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Tim D Spector

Publications and source records attributed to Tim D Spector.

83 records · Page 5Linked to original sources
PubMed2002

The genetic contribution to carpal tunnel syndrome in women: a twin study.

OBJECTIVE: To assess the relative genetic and environmental contribution to carpal tunnel syndrome (CTS) using a classic twin study of monozygotic (MZ) and dizygotic (DZ) twins. METHODS: The study group comprised unselected female twin pairs, between 20 and 80 years of age, from the St Thomas' UK Adult Twin Registry. Individuals completed a questionnaire that included details on potential risk factors for CTS. The diagnosis of CTS was made using a standardized hand pain diagram and validated criteria. The genetic contribution to CTS was assessed using variance component and regression methods, the heritability was adjusted for environmental confounders. The role of individual risk factors was assessed by a nested case-control study. RESULTS: An overall prevalence of 14.2% for CTS was found in a population of 4,488 females, comprising 867 MZ and 970 DZ twin pairs, and 814 singletons. The concordance for CTS was significantly higher in MZ compared with DZ twins (case-wise concordance values of 0.35 and 0.24 respectively, with a significantly increased MZ:DZ ratio of 1.48; P = 0.03). Modeling produced a heritability estimate of 0.46 (95% CI 0.34-0.58) that was essentially unchanged after adjustment for environmental risk factors including age, body mass index, physical activities, and hormonal/reproductive factors. No major influence of any individual risk factor was seen in the case-control analysis of 520 cases and 3,154 controls, apart from a modest association with menopausal status with an increased risk of 1.53 and 1.43 in the peri and postmenopausal groups. There was no overall effect of age or body mass index. CONCLUSION: This is the first study to explore the genetic component of CTS. Our data show that up to half of the liability to CTS in women is genetically determined, and this appears to be the single strongest risk factor, with only minor contributions from known environmental factors. Further studies should focus on genetic mechanisms that may lead to tests for susceptibility and detection of those at risk of developing CTS.

Adult↗
PubMed2002

Activation markers of coagulation and fibrinolysis in twins: heritability of the prethrombotic state.

BACKGROUND: Activation markers of coagulation and fibrinolysis are increased in individuals at risk of coronary-artery disease and other thrombotic disorders--a condition defined as the prethrombotic state. We aimed to find out the extent to which the prethrombotic state is determined by genetic factors. METHODS: We analysed concentrations of prothrombin, prothrombin fragment 1+2, thrombin-antithrombin complex, crosslinked fibrin degradation product D-dimer, and thrombin-activatable fibrinolysis inhibitor by ELISA in 118 monozygotic and 112 dizygotic unselected female twins aged 21-73 years from the St Thomas' UK Adult Twin Registry. We used quantitative genetic-model fitting to estimate heritability. FINDINGS: We found significant heritabilities in concentrations of the activation markers in plasma. Genetic factors contributed 45, 40, and 65% of the variation in concentrations of fragment 1+2, thrombin-antithrombin complex, and D-dimer, respectively. Age was important only in fragment 1+2 concentrations, in which it accounted for 12% of the variation. The remaining variation could be attributed to unique environmental factors. Variation in concentrations of precursor prothrombin in plasma was determined by 57% heritability, and that of zymogen thrombin-activatable fibrinolysis inhibitor showed a very strong genetic component (82%). INTERPRETATION: The activation mechanisms of the coagulation and fibrinolytic systems, and therefore the prethrombotic state, are controlled to a substantial degree by genetic factors. Genes influencing activation of haemostasis are likely to be an important component of the overall thrombotic tendency in the general population.

Adult↗
PubMed2002

Statins as modulators of bone formation.

The use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) to reduce serum cholesterol is well described. However, the recent finding that statins have direct effects on bone was unexpected. A number of epidemiological studies have recently been published that explore the effects of statins on bone mineral density and risk of fracture in humans. Statins may act by directly stimulating the expression of bone morphogenetic protein-2 and increasing osteoblast differentiation or, like nitrogen-containing bisphosphonates, may have effects on the mevalonate pathway that leads to inhibition of osteoclast activity and osteoblast apoptosis. In addition, the demonstration that statins can inhibit inflammation and encourage angiogenesis offers other possibilities for action.

Bone Density↗
PubMed2002

The relationship of bone density and fracture to incident and progressive radiographic osteoarthritis of the knee: the Chingford Study.

OBJECTIVE: Investigators performing cross-sectional studies have reported small increases in bone mineral density (BMD) in subjects with osteoarthritis (OA). This study was undertaken to examine the association of bone mass with incident and progressive disease and to determine whether prior fractures influence the development of OA. METHODS: Eight hundred thirty women had repeat knee radiographs 48 months from baseline. All radiographs were graded on the presence or absence of osteophytes and joint space narrowing (JSN). Incident knee OA was defined as new disease in the 715 women without knee OA at baseline. Progression was a change of at least one grade in the 115 women with baseline knee OA. All women underwent bone densitometry of the lumbar spine and hip. Rates of subsequent incident OA were compared between fracture groups. RESULTS: The 95 women with incident knee osteophytes had significantly higher baseline spine BMD (1.01 gm/cm2 versus 0.95 gm/cm2, or 6.3%; P = 0.002) and significantly higher hip BMD (0.79 gm/cm2 versus 0.76 gm/cm2, or 3.9%; P = 0.02) than those without incident disease. For the 33 women whose osteophytes progressed, no difference was seen compared with nonprogressors in spine BMD, but hip BMD was modestly reduced (-2.5%). The 81 women who had incident JSN had nonsignificantly higher baseline spine BMD (3.0%), while no difference was seen for the 30 women whose JSN had progressed. For hip BMD, a nonsignificant increase was seen in those with incident JSN (1.3%), and a nonsignificant reduction was seen in those whose JSN progressed (-2.7%). One hundred forty-five women sustained peripheral fractures, mainly in the distal forearm (27.6%) and vertebrae (28.3%). Women with a peripheral fracture had a reduced risk of subsequently developing incident knee OA (odds ratio [OR] 0.30, 95% confidence interval [95% CI] 0.11-0.84). Although numbers were smaller, nonsignificant reductions in rates of incident OA were seen for those with distal forearm (OR 0.40, 95% CI 0.11-1.49) and vertebral (OR 0.20, 95% CI 0.07-1.61) fractures. CONCLUSION: These results confirm that for women who develop incident knee OA, defined by osteophytes, BMD is higher and of a magnitude similar to that shown in cross-sectional studies. Low BMD at the hip appears weakly related to progression. Women with previous fractures have less chance of developing OA, independent of BMD status. Although the mechanism for this action is unclear, these results suggest a possible common role of bone turnover and repair in the early manifestations of OA.

Bone Density↗
PubMed2002

Evidence for increased bone resorption in patients with progressive knee osteoarthritis: longitudinal results from the Chingford study.

OBJECTIVE: Several studies have suggested that increased subchondral bone turnover is a determinant of progression of osteoarthritis (OA). To test this hypothesis, the level of urinary N-terminal type I collagen telopeptides (NTx) and C-terminal type I collagen telopeptides (CTx), which are validated markers of bone resorption, was measured at 3 different time points in a subset of patients from the Chingford study. METHODS: The original Chingford study population comprised 1,003 women. From this group, postmenopausal women not receiving any bone-modifying medication who had a baseline knee radiograph and a repeat radiograph 4 years later, and for whom a baseline lumbar spine bone mineral density (BMD) measurement was available, were identified and separated into 4 groups as follows: controls (n = 50), progressive OA (n = 71), nonprogressive OA (n = 36), and osteoporosis (n = 59). NTx and CTx were measured in urine samples collected at baseline, year 1, and year 2. RESULTS: Patient age and years since menopause were similar among groups at baseline. As expected, both body mass index (BMI) and BMD were lowest in patients with osteoporosis. Median resorption marker levels over the 3 time points were 31-87% higher in patients with either progressive OA or osteoporosis than in controls and patients with nonprogressive OA (P < 0.01, except for levels of CTx in patients with progressive OA versus nonprogressive OA). Levels of NTx and CTx did not differ significantly between women with progressive OA (defined either by the presence of osteophytes or by joint space narrowing) and those with osteoporosis or between controls and women with nonprogressive OA. Results were essentially unchanged after adjustment for age, BMI, BMD, and past use of hormone replacement therapy, or when NTx and CTx values at each time point were analyzed separately. CONCLUSION: Our data demonstrate that bone resorption is increased in patients with progressive knee OA and is not increased in those with nonprogressive knee OA. The increase in bone resorption seen in patients with progressive knee OA is similar to that observed in patients with osteoporosis. Altered bone turnover may be a diagnostic or therapeutic target in patients with progressive OA.

Biomarkers↗
PubMed2002

Genetic influence on early age-related maculopathy: a twin study.

OBJECTIVE: Age-related macular degeneration (AMD) is the most common cause of blindness in industrialized countries. There has been considerable interest in the genetics of early age-related maculopathy (ARM) and AMD, because they have phenotypes similar to inherited diseases where mutations have been identified, but the heritability of ARM and AMD is unknown. DESIGN: A classical twin study was performed to compare the concordance in monozygotic (MZ) and dizygotic (DZ) twins in an unselected sample of female volunteer twins. PARTICIPANTS: Five hundred six twin pairs, 226 MZ and 280 DZ, with a mean age of 62 years, were examined. METHODS: ARM was graded from stereoscopic macular photographs of 501 of the twin pairs (99%) according to the International ARM Epidemiologic Study Group grading system. The casewise concordance was calculated for twin pairs from 2 x 2 contingency tables of affected/unaffected twins, and these tables were used in maximum likelihood genetic modeling to estimate the heritabilities of phenotypes graded. MAIN OUTCOME MEASURES: Prevalence of ARM; concordance in MZ and DZ twins of the phenotypes of ARM, soft drusen >63 microm and > or =125 microm diameter, pigmentary changes and hard drusen (<20 and > or =20 in number); heritability of ARM and subphenotypes. RESULTS: The overall prevalence of ARM was 14.6% (95% confidence interval [CI], 12.4%-16.8%). The concordance for ARM in MZ twins was 0.37 compared with 0.19 in DZ twins, suggesting a role for genes. Modeling confirmed a genetic effect for phenotypes of ARM, soft drusen, pigmentary changes, and > or =20 hard drusen, although there was little genetic effect for scattered (<20) hard drusen. The heritability of ARM was estimated as 45% (95% CI, 35%-53%). The most heritable phenotypes were soft drusen > or =125 microm (57%) and > or =20 hard drusen (81%), with the latter being dominantly inherited. CONCLUSIONS: This study confirms a significant genetic influence in ARM and suggests that future genetic studies should examine phenotypes of large (> or =125 microm) soft drusen and > or =20 hard drusen, because these seem to be the most heritable components.

Aged↗
PubMed2002

Genetic contribution to renal function and electrolyte balance: a twin study.

A classical twin study was performed to assess the relative contributions of genetic and environmental factors to serum levels of calcium, phosphate and magnesium, urinary levels of calcium, sodium and potassium, and creatinine clearance. The subjects were 1747 adult female twin pairs: 539 monozygotic and 1208 dizygotic. The intraclass correlations were calculated, and maximum-likelihood model fitting was used to estimate genetic and environmental variance components. The intraclass correlations for all of the variables assessed were higher in monozygotic twin pairs. The heritabilities (with 95% confidence intervals) obtained from model fitting were: serum calcium, 33% (21-45%); serum phosphate, 58% (53-62%), serum magnesium, 27% (15-39%); 24 h urinary potassium, 40% (27-51%); 24 h urinary calcium, 52% (41-61%); 24 h urinary sodium, 43% (30-54%); fractional excretion of sodium, 52% (44-59%); serum creatinine, 37% (25-49); calculated creatinine clearance, 63% (54-72%). This study provides evidence for the importance of genetic factors in determining urinary and blood levels of the major electrolytes involved in blood pressure regulation. Identifying heritability is the first step on the way to finding specific genes, which may improve our insight into the pathophysiology of the metabolism of these electrolytes, and thereby improve our understanding of the aetiology of complex diseases such as renal failure and hypertension.

Adolescent↗
PubMed2002

Femoral neck trabecular patterns predict osteoporotic fractures.

In this paper we show that texture analysis of femoral neck trabecular patterns can be used to predict osteoporotic fractures. The study is based on a sample of 123 women aged 44-66 years with and without fractures. We analyzed trabecular patterns using the Co-occurrence Matrix texture analysis algorithm and compared the predictive utility of the textural data with densitometry. Logistic regression was used to estimate the predictive utility, exp(B), of clinical and textural data per standard deviation. Reproducibility was also demonstrated using paired films at 1-year intervals (CoV=4.5%). Bone mass estimated by DEXA measurements of the spine and hip were the most predictive of fractures giving a two-fold increase in fractures per s.d. bone mass loss (95% CI: 1.2-3.1, p<0.005). Age was also highly predictive with fracture risk increasing by 1.07-fold per year (95% CI: 1.01-1.14, p<0.02). Trabecular texture was found to give a lower, but significant, prediction of fracture of 1.5-fold per s.d. trabecular pattern loss (95% CI: 0.96-2.31, p<0.05). Combining age, weight, and trabecular texture increased the fracture prediction to 1.78-fold per s.d. (95% CI: 1.19-2.67). Combining trabecular texture with densitometry increased the predictive ability to 2.06-fold per s.d. (95% CI: 1.32-3.22) and combined with age and weight as well increased exp(B) to 2.1-fold per s.d. (95% CI: 1.32-3.35). This shows that osteoporotic trabecular texture changes can be "measured." Moreover, the combination of age, weight, and trabecular texture is more predictive than either alone. We propose therefore that this trabecular texture analysis is both reproducible and clinically meaningful. The application of such methods could be used to improve the estimation of fracture risk in conjunction with other clinical data, or where densitometry data cannot be obtained (e.g., in retrospective studies).

Absorptiometry, Photon↗
PubMed2002

Klotho gene polymorphisms associated with bone density of aged postmenopausal women.

Because mice deficient in klotho gene expression exhibit multiple aging phenotypes including osteopenia, we explored the possibility that the klotho gene may contribute to age-related bone loss in humans by examining the association between klotho gene polymorphisms and bone density in two genetically distinct racial populations: the white and the Japanese. Screening of single-nucleotide polymorphisms (SNPs) in the human klotho gene identified 11 polymorphisms, and three of them were common in both populations. Associations of the common SNPs with bone density were investigated in populations of 1187 white women and of 215 Japanese postmenopausal women. In the white population, one in the promoter region (G-395A, p = 0.001) and one in exon 4 (C1818T, p = 0.010) and their haplotypes (p < 0.0001) were significantly associated with bone density in aged postmenopausal women (> or = 65 years), but not in premenopausal or younger postmenopausal women. These associations were also seen in Japanese postmenopausal women. An electrophoretic mobility shift analysis revealed that the G-A substitution in the promoter region affected DNA-protein interaction in cultured human kidney 293 cells. These results indicate that the klotho gene may be involved in the pathophysiology of bone loss with aging in humans.

Aged↗
PubMed2002

The St. Thomas' UK Adult Twin Registry.

The Registry consists of nearly 10,000 monozygous and dizygous adult caucasian twins aged 18-80 from all over the UK and was started in 1993. This is a volunteer sample recruited by successive media campaigns without selecting for particular diseases or traits. All twins receive a series of disease questionnaires. In addition over half the twins have been assessed in detail clinically for several hundred phenotypes related to common diseases or intermediate traits. The focus has been primarily on cardiovascular, metabolic, musculoskeletal, dermatological, and opthalmological diseases. Over 3000 DZ twins have had a genome wide scan performed as well as many candidate genes allowing both linkage and association studies. The registry has led to many successful innovative research projects, particularly in common diseases previously thought to be predominantly environmental and helped positionally clone some novel genes for common diseases.

Adult↗