Sarcoidosis in monozygotic twins.
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Diseases in Twins↗
Biomedical subjects
T D Spector
Publications and source records attributed to T D Spector.
Assessment of bone in Ehlers Danlos syndrome by ultrasound and densitometry.
OBJECTIVE: Ehlers Danlos syndrome (EDS) is an inherited disorder of connective tissue characterised by hyperextensible skin, joint laxity, and easy bruising. There are phenotypic similarities with osteogenesis imperfecta, but in EDS a tendency to fracture or altered bone mass has not previously been considered to be a cardinal feature. METHOD: This case-control design study investigates whether 23 patients with EDS had differences in fracture rates, bone mass, and calcaneal ultrasound parameters compared with age and sex matched controls. RESULTS: 23 cases of EDS (mean (SD) age 38.5 (15.5)) were compared with 23 controls (mean age 37.8 (14.5)). A significant reduction in bone density measured by dual energy x ray absorptiometry was found at the neck of femur by 0.9 SD, p = 0.05, and lumbar spine by 0.74 SD, p = 0.02. At the calcaneum, broad band ultrasound attenuation and speed of sound were significantly reduced compared with controls by 0.95 SD (p = 0.004) and 0.49 SD (p = 0.004) for broad band ultrasound attenuation and speed of sound respectively. Broad band ultrasound attenuation and speed of sound remained significantly reduced after adjusting for bone mineral density (BMD). After adjusting for functional status (HAQ), age and sex, hypermobility was inversely correlated with broad band ultrasound attenuation and SOS, but not BMD at hip or spine. Previous fracture was 10 times more common in EDS (p < 0.001), with 86.9% of patients reporting a total of 47 low impact fractures, compared with 8.7% of controls. CONCLUSION: This study has identified a tendency of EDS patients to fracture, have low bone mass and abnormal bone structure. The aetiology is likely to be multifactorial, with an inherited structural element, accentuated by immobility or reduced exercise. This is one of the first clinical studies to suggest ultrasound can detect structural differences in bone, independent of dual energy x ray absorptiometry.
Absorptiometry, Photon↗
Relation between Heberden's nodes and distal interphalangeal joint osteophytes and their role as markers of generalised disease.
OBJECTIVE: Heberden's nodes are often used as a marker for osteoarthritis (OA). This study examined how often Heberden's nodes and radiological distal interphalangeal (DIP) osteophytes coexist in the same digit and the sensitivity, specificity, and positive predicative value of each for OA at different sites or generalised disease. METHODS: This was a population-based study of 660 middle ages women taking part in a twin study of OA. Distal interphalangeal osteophytes were defined radiologically and graded on a four point scale (0-3) using a published atlas of individual features. Heberden's nodes were defined by standardised clinical examination. OA in other joint (knees, proximal interphalangeal (PIP) joints and carpometacarpal (CMC) joints) was defined radiologically using a published atlas. RESULTS: Poor agreement was observed between a Heberden's node (HN) and a radiological distal interphalangeal osteophyte in the same finger of the same hand (K statistic (95% CI) = 0.36 (0.33, 0.39)). Although HN and radiological DIP osteophytes had similar sensitivity, the specificity and positive predicative value of DIP osteophytes was considerably higher for detecting knee, CMC, PID OA, and OA in more than two groups of joint (knee, CMC, and DIP joints). CONCLUSION: HN are not synonymous with DIP osteophytes. Radiological DIP osteophytes are a better marker of knee and multiple joint OA than HN. HN may still be an imperfect surrogate for hand OA when radiology is impractical, but are not an accurate marker of generalised disease.
Female↗
Effects of cyclical etidronate combined with calcitriol versus cyclical etidronate alone on spine and femoral neck bone mineral density in postmenopausal osteoporotic women.
OBJECTIVES: Few data are available on the effects of combination therapy for the treatment of osteoporosis. The aim of this study was to compare the effects of intermittent cyclical etidronate (E) therapy alone with a combination of cyclical etidronate and calcitriol (E + C) on spine and femoral neck bone mineral density (BMD) at one year. METHODS: Postmenopausal women with at least one non-traumatic vertebral fracture or z score < -1.5 were randomly allocated to an E group (each cycle = oral etidronate 400 mg daily for 14 days followed by calcium 500 mg daily for 76 days) or an E + C group (as for E plus oral calcitriol 0.5 microgram daily). Lumbar spine and femoral neck BMDs were measured by dual energy x ray absorptiometry at baseline and at one year. The study design did not contain a placebo group. RESULTS: The mean % increase in lumbar spine BMD was 5.2% (95% CI = 3.4 to 7.0) in the E + C group (n = 24), which was significantly greater than the 2.7% (95% CI = 1.3 to 4.1) increase in the E group (n = 23) (p < 0.05). The femoral neck BMD in the E + C group increased by 2.0% (95% CI = 0.8 to 3.2), which was significantly different from the E group where there was a -0.4% (95% CI = -2.4 to 1.6) change (p = 0.046). CONCLUSIONS: These data show that a combination of cyclical etidronate and calcitriol is better than cyclical etidronate alone in terms of changes in BMD at both spine and femoral neck sites. Although further data are needed on fracture efficacy, this study suggests that combination therapies have additive therapeutic potential that may exceed that expected from their theoretical mode of action.
Absorptiometry, Photon↗
Genes control the cessation of a woman's reproductive life: a twin study of hysterectomy and age at menopause.
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.
Age Factors↗
Genes versus environment. The relationship between dietary fat and total and central abdominal fat.
OBJECTIVE: The influence of diet on body fat has not been quantified independently of genetic influences, although both are held to contribute to regulation of body fat stores. This study examined 1) the relationship between recent diet and total body and central abdominal fat in middle-aged female twins independent of genetic and important environmental factors and 2) evidence of interaction between diet and genetic predisposition. RESEARCH DESIGN AND METHODS: Measurements in 436 healthy female twins (aged 58 +/- 10 years) included dietary intake by food frequency questionnaire (validated against a 7-day food diary, n = 162), BMI, total body and central abdominal fat by dual-energy X-ray absorptiometry, and environmental covariates (smoking habit, hormone replacement, and physical activity) by standardized questionnaire. Dietary energy underreporters were excluded. RESULTS: Intake of dietary fat (total and subtype) and carbohydrates was not related to BMI or to total or central fat, confirmed in quintile analysis. With genetic and environmental factors controlled in 90 monozygotic pairs, differences in the intake of energy, fat, or protein were not related to intrapair differences in total and central body fat. However, a minor inverse relationship between carbohydrate intake and total adiposity was confirmed (r = -0.25, P = 0.02). In paired analyses, the twin with the higher intake of total sugars had significantly lower total body and central abdominal adiposity. There was no evidence of a gene-environment interaction between intake of fat or carbohydrates contributing to greater body fat mass in subjects genetically predisposed to obesity. CONCLUSIONS: Using validated dietary measures and direct measures of body fat and excluding underreporters, no relationship between dietary fat and body fat was found in middle-aged women, particularly after controlling for genetic and some environmental factors. The role of dietary factors in determining total body and central abdominal fat appears to have been overestimated in past cross-sectional studies.
Abdomen↗
Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease.
OBJECTIVE: To examine the role of low-grade inflammation in the etiology and progression of early osteoarthritis (OA) of the knee. METHODS: We used a new, high-sensitivity, automated monoclonal antibody immunoassay for the classic acute-phase protein, C-reactive protein (CRP), in serum. Anteroposterior radiographs of the knee with weight bearing were obtained on 845 women (ages 44-67) on entry into a population-based study of OA in Chingford, North London. In those defined radiologically as "cases," the knee radiographs were repeated after 4 years. RESULTS: Levels of CRP were higher in 105 women with knee OA defined radiologically as Kellgren-Lawrence grade 2+ (median 2.4 mg/liter, interquartile range [IQR] 1.0-5.1), compared with 740 women without OA (median 0.7 mg/liter, IQR 0.3-1.8) (P < 0.001). Median levels of CRP were higher in the 31 women whose disease progressed at least 1 Kellgren-Lawrence grade (median 2.6 mg/liter, IQR 1.9-4.6), compared with the 39 whose disease did not (median 1.3 mg/liter, IQR 0.6-2.4) (P = 0.006) . The significance of these differences persisted after adjustment for age, weight, height, smoking, knee pain, or injury. Classifying disease by the presence of joint space narrowing or osteophytes alone produced similar results. CONCLUSION: CRP levels are modestly but significantly increased in women with early knee OA, and higher levels predict those whose disease will progress over 4 years, suggesting that low-grade inflammation may be a significant aspect of early OA and may be amenable to therapeutic intervention and secondary prevention.
Adult↗
Association of early osteoarthritis of the knee with a Taq I polymorphism of the vitamin D receptor gene.
OBJECTIVE: To determine whether a polymorphism of the vitamin D receptor (VDR) gene, already associated with osteoporosis, might also relate to the risk of osteoarthritis (OA). METHODS: A population cohort of 351 postmenopausal women (ages 45-64 years) was studied using anteroposterior radiographs of the knee, which were graded for OA according to the Kellgren and Lawrence classification system. The VDR genotype was determined by using polymerase chain reaction and by digestion with the restriction enzyme Taq I. RESULTS: The VDR allele "T" was associated with an increased risk of knee OA compared with the "t" allele, with an odds ratio of 2.82 (95% confidence interval 1.16-6.85; P = 0.02). A dominant pattern of risk was suggested. The frequency of the VDR genotype differed significantly between OA cases and controls (P = 0.03 by Fisher's exact test). CONCLUSION: A Taq I polymorphism of the VDR gene appears to be associated with an increased risk of knee OA. This is the first genetic locus that has been shown to influence the risk of early knee OA within the general population.
Bone Density↗
Polymorphisms of the vitamin D receptor, infant growth, and adult bone mass.
Family and twin studies have demonstrated a strong genetic component to the development of peak bone mass. Early fetal and infant environment has also been shown to influence bone mass through an effect on skeletal size and mineral content. We report a retrospective study that has examined whether early infant growth is regulated by genetic factors shown to be associated with bone mass. We have determined the vitamin D receptor (VDR) gene alleles for 66 women (mean age 65.5 years) on whom detailed birth records were available. There was a statistically significant trend (P = 0.04) for VDR genotype against weight at the age of 1 year, with the "tt" homozygote group having 7% higher weight. We conclude that early fetal or infant environment may interact with an individual's underlying genotype to program early skeletal growth, and that this may track through later life to influence adult characteristics. Further prospective studies are required, however, to fully clarify the precise environmental and genetic mechanisms underlying these findings.
Absorptiometry, Photon↗
What is the evidence that osteoarthritis is genetically determined?
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.
Cartilage, Articular↗
Is hormone replacement therapy protective for hand and knee osteoarthritis in women?: The Chingford Study.
OBJECTIVES: To explore whether hormone replacement therapy (HRT) has a protective role for osteoarthritis (OA) of the hand and knee in a cross sectional study of women in the general population. METHODS: 1003 women aged 45-64 (mean age 54.2) from the Chingford Study were asked details of HRT use. Standard anteroposterior radiographs of hands, knees were taken and scored according to the methods of Kellgren and Lawrence (grade 2+ positive for OA), and using individual features of osteophytes and joint space narrowing. Analysis compared ever use (> 12 months) versus never use, and current use (> 12 months) versus never use. Only 606 definitely postmenopausal women were included in the analysis. Odds ratios and 95% confidence intervals were calculated using logistic regression for risk of user versus non-user at each site, adjusted for age, height and weight, menopausal age and for bone mineral density of the femoral neck. RESULTS: For current users (n = 72) there was a significant protective effect of HRT for knee OA (defined by Kellgren and Lawrence grade or osteophytes 0.31 (95% CI 0.11, 0.93), and a similar but not significant effect for moderate joint space narrowing of the knee, 0.41 (95% CI 0.05, 3.15) and for distal interphalangeal OA 0.48 (95% CI 0.17, 1.42). No clear effect was seen for the carpometacarpal joint, CMC OA 0.94 (95% CI 0.44, 2.03). When analysing ever users (n = 129) the protective effect was reduced. For ex-users of > 12 months (mean duration 40.7 months), there was no overall protective effect of HRT for OA. Additional adjustment for hysterectomy, physical activity, social class, and smoking made little difference to the results. CONCLUSIONS: These data show an inverse association of current HRT use and radiological OA of the knee suggestive of a protective effect. The effect was weaker in the hand joints. The mechanism of the protection is unclear but has important implications for aetiopathogenesis.
Cross-Sectional Studies↗
Independent genetic factors determine the amount and distribution of fat in women after the menopause.
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.
Adipose Tissue↗
Genetic influences on muscle strength, lean body mass, and bone mineral density: a twin study.
Lean body mass and muscle strength are both associated with bone mineral density (BMD), which is known to be under strong genetic control. In this classical twin study, we examine the size of the genetic component of both muscle strength and lean body mass and to what degree they account for the genetic component of BMD. In all, 706 postmenopausal women were examined; 227 pairs of monozygous (MZ) twins and 126 pairs of dizygous (DZ) twins. Grip strength was measured using a hand-help grip bulb and leg strength using a dynamic leg extensor power rig. Lean body mass and BMD at multiple sites were measured by dual-energy X-ray absorptiometry. BMD correlated with both leg extensor strength (r = 0.16-0.26) and grip strength (r = 0.12-0.21). Lean mass was significantly correlated with BMD at all sites (r = 0.20-0.39). All three muscle variables have a moderate genetic component with heritability estimates of 0.52 for lean body mass, 0.46 for leg extensor strength, and 0.30 for grip strength (all p < 0.05). The genetic component of BMD was not significantly reduced after adjusting for lean mass and muscle strength, with less than 20% of the genetic variance of BMD explained by the muscle variables. In conclusion, these data suggest that the three muscle variables have a modest genetic component, suggesting the potential for clinical intervention and lifestyle modifications. The genetic component to muscle bulk and strength accounts for little of the genetic component to BMD, confirming the rationale for research into bone-specific genes.
Age Factors↗
Beta 3-adrenergic receptor gene polymorphisms and determination of adiposity and fat distribution in normal female twins.
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Alleles↗
[Radiological evaluation of osteoarthritis].
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Humans↗
Patients who have had fractures of the distal forearm do not lose bone as expected.
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Bone Density↗
Genetic influences on osteoarthritis in women: a twin study.
OBJECTIVES: To assess the relative contribution of genetic and environmental factors to common forms of osteoarthritis of the 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 48-70 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 of the common disabling disease.
Aged↗
Risk of osteoarthritis associated with long-term weight-bearing sports: a radiologic survey of the hips and knees in female ex-athletes and population controls.
OBJECTIVE: To estimate the risk of osteoarthritis (OA) of the hip and knee due to long-term weight-bearing 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] 3.57, 95% confidence interval [95% CI] 1.89-6.71), at the PF joints (OR 3.50, 95% CI 1.80-6.81), narrowing at the PF joints (OR 2.97, 95% CI 1.15-7.67), femoral osteophytes (OR 2.52, 95% CI 1.01-6.26), and hip joint narrowing (OR 1.60, 95% CI 0.73-3.48), 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 TF joints 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.
Adult↗