Biomedical subjects

T D Spector

Publications and source records attributed to T D Spector.

At least 37 records · Page 2Linked to original sources

PubMed2004

Do gene-environment interactions influence fasting plasma lipids? A study of twins.

BACKGROUND: The aims of this study were to determine the influence of smoking, alcohol consumption, physical activity and hormone replacement therapy (HRT) on lipids, independently of genetic factors, and to detect whether gene-environment interactions influence these associations. MATERIALS AND METHODS: Fasting plasma total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apolipoproteins AI and B and lipoprotein(a) were measured in 685 female twins (96 monozygotic, 230 dizygotic pairs and 33 singletons). RESULTS: Smokers had higher triglyceride and lower HDL cholesterol levels than never-smokers (P < 0.001). After controlling for genetic influences, smoking accounted for 0.35 mmol L(-1) and 0.22 mmol L(-1) differences in triglyceride and HDL cholesterol levels, respectively (P < 0.005), remaining significant after excluding alcohol-discordant twin pairs. In a gene-environment interaction analysis, the association between smoking and triglycerides was exaggerated in subjects at high genetic risk of hypertriglyceridaemia (interaction P=0.04). All levels of alcohol consumption were associated with higher HDL cholesterol levels than abstinence, but only moderate alcohol consumers had lower LDL cholesterol and triglyceride levels. In monozygotic twins concordant for smoking, an alcohol intake > 10 units week(-1) accounted for a 0.32 mmol L(-1) difference in LDL cholesterol, independently of genetic effects (P=0.04). In postmenopausal women, those using HRT had 0.54 mmol L(-1) lower LDL cholesterol and 0.21 micromol L(-1) lower lipoprotein(a) levels than nonusers (P < 0.001 and P=0.04, respectively); these differences were attenuated after accounting for genetic effects in monozygotic twins. Although physically active subjects had higher levels of HDL cholesterol than nonactive subjects, this was nonsignificant after adjusting for genetic factors. CONCLUSIONS: Smoking-induced aberrations in HDL cholesterol and triglycerides and alcohol-related differences in LDL cholesterol were independent of genetic influences. The association between smoking and hypertriglyceridaemia was accentuated in high genetic risk individuals.

Adult↗

PubMed2003

Can the WHO definition of osteoporosis be applied to multi-site axial transmission quantitative ultrasound?

Osteoporosis is a highly prevalent but preventable disease and, as such, it is important that there are appropriate diagnostic criteria to identify those at risk of low trauma fracture. In 1994 the World Health Organization (WHO) introduced definitions of osteoporosis and osteopenia using T-scores, which identified 30% of all Caucasian post-menopausal women as having osteoporosis. However, the use of the WHO T-score thresholds of -2.5 for osteoporosis and -1.0 for osteopenia may be inappropriate at skeletal sites other than the spine, hip and forearm or when other modalities, such as quantitative ultrasound (QUS) are used. The aim of this study was to evaluate the age-dependence of T-scores for speed of sound (SOS) measurements at the radius, tibia, phalanx and metatarsal by use of the Sunlight Omnisense, to evaluate the prevalence of osteoporosis and osteopenia at these sites by use of the WHO criteria, and calculate appropriate equivalent T-score thresholds. The study population consisted of 278 healthy pre-menopausal women, 194 healthy post-menopausal women and 115 women with atraumatic vertebral fractures. All women had SOS measurements at the radius, tibia, phalanx and metatarsal and bone mineral density (BMD) measurements at the lumbar spine and hip. A group of healthy pre-menopausal women aged 20-40 years from the pre-menopausal group were used to estimate the population mean and SD for each of the SOS and BMD measurement sites. Healthy post-menopausal women were classified into normal, osteopenic or osteoporotic, based upon the standard WHO definition of osteoporosis and expressed as a percentage. We investigated the age-related decline in T-scores from 20-79 by stratifying the healthy subjects into 10-year age groups and calculating the mean T-score for each of these groups. Finally, we estimated appropriate T-score thresholds, using five different approaches. The prevalence of osteoporosis in the post-menopausal women aged 50 years and over ranged from 1.4 to 12.7% for SOS and 1.3 to 5.2% for BMD. The age-related decline in T-scores ranged from -0.92 to -1.80 for SOS measurements in the 60 to 69-year age group and -0.60 to -1.19 for BMD measurements in the same age group. The WHO definition was not suitable for use with SOS measurements, and revised T-score thresholds for the diagnosis of osteoporosis of -2.6, -3.0, -3.0 and -2.2 and for osteopenia of -1.4, -1.6, -2.3, and -1.4, for the radius, tibia, phalanx and metatarsal, respectively, were recommended.

Adult↗

PubMed2003

A genome-screen of a large twin cohort reveals linkage for quantitative ultrasound of the calcaneus to 2q33-37 and 4q12-21.

UNLABELLED: A genome-wide screen was performed on a large cohort of dizygous twin pairs to identify regions of the genome that contain QTL for QUS of bone. Suggestive linkage of QUS parameters to 2q33-37 and 4q12-21 highlighted these regions as potentially important for studies of genes that regulate bone. INTRODUCTION: The genetics of osteoporotic fracture is only partly explained by bone mineral density (BMD). Quantitative ultrasound (QUS) of the calcaneus can also be used for independent clinical assessment of osteoporotic fracture risk. Two specific indices are derived from this assessment: broadband ultrasound attenuation (BUA) and velocity of sound (VOS). Both parameters provide information on fracture risk; however, BUA has been studied more extensively and may be favored because it is thought to have a stronger predictive value for osteoporotic fracture and incorporates aspects of trabecular structure and bone quality as well as BMD. Studies of QUS in twins have shown that both derived parameters are under substantial genetic control, independent of BMD. MATERIALS AND METHODS: To identify regions of the genome that contain quantitative trait loci (QTL) for QUS of bone, we performed a genome-wide screen on a large cohort of dizygous twin pairs. Unselected female dizygous twins from 1067 pedigrees from the St Thomas' UK Adult Twin Registry were genome scanned (737 highly polymorphic microsatellite markers). Multipoint linkage analyses provided maximum evidence of linkage for BUA (LOD 2.1-5.1) to 2q33-37. Linkage for VOS (LOD 2.2-3.4) was maximal at 4q12-21. Potential evidence of linkage in the cohort indicated five other possible locations of QTL (LOD > 2.0) relevant to bone density or structure on chromosomes 1, 2, 13, 14, and X. RESULTS AND CONCLUSIONS: This study has identified eight genomic locations with linkage of LOD > 2.0. This data should be of value in assisting researchers to localize genes that regulate bone mass and microstructure. These results should complement genome screens of BMD and bone structure and serve to enable further targeted positional candidate and positional cloning studies to advance our understanding of genetic control of bone quality and risk of fracture.

Adolescent↗

PubMed2003

Evidence of altered bone turnover, vitamin D and calcium regulation with knee osteoarthritis in female twins.

BACKGROUND: Osteoarthritis (OA) is a disorder of the whole synovial joint organ. There is growing evidence of the importance of bone turnover in OA, and human studies have demonstrated that the subchondral bone is metabolically active in OA. The aim of this study was to assess the relationships of radiographic knee OA with altered bone turnover and calcium regulation. METHODS: We performed a matched and unmatched case-control study using twins assessed for OA. The subjects were 1644 female Caucasian twin pairs (266 monozygotic and 556 dizygotic) aged 24-79 yr from the St Thomas' UK Adult Twin Registry. Assays for measures of bone turnover [bone-specific alkaline phosphatase, osteocalcin and urinary deoxypyridinoline (DPD)] and calcium regulation [serum parathyroid hormone (PTH), 25-hydroxyvitamin D, serum calcium, serum magnesium and serum phosphate] were performed. The radiological features of knee OA were graded on a four-point scale (0-3) for osteophytes and a five-point scale (0-4) for Kellgren and Lawrence classification. Adjustment for age, body mass index (BMI) and relatedness was made. Conditional logistic regression analysis was also used to estimate the odds ratio (OR) and 95% confidence intervals (CI) for having radiological features of knee OA per standardized unit difference of serum variable between twins. RESULTS: Of the 1644 women studied, 474 (28.8%) had radiological evidence of knee osteophytes. There was evidence of increased bone turnover, increased PTH levels and decreased vitamin D levels in this group compared with those without osteophytes. No association was seen with joint space loss. After adjusting for age, BMI and relatedness, all of the differences disappeared except for a significant increase 10% in urinary DPD (P = 0.04). Discordant twin pair analysis (performed on a subgroup of 229 pairs) confirmed modest increases in bone resorption indicated by urinary DPD (OR 1.67, 95% CI 0.88-3.16) and a significant decrease in serum magnesium (OR 0.65, 95% CI 0.46-0.92) in the co-twins with OA. CONCLUSION: Bone resorption is increased in women with knee OA, consistent with metabolically active subchondral bone. However, bone formation, vitamin D and calcium regulation were not different after adjusting for age and BMI. The results suggest that bone resorption is increased in the presence of OA. Although we cannot clearly differentiate a cause or effect relationship, these results suggest that this is related to disease mechanisms and point to potential diagnostic or therapeutic avenues for bone resorption in OA.

Adult↗

PubMed2003

Genetic associations between frozen shoulder and tennis elbow: a female twin study.

OBJECTIVES: To estimate the heritability of frozen shoulder (FS) and tennis elbow (TE) and to examine the two disorders for possible genetic or environmental associations. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Adult↗

PubMed2003

Association of birth weight with osteoporosis and osteoarthritis in adult twins.

OBJECTIVES: Twin studies present a unique opportunity to examine the association of birth weight with adult life phenotypes in a design that naturally accounts for maternal factors and a range of early environmental factors, which might potentially bias the association. In this study, we explored the association of birth weight with osteoporosis (OP) and osteoarthritis (OA), in a large national cohort of female twins. METHODS: Intra-pair differences between the reported birth weight of the twins (n=4008) were examined for an association with: (i) intra-pair differences in bone mineral density (BMD) and bone mineral content (BMC) at the lumbar spine, hip and forearm using linear regression; and (ii) osteoarthritis status in pairs discordant for radiographic disease at the hand, hip and knee using matched logistic regression. The confounding influences of height and weight were taken into account. RESULTS: The mean age of the twins was 47.5+/-12.3 yr. Intra-pair differences in birth weight were significantly associated with BMD at the spine (P=0.047), total hip (P=0.016) and femoral neck (P<0.001), but not at the forearm (P=0.245). These were entirely explained by the birth weight association with height and weight. The associations of intra-pair differences in birth weight and BMC were highly significant (P<0.001) at all sites, but were partly explained by adjustment for adult height and weight. We found no clear association between intra-pair birth weight differences and OA in twins discordant for any of the radiographic OA phenotypes at any site. CONCLUSIONS: Bone mass and especially BMC are highly associated with birth weight. These associations are accounted for mainly by environmental factors that are independent of maternal factors such as gestational age, maternal smoking and nutrition, and are largely mediated by skeletal size and particularly adult height. Birth weight does not appear to be a major influence on the later development of radiographic OA in women.

Adult↗

PubMed2003

Differential effects of hormone replacement therapy on bone mineral density and axial transmission ultrasound measurements in cortical bone.

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.

Absorptiometry, Photon↗

PubMed2003

Risk factors for progression of lumbar spine disc degeneration: the Chingford Study.

OBJECTIVE: Few data exist concerning the natural history of lumbar spine disc degeneration and associated risk factors. We therefore undertook this study to examine the radiographic progression of lumbar spine disc degeneration over the course of 9 years in a population-based inception cohort of women from the Chingford Study. METHODS: Seven hundred ninety-six paired lumbar spine radiographs were read by a single reader for anterior osteophytes (AO) and disc space narrowing (DSN) using the Lane atlas at each lumbar disc space (L1-5). Disc degeneration was defined using thresholds of AO and DSN grade 1+ in one or more vertebrae (L1-5) within a subject. Progression was defined as an increase in grade in an affected year-1 vertebra. Potential risk factors were assessed using odds ratios and 95% confidence intervals adjusted for age, body mass index (BMI), and other potential confounders in logistic regression models using the STATA statistical package. RESULTS: The mean +/- SD age at baseline was 53.8 +/- 6.0 years, and mean +/- SD BMI was 25.4 +/- 4.1 kg/m(2). Progression rates for AO and DSN were 4% per annum and 3% per annum, respectively. Progression of DSN was predicted by age, back pain, and radiographic hip and knee osteoarthritis (OA). Progression of AO was predicted by age and radiographic hip OA, with borderline significance for BMI >30 kg/m(2). No significant effects were seen for smoking, physical activity, hormone replacement therapy use, multiparity, or hand OA. CONCLUSION: This is the first population-based longitudinal study to assess progression of the individual radiographic features of AO and DSN in lumbar spine disc degeneration. We demonstrated progression rates of 3-4% per annum, with important risk factors for progression, including age, back pain, and radiographic OA at the hip and knee.

Disease Progression↗

PubMed2003

Genetic and environmental influences on psychological distress in the population: General Health Questionnaire analyses in UK twins.

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.

Adolescent↗

PubMed2003

Novel association suggests multiple independent QTLs within chromosome 5q21-33 region control variation in total humans IgE levels.

Asthma is a common, heterogeneous, complex disease accompanied by raised total and specific immunoglobulin-E (IgE) antibody levels. Despite numerous previous reports of linkage and association of asthma, atopy and serum IgE levels to genes within the 5q21-33 region, definitive, replicable results are still not available. We used the classical twin design to (i) estimate the relative contributions of genes and environment to variation in total IgE levels, (ii) assess genetic linkage, and (iii) examine allelic association of 11 microsatellite markers spanning the 5q21-33 region to total IgE. Variation in total IgE level was shown to be highly heritable (65%). Although evidence for linkage of the 11 microsatellites to IgE was not observed, the omnibus test of association, not confounded by population substructure, showed positive association of D5S393 and D5S673 to IgE. Genes in the vicinity of D5S673 include hepatitis A virus receptor (HAVCR-1) and IL-12B. Recently, the mouse orthologue of HAVCR-1, the T-cell membrane family of proteins, have been shown to be in strong association with expression of airway hyperactivity in a mouse model of human asthma and atopy. IL-12B subserves many proinflammatory functions and also induces B cells proliferation.

Adolescent↗

PubMed2003

Kellgren & Lawrence grade 1 osteophytes in the knee--doubtful or definite?

The most universally accepted methods of classification of radiographic osteoarthritis (OA) is the Kellgren & Lawrence (K&L) grading system. However, there have been many criticisms of this including the grading of a doubtful osteophyte as a grade 1. We report the natural history of a given prevalent grade 1 osteophyte in a 10-year follow-up knee study. 62% of women graded at baseline with a doubtful osteophyte went on to develop true osteophytic knee OA compared with only 22% of controls with no sign of disease. So called 'doubtful' osteophytes appear to be 'real' and significantly related to OA knee and therefore cannot be ignored or classified as normal.

Chondrocytes↗

PubMed2003

Genetic influences in gastro-oesophageal reflux disease: a twin study.

BACKGROUND: A number of families have been described which include multiple members with symptomatic, endoscopic, or complicated gastro-oesophageal reflux disease (GORD). First degree relatives of patients with GORD are more likely to suffer with GORD symptoms. These observations raise the possibility of a genetic contribution to the aetiology of GORD. AIMS: To determine the relative contribution of genetic factors to GORD by evaluating GORD symptoms in monozygotic (MZ) and dizygotic (DZ) twins. METHODS: A total of 4480 unselected twin pairs, identified from a national volunteer twin register, were asked to complete a validated symptom questionnaire. GORD was defined as symptoms of heartburn or acid regurgitation at least weekly during the past year. RESULTS: Replies were obtained from 5032 subjects (56% response rate). A total of 1960 twin pairs were evaluable: 928 MZ pairs (86 male pairs, mean (SD) age 52 (13) (range 19-81) years) and 1032 DZ pairs (71 male pairs, mean age 52 (13) (20-82) years). The prevalence of GORD among both groups of twins was 18%. Casewise concordance rates were significantly higher for MZ than DZ twins (42% v 26%; p<0.001). Multifactorial liability threshold modelling suggests that additive genetic effects combined with unique environmental factors provide the best model for GORD. Heritability estimates suggest that 43% (95% confidence interval 32-55%) of the variance in liability to GORD is due to additive genetic factors. CONCLUSIONS: There is a substantial genetic contribution to the aetiology of GORD.

Adult↗

PubMed2002

Comparison of genome screens for two independent cohorts provides replication of suggestive linkage of bone mineral density to 3p21 and 1p36.

Low bone mineral density (BMD) is a major risk factor for osteoporotic fracture. Studies of BMD in families and twins have shown that this trait is under strong genetic control. To identify regions of the genome that contain quantitative trait loci (QTL) for BMD, we performed independent genomewide screens, using two complementary study designs. We analyzed unselected nonidentical twin pairs (1,094 pedigrees) and highly selected, extremely discordant or concordant (EDAC) sib pairs (254 pedigrees). Nonparametric multipoint linkage (NPL) analyses were undertaken for lumbar spine and total-hip BMD in both cohorts and for whole-body BMD in the unselected twin pairs. The maximum evidence of linkage in the unselected twins (spine BMD, LOD 2.7) and the EDAC pedigrees (spine BMD, LOD 2.1) was observed at chromosome 3p21 (76 cM and 69 cM, respectively). These combined data indicate the presence, in this region, of a gene that regulates BMD. Furthermore, evidence of linkage in the twin cohort (whole-body BMD; LOD 2.4) at chromosome 1p36 (17 cM) supports previous findings of suggestive linkage to BMD in the region. Weaker evidence of linkage (LOD 1.0-2.3) in either cohort, but not both, indicates the locality of additional QTLs. These studies validate the use, in linkage analysis, of large cohorts of unselected twins phenotyped for multiple traits, and they highlight the importance of conducting genome scans in replicate populations as a prelude to positional cloning and gene discovery.

Adolescent↗

PubMed2002

Multisite quantitative ultrasound: Colles' fracture discrimination in postmenopausal women.

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.

Absorptiometry, Photon↗

PubMed2002

Linkage and association for bone mineral density and heel ultrasound measurements with a simple tandem repeat polymorphism near the osteocalcin gene in female dizygotic twins.

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.

Adult↗

PubMed2002

The influence of genetics and environmental factors in the pathogenesis of acne: a twin study of acne in women.

Acne is common and often leads to significant psychologic and physical morbidity. From clinical experience, acne appears to run in families; however, very few studies have investigated the genetic basis of this very common skin disease. A large twin study based on 458 pairs of monozygotic and 1099 pairs of dizygotic twins, all women with a mean age of 46 y was performed to investigate the relative contribution of genetic and environmental factors on the liability to acne. In addition, potential risk factors were assessed in twins with and without acne in a nested cross-sectional design. Fourteen percent of the twins reported a history of acne. Genetic modeling using acne scores showed that 81% (95% confidence interval 73-87%) of the variance of the disease was attributable to additive genetic effects. The remaining 19% was attributed to unique (i.e., unshared) environmental factors. Of the potential risk factors tested in 400 acne twins and 2414 unaffected twins, only apolipoprotein A1 serum levels were significantly lower in acne twins even after adjusting for age and weight. Family history of acne was also significantly associated with an increased risk. No significant differences were found between acne twins and nonacne twins for weight, body mass index, height, birth weight, hair thinning, reproductive factors as well as cholesterol, triglycerides, high-density lipoprotein, and glucose levels. The lower serum levels of apolipoprotein A1 in acne twins were also confirmed when analyzing acne discordant twin pairs. The evidence of a major genetic influence on acne should stimulate the search for potential genes that may lead to new therapeutic approaches.

Acne Vulgaris↗

PubMed2002

Size at birth, adult intestinal calcium absorption and 1,25(OH)(2) vitamin D.

BACKGROUND: Adult bone mineral status is modified by early environmental influences, but the mechanism of this phenomenon is unknown. Intestinal calcium absorption and vitamin D metabolism are integrally involved in bone metabolism and may be programmed during early life. AIM: To examine the early-life influences on calcium absorption and its control in 322 post-menopausal female twins. METHODS: Intestinal calcium absorption was assessed by the stable strontium (Sr) method. Serum PTH, 25(OH) and 1,25(OH)(2) vitamin D were measured and recalled birth weight recorded. RESULTS: Fractional intestinal Sr absorption (alpha Sr) was correlated with serum 1,25(OH)(2) vitamin D (p<0.001), but not with 25(OH) vitamin D. Birth weight was inversely associated with serum 1,25(OH)(2) vitamin D (p=0.04), the association being independent of serum calcium, phosphate, creatinine and PTH. Birth weight was inversely correlated with alpha Sr (p=0.03), this association being independent of age, season, customary calcium intake and serum 25(OH) vitamin D; however, when serum 1,25(OH)(2) vitamin D was added into the model, the association became non-significant, suggesting that the association was partially mediated via serum 1,25(OH)(2) vitamin D. DISCUSSION: We found a significant inverse association between birth weight and intestinal calcium absorption that is partially explained by an association between serum 1,25(OH)(2) vitamin D and birth weight. This suggests a mechanism whereby the intra-uterine environment might affect adult skeletal status.

Aged↗

PubMed2001

A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity.

Multiple epiphyseal dysplasia (MED) is an autosomal dominantly inherited chondrodysplasia. It is clinically highly heterogeneous, partially because of its complex genetic background. Mutations in four genes, COL9A2, COL9A3, COMP, and MATR3, all coding for cartilage extracellular matrix components (i.e., the alpha2 and alpha 3 chains of collagen IX, cartilage oligomeric matrix protein, and matrilin-3), have been identified in this disease so far, but no mutations have yet been reported in the third collagen IX gene, COL9A1, which codes for the alpha1(IX) chain. MED with apparently recessive inheritance has been reported in some families. A homozygous R279W mutation was recently found in the diastrophic dysplasia sulfate transporter gene, DTDST, in a patient with MED who had a club foot and double-layered patella. The series consisted of 41 probands with MED, 16 of whom were familial and on 4 of whom linkage analyses were performed. Recombination was observed between COL9A1, COL9A2, COL9A3, and COMP and the MED phenotype in two of the families, and between COL9A2, COL9A3, and COMP and the phenotype in the other two families. Screening of COL9A1 for mutations in the two probands from the families in which this gene was not involved in the recombinations failed to identify any disease-causing mutations. The remaining 37 probands were screened for mutations in all three collagen IX genes and in the COMP gene. The probands with talipes deformities or multipartite patella were also screened for the R279W mutation in DTDST. The analysis resulted in identification of three mutations in COMP and one in COL9A1, but none in the other two collagen IX genes. Two of the probands with a multipartite patella had the homozygous DTDST mutation. The results show that mutations in COL9A1 can cause MED, but they also suggest that mutations in COL9A1, COL9A2, COL9A3, COMP, and DTDST are not the major causes of MED and that there exists at least one additional locus.

Adolescent↗