consistency in the definition of osteoarthritis. Based on a radiographical definition of osteoarthritis, which is currently the optimal method for epidemiological and genetic studies, data from a recent twin study have provided an estimate of the hereditable component of osteoarthritis to be in the order of 50 to 65%. In addition, sophisticated molecular biology techniques are being increasingly used to explore potential genetic abnormalities in cartilage and matrix components in osteoarthritis. These exciting new data are examined as we address the role of genetic factors in osteoarthritis.

Central adiposity is a strong predictor of cardiovascular disease in women. We studied postmenopausal twins to explore the strength and the relationship between genetic influences on body fat and its distribution in a group where cardiovascular disease is the major cause of mortality. Healthy twin women were recruited from a national media campaign. One hundred nineteen monozygotic (MZ) and 97 dizygotic twin pairs were studied (mean +/- SE age 60 +/- 0.3 yr; 10 +/- 0.4 yr post menopausal). Total and central body fat were measured by dual-energy x-ray absorptiometry. Intrapair resemblance was significantly greater in MZ pairs for total fat (MZ vs. dizygotic, r = 0.70 +/- 0.05 vs. r = 0.46 +/- 0.08, P = 0.005) and central fat (r = 0.62 +/- 0.06 vs. r = 0.35 +/- 0.09, P = 0.005), suggesting a strong genetic influence on these traits. Model-fitting analysis indicated that genetic factors contribute up to 60% of total population variance in both total and central body fat. The heritability of central fat remained, after adjustment for the heritability of total fat, suggesting an independent genetic influence on fat distribution. These results were unchanged after adjusting for the effects of estrogen replacement and smoking. In conclusion, total adiposity and central abdominal fat mass in normal postmenopausal women are under strong genetic influence. The data suggest that some of the genes responsible for central adiposity and its metabolic sequelae will be different from those responsible for total adiposity.

To ascertain whether clustering between joint sites in osteoarthritis (OA) is more common than would be expected simply from the rising prevalence of the disorder with age, and to explore a definition of generalized OA (GOA) by determining the pattern of joint group involvement, in a population sample of peri and postmenopausal women.Radiographs of the hands, knees, and hips were obtained in a population sample of 702 women aged 45 to 64 years. Distal interphalangeal, proximal interphalangeal, carpometacarpal, knee, and hip OA were assessed using the Kellgren-Lawrence grading system. Logistic regression was used to test for overall clustering of OA between joint sites, and log linear models were used to study the patterns of association between different sites.Multiple involvement of the 5 joint groups studied occurred significantly more frequently than could be expected by chance alone (chi 2 = 52.3, df = 5, p0.001), and this clustering remained significant after age adjustment (chi 2 = 26.1, df = 5, p0.001). Thresholds could be defined for the number of involved joint groups that distinguished a polyarticular subset of OA. These thresholds varied with age and the radiographic cutoff at which OA was assigned. Thus, for grade 2+ disease, GOA could be defined by involvement of 2 or more joint groups at age 45-47 years, but required involvement of all 5 joint groups at age 60-64 years. Symmetry within joint groups was the most pronounced feature in the pattern of joint involvement in the sample as a whole, with associations between different joint groups being substantially weaker than those for symmetrical bilateral involvement of a particular joint.There is a clear tendency towards polyarticular OA among women aged 45-64 years. However, there is no single threshold number of joint sites that can be used to define GOA. The pattern of joint involvement in OA is primarily symmetrical, and this pattern strongly suggests a systemic etiology in this subset of postmenopausal women.