Biomedical subjects

Timothy D Spector

Publications and source records attributed to Timothy D Spector.

6 recordsLinked to original sources

PubMed2026

Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic study (n = 544,513), we expand the number of genetic loci from 16 to 29, and additionally identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to an increased oocyte number and/or availability across the lifespan. Hormonal regulation in the etiology of this condition, through metabolic and reproductive features, was emphasized. The proteomic analysis highlighted metabolic biology known to be related to PCOS. A polygenic risk score (PRS) was associated with adverse cardiometabolic outcomes, with differing relevance of testosterone and body mass index in women and men. Finally, while oligo-anovulation and anovulatory infertility are features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.

Humans↗

PubMed2006

Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study.

OBJECTIVE: Bisphosphonates have slowed the progression of osteoarthritis (OA) in animal models and have decreased pain in states of high bone turnover. The Knee OA Structural Arthritis (KOSTAR) study, which is the largest study to date investigating a potential structure-modifying OA drug, tested the efficacy of risedronate in providing symptom relief and slowing disease progression in patients with knee OA. METHODS: The study group comprised 2,483 patients with medial compartment knee OA and 2-4 mm of joint space width (JSW), as determined using fluoroscopically positioned, semiflexed-view radiography. Patients were enrolled in 2 parallel 2-year studies in North America and the European Union. These studies evaluated the efficacy of risedronate at dosages of 5 mg/day, 15 mg/day, 35 mg/week (in Europe), and 50 mg/week (in North America) compared with placebo in reducing signs and symptoms, as measured by the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and patient global assessment (PGA) scores, and in slowing radiographic progression. RESULTS: A reduction of approximately 20% in signs and symptoms, as measured by WOMAC subscales and PGA scores, was observed in all groups, with no treatment effect of risedronate demonstrated. Risedronate did not significantly reduce radiographic progression as measured by decreased JSW or using a dichotomous definition of progression (joint space loss of >or=0.6 mm). Thirteen percent of patients receiving placebo demonstrated significant disease progression over 2 years. A dose-dependent reduction in the level of C-terminal crosslinking telopeptide of type II collagen, a cartilage degradation marker associated with progressive OA, was seen in patients who received risedronate. No increase in the number of adverse events was demonstrated for risedronate compared with placebo. CONCLUSION: Although risedronate (compared with placebo) did not improve signs or symptoms of OA, nor did it alter progression of OA, a reduction in the level of a marker of cartilage degradation was observed. A sustained clinically relevant improvement in signs and symptoms was observed in all treatment and placebo groups.

Adult↗

PubMed2006

Evidence for independent heritability of the glycation gap (glycosylation gap) fraction of HbA1c in nondiabetic twins.

OBJECTIVE: HbA(1c) (A1C) is substantially determined by genetic factors not shared in common with glucose. Fractions of the variance in A1C, the glycation gap (GG; previously called the glycosylation gap) and the hemoglobin glycosylation index, correlate with diabetes complications. We therefore tested whether GG (measured A1C - A1C predicted from glycated serum proteins [GSPs]) was genetically determined and whether it accounted for the heritability of A1C. RESEARCH DESIGN AND METHODS: We conducted a classic twin study on A1C and GSP collected in 40 and 46 pairs of monozygotic and dizygotic healthy female twins, respectively. The predicted A1C was based on the regression line between A1C and GSP in a separate population spanning the pathophysiologic range. RESULTS: GG was more strongly correlated between monozygotic (r = 0.65) than dizygotic (r = 0.48) twins, adjusted for age and BMI. The best-fitting quantitative genetic model adjusted for age and BMI showed that 69% of population variance in GG is heritable, while the remaining 31% is due to unique environmental influences. In contrast, GSP was similarly correlated between monozygotic (r = 0.55) and dizygotic (r = 0.49) twins, hence not genetically determined. GG was strongly correlated to A1C (r = 0.48), attributable mostly to genetic factors. About one-third of the heritability of A1C is shared with GG; the remainder is specific to A1C. CONCLUSIONS: Heritability of the GG accounts for about one-third of the heritability of A1C. By implication, there are gene(s) that preferentially affect erythrocyte lifespan or glucose and/or nonenzymatic glycation or deglycation in the intracellular, rather than extracellular, compartment.

Adult↗

PubMed2003

Genetics of fibrin clot structure: a twin study.

Coronary artery thrombosis following plaque rupture is an important feature of myocardial infarction, and studies have highlighted the role of coagulation in this condition. Although genetic and environmental influences on the variance in coagulation protein concentrations have been reported, there are no data on the heritability of structure/function of the final phenotype of the coagulation cascade, the fibrin clot. To assess genetic and environmental contributions to fibrin structure, permeation and turbidity studies were performed in 137 twin pairs (66 monozygotic, 71 dizygotic). The environmental influence (e2) on pore size (Ks) (e2 = 0.61 [95% confidence interval (CI), 0.45-0.80]) and fiber size (e2 = 0.54 [95% CI, 0.39-0.73]) was greater than the heritability (h2 = 0.39 [95% CI, 0.20-0.55] and 0.46 [95% CI, 0.27-0.62], respectively). After correction for fibrinogen levels, the environmental effect persisted for Ks (e2 = 0.61), but genetic influence assumed a greater importance in determining fiber size (h2 = 0.73). Multivariate analysis revealed an overlap in the influence of genetic and environmental factors on fibrinogen levels, Ks, and fiber size. Factor XIII B subunit showed environmental and genetic correlation with fibrinogen and fiber size and a genetic correlation with Ks. The results indicate that genetic and environmental influences are important in determining fibrin clot structure/function.

Adolescent↗

PubMed2003

The association of body mass index and osteoarthritis of the knee joint: an examination of genetic and environmental influences.

OBJECTIVE: To examine the genetic and environmental influences on the known association between body mass index (BMI) and knee osteoarthritis (OA), using adult twin data. METHODS: Bilateral knee radiographs were obtained from 785 pairs of healthy female twins (mean age 54.5 +/- 7.8 years) from the St. Thomas' Hospital Adult Twin Registry (261 monozygotic [MZ] and 524 dizygotic [DZ] twin pairs). Tibiofemoral knee OA was graded according to the Kellgren and Lawrence (K/L) scoring system on an ordinal scale of 0-4. Presence of knee OA was defined as a K/L grade of > or =2 on either side of the knee joint. Body weight and height were measured and the subjects were stratified into quartiles of BMI. Cross-trait cross-twin association of BMI and knee OA was assessed by logistic regression, to assess whether genetic or environmental influences explain the BMI-knee OA link. The genetic (heritability) and environmental contributions to each of the measures were estimated using path modeling. RESULTS: A strong association was found between high BMI and the presence of knee OA (odds ratio 3.90 for highest versus lowest quartile of BMI; P = 0.0001). The heritability of knee OA was 50.4% (95% confidence interval [95% CI] 34-62%) and that of BMI was 55.7% (95% CI 35-72%). However, cross-trait cross-twin associations were not significantly different from unity in either the MZ or DZ twin pairs, indicating that shared genetic influences were unlikely to explain the association. Path modeling showed that the model containing additive genetic factors, common environmental factors, and unique environmental factors had the best fit to the data overall. The shared genetic path between BMI and knee OA could be dropped without deterioration in the fit of the model. CONCLUSION: The strong association between high BMI and knee OA is not likely to be mediated by shared genetic factors. The results imply that environmental modification of BMI can influence knee OA.

Body Mass Index↗

PubMed1997

Determinants of pressure pain threshold in adult twins: evidence that shared environmental influences predominate.

The objective of this study was to examine the relative contribution of genetic and environmental factors in determining pain perception in a classical twin study. Dolorimeter measurements of pressure pain threshold (PPT) were recorded in 609 healthy female-female twin pairs of whom 269 pairs were monozygotic (MZ) and 340 were dizygotic (DZ). There was a strong correlation (R) in PPT in both MZ and DZ pairs (R(MZ) = 0.57, 95% confidence interval (CI): [0.49, 0.65]; R(DZ) = 0.51, 95% CI: [0.42, 0.59]). The slight excess in intraclass correlation observed in MZ when compared with DZ twins corresponds to a heritability for PPT of only 10% and is not statistically significant. Neither estimate of intraclass correlation was substantially altered after adjusting for a range of potential confounding variables including age, current tobacco and alcohol use, current analgesic use, psychological status assessed by the general health questionnaire, and social class. The dolorimeter measurements were shown to be reliable (between observer agreement R = 0.66; within observer agreement R = 0.70-0.76) and stable over time. In conclusion, these data suggest that there is no significant genetic contribution to the strong correlation in PPT that is observed in twin pairs. These findings reinforce the view that learned patterns of behaviour within families are an important determinant of perceived sensitivity to pain.

Adult↗