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1.  Individuals with high bone mass have an increased prevalence of radiographic knee osteoarthritis 
Bone  2015;71:171-179.
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 < 0.001. The association between HBM and osteophytosis was stronger than that for JSN, both before and after adjustment for BMI which attenuated the ORs for knee OA and osteophytes in cases vs. controls by approximately 50%.
Our findings support a positive association between HBM and knee OA. This association was strongest for osteophytes, suggesting HBM confers a general predisposition to a subtype of OA characterised by increased bone formation.
•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.
PMCID: PMC4289915  PMID: 25445455
Osteoarthritis; DXA; Bone mineral density; High bone mass
3.  Prevalence of radiographic hip osteoarthritis is increased in high bone mass 
Osteoarthritis and Cartilage  2014;22(8):1120-1128.
Epidemiological studies have shown an association between increased bone mineral density (BMD) and osteoarthritis (OA), but whether this represents cause or effect remains unclear. In this study, we used a novel approach to investigate this question, determining whether individuals with High Bone Mass (HBM) have a higher prevalence of radiographic hip OA compared with controls.
HBM cases came from the UK-based HBM study: HBM was defined by BMD Z-score. Unaffected relatives of index cases were recruited as family controls. Age-stratified random sampling was used to select further population controls from the Chingford and Hertfordshire cohort studies. Pelvic radiographs were pooled and assessed by a single observer blinded to case-control status. Analyses used logistic regression, adjusted for age, gender and body mass index (BMI).
530 HBM hips in 272 cases (mean age 62.9 years, 74% female) and 1702 control hips in 863 controls (mean age 64.8 years, 84% female) were analysed. The prevalence of radiographic OA, defined as Croft score ≥3, was higher in cases compared with controls (20.0% vs 13.6%), with adjusted odds ratio (OR) [95% CI] 1.52 [1.09, 2.11], P = 0.013. Osteophytes (OR 2.12 [1.61, 2.79], P < 0.001) and subchondral sclerosis (OR 2.78 [1.49, 5.18], P = 0.001) were more prevalent in cases. However, no difference in the prevalence of joint space narrowing (JSN) was seen (OR 0.97 [0.72, 1.33], P = 0.869).
An increased prevalence of radiographic hip OA and osteophytosis was observed in HBM cases compared with controls, in keeping with a positive association between HBM and OA and suggesting that OA in HBM has a hypertrophic phenotype.
PMCID: PMC4147962  PMID: 24971870
Osteoarthritis; Osteoporosis; DXA; Radiology; Epidemiology
4.  Alcohol-induced metabolomic differences in humans 
Translational Psychiatry  2013;3(7):e276-.
Alcohol consumption is one of the world's major risk factors for disease development. But underlying mechanisms by which moderate-to-heavy alcohol intake causes damage are poorly understood and biomarkers are sub-optimal. Here, we investigated metabolite concentration differences in relation to alcohol intake in 2090 individuals of the KORA F4 and replicated results in 261 KORA F3 and up to 629 females of the TwinsUK adult bioresource. Using logistic regression analysis adjusted for age, body mass index, smoking, high-density lipoproteins and triglycerides, we identified 40/18 significant metabolites in males/females with P-values <3.8E−04 (Bonferroni corrected) that differed in concentrations between moderate-to-heavy drinkers (MHD) and light drinkers (LD) in the KORA F4 study. We further identified specific profiles of the 10/5 metabolites in males/females that clearly separated LD from MHD in the KORA F4 cohort. For those metabolites, the respective area under the receiver operating characteristic curves were 0.812/0.679, respectively, thus providing moderate-to-high sensitivity and specificity for the discrimination of LD to MHD. A number of alcohol-related metabolites could be replicated in the KORA F3 and TwinsUK studies. Our data suggests that metabolomic profiles based on diacylphosphatidylcholines, lysophosphatidylcholines, ether lipids and sphingolipids form a new class of biomarkers for excess alcohol intake and have potential for future epidemiological and clinical studies.
PMCID: PMC3731787  PMID: 23820610
alcohol; alcoholism; biomarkers; gender; lipids; metabolomics
5.  Change in body mass index during middle age affects risk of total knee arthoplasty due to osteoarthritis: A 19-year prospective study of 1003 women 
The Knee  2012;19(4):316-319.
The evidence linking body mass index (BMI) to severe OA shows a strong association in the knee. There are limited data exploring the effect of BMI on the risk of joint arthroplasty in a healthy population with long periods of follow up. We compared the self-reported BMI at age 20, measured BMI at baseline, year 5 and year 10 with the year 19 risk of total knee arthroplasty (TKA) in a well-described, population based cohort of healthy women. A total of 733 women attended the 19th year visit, of whom 31 underwent TKA and 676 were used as a control group after 26 were removed for having hip arthoplasty.
Using logistic regression, an increase in 1 unit of BMI at baseline was associated with a 10.5% increased risk of TKA (p = 0.017) and at year 5 the increased risk is 8.6% (p = 0.042). When adjusted for baseline age and smoking, baseline BMI was the only significant predictor of TKA at 10.0% with p = 0.024. There was no significant association at 10 years or for change in BMI over time.
In this prospective, population based study, BMI predicted the risk of TKA for OA. The risk was greatest at baseline when the patients were in middle age suggesting that this is the most important time to target weight reduction interventions.
PMCID: PMC3381226  PMID: 21782451
Knee; Arthroplasty; Risk; BMI
6.  Loci at 9p21 and 22q13 harbour alleles for development of cutaneous nevi and melanoma 
Nature genetics  2009;41(8):915-919.
High number of melanocytic nevi is the most important known risk factor for cutaneous melanoma. We conducted a genome-wide association study for nevus count using 297,108 tag-SNPs in 1,524 twins and validated our results in an independent cohort of 4,107 subjects. We identified strongly associated variants in MTAP, a gene adjacent to the familial melanoma susceptibility locus CDKN2A on 9p21 (rs4636294, P = 3.4 × 10-15). We further identified PLA2G6 on 22q13.1 (rs2284063, P = 3.4 × 10-8). Both loci were also associated with melanoma risk in 3,131 melanoma cases from two independent studies (odds-ratios 1.23 at rs10757257 and rs132985). About one subject in 11 is homozygous for the variant at both loci with twice the number of nevi compared to those homozygous for the protective alleles, and double the risk for melanoma. These data provide the first evidence for common melanoma alleles whose effects are mediated through nevus number.
PMCID: PMC3080738  PMID: 19578365
7.  Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study 
Annals of the Rheumatic Diseases  2010;70(5):864-867.
The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis.
The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44 449 individuals), and de novo in 14 534 independent samples, all of European descent.
None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects.
Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.
PMCID: PMC3070286  PMID: 21177295
8.  AMP‐kinase α2 subunit gene PRKAA2 variants are associated with total cholesterol, low‐density lipoprotein‐cholesterol and high‐density lipoprotein‐cholesterol in normal women 
Journal of Medical Genetics  2006;43(12):936-942.
5′‐AMP‐activated protein kinase (AMPK) inactivates critial ensymes in fatty acid and cholesterol synthesis. We hypothesised that the serum lipid profile may be influenced by genetic variation in the AMPK catalytic α2 subunit.
We examined association of 5 tagging SNPs (tSNPs) in the PRKAA2 gene with serum lipids in 2777 normal Caucasian females (mean age 47.4±12.5 years).
All tSNPs were associated with total‐ and LDL‐cholesterol, (p<0.001 to 0.034), explaining variances of 0.13–0.59% and 0.11–0.55% respectively. One haplotype (frequency 34.7%) showed lower total‐ and LDL‐cholesterol compared with the most common haplotype (frequency 45.7%) (p≤0.001), explaining 0.78% of total‐ and 0.75% of LDL‐cholesterol. Another haplotype (frequency 10.5%) was significantly associated with lower HDL‐cholesterol (p = 0.005), explaining 0.59% of variance.
PRKAA2 gene variants are significantly associated with serum lipoproteins in a large sample of normal female Caucasians.
PMCID: PMC1780024  PMID: 16801347
9.  The Big Finger: the second to fourth digit ratio is a predictor of sporting ability in women 
British Journal of Sports Medicine  2006;40(12):981-983.
The second to fourth finger length ratio (2d:4d) is thought to be related to diverse traits including cognitive ability, disease susceptibility, and sexuality.
To examine the relationship between 2d:4d and sports ability in women.
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).
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.
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.
PMCID: PMC2577466  PMID: 17008344
finger length ratio; ability; profiling; talent identification; women
10.  Reduction of leucocyte telomere length in radiographic hand osteoarthritis: a population‐based study 
Annals of the Rheumatic Diseases  2006;65(11):1444-1448.
Although age is the strongest predictor of osteoarthritis, the exact mechanism underlying this disorder remains elusive.
To examine the association between leucocyte telomere length (LTL), a bio‐indicator of ageing, and radiographic hand osteoarthritis.
An unselected, predominantly female sample from the TwinsUK Adult Twin Registry (Twin Research and Genetic Epidemiology Unit, St Thomas Hospital, London, UK) was studied. Radiographs of both hands were obtained with a standard posteroanterior view and assessed for radiographic osteoarthritis according to the Kellgren/Lawrence (K/L) score. Individual radiographic features including osteophytes and joint space narrowing (JSN) were also assessed on a four‐point scale using a standard atlas. Hand osteoarthritis was defined radiographically as having ⩾3 osteoarthritis‐affected joints of both hands (K/L score⩾2). Severity of hand osteoarthritis was indicated semiquantitatively by total K/L scores, osteophytes, JSN scores and proportion of joints affected. Mean LTL was measured by the terminal restriction fragment length using the Southern blot.
A total of 1086 Caucasian subjects (mean (SD) age 55 (8.0) years) were studied. LTL was 6.95 (0.64) kb and was inversely correlated with age. After adjustment for age, sex, body mass index and smoking, LTL was significantly shorter by 178 bp in subjects with hand osteoarthritis (n = 160) than in those without (n = 926; p = 0.04). LTL was also significantly associated with semicontinuous measures of osteoarthritis (eg, total K/L score, JSN score, osteophyte score and proportion of joints affected) after adjustment (all p⩽0.02) in a dose–response fashion.
Shorter LTL equivalent to around 11 years of annual loss in normal people is associated with radiographic hand osteoarthritis and disease severity, suggesting potential shared mechanisms between osteoarthritis and ageing, and implicating oxidative stress and low‐level chronic inflammation in both conditions.
PMCID: PMC1798337  PMID: 17038452
11.  Heritability of insulin sensitivity and lipid profile depend on BMI: evidence for gene–obesity interaction 
Diabetologia  2009;52(12):2578-2584.
Evidence from candidate gene studies suggests that obesity may modify genetic susceptibility to type 2 diabetes and dyslipidaemia. On an aggregate level, gene–obesity interactions are expected to result in different heritability estimates at different obesity levels. However, this hypothesis has never been tested.
The present study included 2,180 British female twins. BMI was used as an index of general obesity. Outcome measures were insulin sensitivity (indexed by quantitative insulin-sensitivity check index [QUICKI]) and fasting plasma lipid profile. Structural equation modelling was used to test whether BMI interacted with latent genetic and environmental effects to impact on the outcome measures.
Genetic influences on triacylglycerol increased with BMI (p < 0.001) whereas the unique environmental influence on QUICKI decreased with BMI (p < 0.001), resulting in a higher heritability estimate for both measures at higher BMI levels. This was further illustrated by stratified analysis in twin pairs concordant for normal weight and twin pairs concordant for overweight. Heritability was 19 percentage points higher for triacylglycerol (p < 0.001) and 31 percentage points higher for QUICKI (p < 0.01) among twins concordant for overweight than among twins concordant for normal weight. BMI had no moderator effect on the latent genetic and environmental factors for total cholesterol and HDL-cholesterol.
Our results suggest that the expression of genes influencing triacylglycerol and insulin sensitivity can vary as a function of obesity status. The substantial increases in the genetic contribution to the total variance in insulin sensitivity and triacylglycerols at higher BMIs may prove extremely valuable in the search for candidate genes.
PMCID: PMC2776165  PMID: 19820914
Gene–environment interaction; Heritability; Insulin sensitivity; Lipid; Obesity
12.  A genome-wide association study suggests that a locus within the ataxin 2 binding protein 1 gene is associated with hand osteoarthritis: the Treat-OA consortium 
Journal of Medical Genetics  2009;46(9):614-616.
To identify the susceptibility gene in hand osteoarthritis (OA) the authors used a two-stage approach genome-wide association study using two discovery samples (the TwinsUK cohort and the Rotterdam discovery subset; a total of 1804 subjects) and four replication samples (the Chingford Study, the Chuvasha Skeletal Aging Study, the Rotterdam replication subset and the Genetics, Arthrosis, and Progression (GARP) Study; a total of 3266 people). Five single-nucleotide polymorphisms (SNPs) had a likelihood of association with hand OA in the discovery stage and one of them (rs716508), was successfully confirmed in the replication stage (meta-analysis p = 1.81×10−5). The C allele conferred a reduced risk of 33% to 41% using a case–control definition. The SNP is located in intron 1 of the A2BP1 gene. This study also found that the same allele of the SNP significantly reduced bone density at both the hip and spine (p<0.01), suggesting the potential mechanism of the gene in hand OA might be via effects on subchondral bone. The authors' findings provide a potential new insight into genetic mechanisms in the development of hand OA.
PMCID: PMC2729370  PMID: 19508968
13.  Vertebral anti-fracture efficacy of strontium ranelate according to pre-treatment bone turnover 
Osteoporosis International  2009;21(2):233-241.
Osteoporotic post-menopausal women patients in two randomised trials comparing the anti-fracture efficacy of strontium ranelate with placebo were separated into tertiles according to their baseline levels of biochemical markers of bone formation and resorption. The vertebral anti-fracture efficacy of strontium ranelate was shown to be independent of baseline bone turnover levels.
Bone turnover (BTO) levels vary among women at risk of osteoporotic fracture. Strontium ranelate is an anti-osteoporotic treatment increasing bone formation and reducing bone resorption. It was hypothesised that its anti-fracture efficacy would be independent of baseline BTO levels.
Post-menopausal women with osteoporosis from two pooled studies were stratified in tertiles according to baseline levels of two BTO markers: bone-specific alkaline phosphatase (b-ALP, n = 4995) and serum C-telopeptide cross-links (sCTX, n = 4891). Vertebral fracture risk was assessed over 3 years with strontium ranelate 2 g/day or placebo.
In the placebo group, relative risk of vertebral fractures increased with BTO tertiles by 32% and 24% for patients in the highest tertile for b-ALP and CTX, respectively, compared to those in the lowest tertile. In the strontium ranelate group, incidences of vertebral fracture did not differ significantly across BTO tertiles. Significant reductions in vertebral fractures with strontium ranelate were seen in all tertiles of both markers, with relative risk reductions of 31% to 47% relative to placebo. Risk reduction did not differ among tertiles (b-ALP: p = 0.513; sCTX: p = 0.290).
The vertebral anti-fracture efficacy of strontium ranelate was independent of baseline BTO levels. Strontium ranelate offers clinical benefits to women across a wide range of metabolic states.
PMCID: PMC2801841  PMID: 19436941
Anti-fracture efficacy; Biochemical marker; Bone turnover; Osteoporosis; Strontium ranelate; Vertebral fracture
14.  Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study 
Lancet  2008;371(9623):1505-1512.
Osteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density.
In this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies.
We identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5×10−8). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6·3×10−12 for lumbar spine and p=1·9×10−4 for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1·3, 95% CI 1·09–1·52, p=0·002) and osteoporosis (OR 1·3, 1·08–1·63, p=0·008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7·6×10−10 for lumbar spine and p=3·3×10−8 for femoral neck) and increased risk of osteoporosis (OR 1·2, 95% CI 1·01–1·42, p=0·038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3·0×10−6). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2·3×10−17). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1·3, 1·08–1·63, p=0·006) and this effect was independent of bone mineral density.
Two gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening.
PMCID: PMC2679414  PMID: 18455228
15.  The relation between progressive osteoarthritis of the knee and long term progression of osteoarthritis of the hand, hip, and lumbar spine 
Annals of the Rheumatic Diseases  2005;65(5):623-628.
The association between progression of knee osteoarthritis and progression of osteoarthritis at sites distant from the knee is unclear because of a lack of multisite longitudinal progression data.
To examine the association between radiological progression of knee osteoarthritis and osteoarthritis of the hands, hips, and lumbar spine in a population based cohort.
914 women had knee x rays taken 10 years apart, which were read for the presence of osteophytes and joint space narrowing (JSN). Progression status was available for hand, hip, and lumbar spine x rays over the same 8 to 10 year period. The association between progression of knee osteoarthritis and osteoarthritis at other sites was analysed using odds ratios (OR) and 95% confidence intervals (CI) in logistic regression models.
89 of 133 women had progression of knee osteoarthritis based on osteophytes, and 51 of 148 based on JSN definition. Progression of JSN in the knee was predicted by progression in lumbar spine disc space narrowing (OR = 2.9 (95% CI 1.2 to 7.5)) and hip JSN (OR = 2.0 (1.0 to 4.2)). No consistent effects were seen for hand osteoarthritis. The associations remained after adjustment for age and body mass index.
Progression of knee osteoarthritis is associated with progression of lumbar spine and hip osteoarthritis. This may have implications for trial methodology, the selection of patients for osteoarthritis research, and advice for patients on prognosis of osteoarthritis.
PMCID: PMC1798151  PMID: 16219710
osteoarthritis; knee; lumbar spine; outcome
16.  A genome-wide association study identifies a novel locus on chromosome 18q12.2 influencing white cell telomere length 
Journal of Medical Genetics  2009;46(7):451-454.
Telomere length is a predictor for a number of common age related diseases and is a heritable trait.
Methods and results:
To identify new loci associated with mean leukocyte telomere length we conducted a genome wide association study of 314 075 single nucleotide polymorphisms (SNPs) and validated the results in a second cohort (n for both cohorts combined  =  2790). We identified two novel associated variants (rs2162440, p = 2.6×10−6; and rs7235755, p = 5.5×10−6) on chromosome 18q12.2 in the same region as the VPS34/PIKC3C gene, which has been directly implicated in the pathway controlling telomere length variation in yeast.
These results provide new insights into the pathways regulating telomere homeostasis in humans.
PMCID: PMC2696823  PMID: 19359265
17.  The genetic influence on radiographic osteoarthritis is site specific at the hand, hip and knee 
Rheumatology (Oxford, England)  2009;48(3):277-280.
Objective. To identify whether a shared genetic influence accounts for the occurrence of OA at different skeletal sites.
Methods. Multivariate modelling of data on prevalent radiographic OA at the hand (DIP, PIP and CMC joints), hip and knee joints assessed in 992 monozygotic and dizygotic female twin participants from the TwinsUK Registry.
Results. OA at all the five joint sites was heritable. Genetic influences were strongly correlated among joints in the hand; however, there was little evidence of common genetic pathways to account for the co-occurrence of OA at the hand, hip and knee.
Conclusions. While genetic influences are important in explaining the variation in occurrence of OA at the hand, hip and knee, there is no evidence that common or shared genetic factors determine the occurrence of disease across all these skeletal sites. The findings suggest that there are important aetiological differences in the disease that are site-specific in women. These results have implications for the design of studies examining the genetic basis of OA as well as for strategies aimed at preventing and treating the disease.
PMCID: PMC2644047  PMID: 19153142
Osteoarthritis; Site; Twin; Hand; Hip; Knee; Structural equation modelling; Genetic linkage; Genetic association
18.  Is telomere length in peripheral blood lymphocytes correlated with cancer susceptibility or radiosensitivity? 
British Journal of Cancer  2007;97(12):1696-1700.
Mean terminal restriction fragment (TRF) lengths in white blood cells (WBCs) have been previously found to be associated with breast cancer. To assess whether this marker could be used as a test for breast cancer susceptibility in women, TRF length was measured in 72 treated female breast cancer patients and 1696 unaffected female controls between the ages of 45 and 77 from the Twin Research Unit at St Thomas' Hospital, as well as 140 newly diagnosed breast cancer cases and 108 mammographically screened unaffected controls from Guy's Hospital. Mean TRF was also tested for correlation with chromosome radiosensitivity and apoptotic response in the Guy's Hospital patients. After adjusting for age, smoking and body mass index, there was no significant difference in TRF lengths between the treated breast cancer patients and unaffected controls (P=0.71). A positive correlation between age-adjusted apoptotic response and mean TRF in newly diagnosed untreated breast cancer patients (P=0.008) was identified but no significant difference in TRF lengths between breast cancer patients and unaffected controls was detected (P=0.53). This suggests that TRF lengths in WBC, is not a marker of breast cancer susceptibility and does not vary significantly between affected women before and after treatment.
PMCID: PMC2360286  PMID: 18000505
telomere; breast cancer susceptibility; radiosensitivity; chromosome; apoptosis
19.  SHP-2 and PI3-kinase genes PTPN11 and PIK3R1 may influence serum apoB and LDL cholesterol levels in normal women 
Atherosclerosis  2007;194(2):e26-e33.
Insulin regulates apoB metabolism via activation of PI3K or regulation of MTP via MAPK/ERK signalling. SHP-2 enhances both pathways through increased IRS-1 phosphorylation. We hypothesized that variants in the SHP-2 gene PTPN11 and PI3K p85alpha subunit gene PIK3R1 may influence fasting levels of plasma apoB and/or LDL cholesterol. We tested association of tagging SNPs (tSNPs) in each gene with serum lipids in a large sample of unselected population-based Caucasian female twins (n=2771, mean age 47.4±12.5 years) and then tested interaction between tSNPs in determining apoB and LDL levels. PTPN11 tSNP rs11066322 was associated with apoB (P=0.007) and rs11066320 was associated with LDL cholesterol (P=0.016). PIK3R1 tSNP rs251406 was associated with apoB (P=0.0003) and rs706713 was associated with LDL cholesterol (P=0.009). PTPN11 tSNP rs11066322 interacted with PIK3R1 tSNP rs251406 in determining serum apoB levels (P=0.012) and with PIK3R1 tSNP rs40318 in determining LDL cholesterol levels (P=0.009). Association of single tSNPs with both apoB and LDL cholesterol as well as interactions between the two genes suggest that variants influencing SHP-2 activity may modulate the acute pathway by which insulin regulates these lipids.
PMCID: PMC2084489  PMID: 17214991
SHP-2; PI3-kinase; apoB; LDL-cholesterol; metabolic syndrome; genetic susceptibility
20.  Heritability of DNA-damage-induced apoptosis and its relationship with age in lymphocytes from female twins 
British Journal of Cancer  2006;95(4):520-524.
Apoptosis is a physiological form of cell death important in normal processes such as morphogenesis and the functioning of the immune system. In addition, defects in the apoptotic process play a major role in a number of important areas of disease, such as autoimmune diseases and cancer. DNA-damage-induced apoptosis plays a vital role in the maintenance of genomic stability by the removal of damaged cells. Previous studies of the apoptotic response (AR) to radiation-induced DNA damage of lymphoid cells from individuals carrying germline TP53 mutations have demonstrated a defective AR compared with normal controls. We have also previously demonstrated that AR is reduced as individuals age. Results from the current study on 108 twins aged 18–80 years confirm these earlier findings that the AR of lymphoid cells to DNA damage is significantly reduced with increasing age. In addition this twin study shows, for the first time, that DNA-damage-induced AR has a strong degree of heritability of 81% (95% confidence interval 67–89%). The vital role of DNA-damage-induced apoptosis in maintaining genetic stability, its relationship with age and its strong heritability underline the importance of this area of biology and suggest areas for further study.
PMCID: PMC2360659  PMID: 16819540
apoptosis; ageing; twins; DNA damage; lymphocytes
21.  Phosphatidylinositol 3-kinase p85 alpha regulatory subunit gene PIK3R1 haplotype is associated with body fat and serum leptin in a female twin population 
Diabetologia  2006;49(11):2659-2667.
Phosphatidylinositol 3-kinase (PI3K) couples the leptin and insulin signalling pathways via IRS-1 and IRS-2. Hence, defective activation of PI3K could be a novel mechanism of peripheral leptin or insulin resistance. We investigated association of tagging SNPs (tSNPs) in the PI3K p85α regulatory subunit gene PIK3R1 with anthropometry, leptin, body fat and insulin sensitivity in a female twin population of European extraction.
Eight tSNPs were genotyped in 2778 women (mean age 47.4±12.5 years) from the St Thomas’ UK Adult Twin Registry (Twins UK).
SNP rs1550805 was associated with serum leptin (P=0.028), BMI (P=0.025), weight (P=0.019), total fat (P=0.004), % total fat (P=0.002), waist (P=0.025), central fat (P=0.005) and % central fat (P=0.005). SNPs rs7713645 and rs7709243 were associated with BMI (P=0.020; P=0.029), rs7709243 with weight, total and central fat, (P=0.026; P=0.031; P=0.023) and both SNPs with fasting glucose (P=0.003; P=0.001) and glucose 2h post OGTT (P=0.023; P=0.007). Haplotype 222 (freq. 7.2%) showed higher serum leptin (P=0.007) and body fat measures (Ps≤0.001) and haplotype 221 (freq. 38.7%) showed higher fasting and 2h-glucose (P=0.035; P=0.021), compared with the most common haplotype 111 (freq. 45.5%).
Association of the PIK3R1 SNP rs1550805 with serum leptin and body fat may reflect diminished ability of PI3K to signal via IRS-1 or IRS-2 in response to leptin.
PMCID: PMC1626353  PMID: 17016694
Genetics/epidemiology; cytokines; weight regulation and obesity; D′: pairwise LD statistic; DEXA: dual X-ray absorptiometry; GEE: Generalized Estimating Equations; HOMA: homeostasis model assessment; JAK2: Janus activating kinase-2; LD: linkage disequibrium; MAF: minor allele frequency; NCBI: National Center for Biotechnology Information (US); PI3K: phosphoinositol 3-kinase; PIK3R1: PI3K p85 alpha regulatory subunit gene; PKB: protein kinase B; r2: pairwise correlation coefficient; SiB: insulin sensitivity baseline (fasting); SiH2 insulin sensitivity 2h post OGTT; SiM: insulin sensitivity measure; STAT3: Signal transducer and activator of transcription-3; tSNP: tagging single nucleotide polymorphism; VD: distribution volume
22.  Genetic influences in gastro-oesophageal reflux disease: a twin study 
Gut  2003;52(8):1085-1089.
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.
PMCID: PMC1773757  PMID: 12865263
gastro-oesophageal reflux disease; twin study; heritability; genetics
23.  Relation between insulin-like growth factor-I concentrations, osteoarthritis, bone density, and fractures in the general population: the Chingford study. 
Annals of the Rheumatic Diseases  1996;55(12):870-874.
OBJECTIVE: To assess the association between serum insulin-like growth factor-I (IGF-1) concentrations and osteoarthritis, and bone mineral density, and fractures in a large group of middle aged women from the general population. METHODS: 761 women aged 44-64 years from the Chingford study had serum IGF-I concentrations measured; hand, hip, spine, and anteroposterior weight bearing knee radiographs taken; and dual energy x ray absorptiometry (DEXA) scans of the hip and spine. X rays were scored using the Kellgren and Lawrence system. In addition knee x rays were scored using a standard atlas for individual features of osteophytes and joint space narrowing (both graded 0-3). IGF-I concentrations were adjusted for the effects of age. RESULTS: In the osteoarthritis analysis results were compared to a constant group of 155 subjects with no evidence of osteoarthritis at any site. There was no significant difference in serum IGF-I between these subjects and 606 subjects with osteoarthritis at any site. When individual sites were analysed, serum IGF-I was higher in those cases with more severe bilateral knee osteoarthritis and in those with distal interphalangeal (DIP) joint disease. There was no significant association between serum IGF-I and other forms of osteoarthritis or milder forms of knee osteoarthritis. There was no correlation between IGF-I concentrations and bone mineral density at the spine or hip, nor any difference between IGF-I concentrations in subjects with and without a history of non-traumatic fracture [22.8 (SD 6.6) v 23.1 (SD 6.6) nmol litre-1, P = 0.6] CONCLUSIONS: There is a modest association between IGF-I concentrations and the development of DIP osteoarthritis and more severe or bilateral knee joint osteoarthritis in women from the normal population, but no association with other forms of osteoarthritis, bone density, or fractures.
PMCID: PMC1010336  PMID: 9014579
24.  Association between birth weight and adult blood pressure in twins: historical cohort study 
BMJ : British Medical Journal  1999;319(7221):1330-1333.
To evaluate the associations in twins between within pair differences in birth weight and subsequent blood pressures as adults thereby removing the impact of potential parental confounding variables.
Historical cohort study.
St Thomas's UK adult twin register, June 1992 to September 1995.
492 pairs of female twins (mean age 54 years).
Main outcome measures
Mean within pair differences in adult blood pressure in each of four strata of within pair differences in birth weight (0, 1-500 g, 501-1000 g, >1000 g). Differences in blood pressure were analysed before and after adjustment for potential confounders between adult twins, after exclusion of those twin pairs including at least one twin taking antihypertensive drugs, and by zygosity.
Reported mean birth weights of heavier and lighter twins were 2.51 (SD 0.61) v 2.12 (0.59) kg respectively. A graded inverse relation between strata of within pair differences in birth weight and differences in adult blood pressure was apparent, with an adjusted blood pressure range of 8.7/5.1 mm Hg across the four strata (test for trend: systolic, P=0.05; diastolic, P=0.09). After excluding those women taking antihypertensive drugs the significance of the association was similar (systolic, P=0.04; diastolic, P=0.10). When differences in blood pressure were stratified for zygosity similar but non-significant trends were apparent.
It would seem that birth weight is inversely associated with adult blood pressure and that this association is independent of parental confounding variables probably including, in view of the findings in monozygotic twins, genetic factors. The observed blood pressure differences are likely to result from retarded intrauterine growth due to placental dysfunction rather than inadequate maternal nutrition.
Key messagesAmong adult twins, blood pressures tend to be lower among those twins who were heavier at birthStrata of within pair birthweight differences of twins show a graded inverse relation with adult blood pressure differencesMonozygotic and dizygotic twins show a similar inverse association between birthweight differences and adult blood pressure differencesThe inverse association between birth weight and adult blood pressure is independent of parental confounding variables
PMCID: PMC28278  PMID: 10567135
25.  Genetics of osteoarthritis. 
Annals of the Rheumatic Diseases  1996;55(9):665-667.
The available evidence suggests that genetic factors have a major role in osteoarthritis. It has been believed for over 50 years that a strong genetic component to certain forms of osteoarthritis is present. This genetic influence has now been estimated to be up to 65% in a recent twin study. The nature of the genetic influence in osteoarthritis is speculative and may involve either a structural defect (that is, collagen), alterations in cartilage or bone metabolism, or alternatively a genetic influence on a known risk factor for osteoarthritis such as obesity. Exciting work has showed that mutations in the collagen type 2 are important in some rare, familial forms of osteoarthritis. Further work is needed on isolating the gene or genes involved in the pathogenesis of this common, disabling condition.
PMCID: PMC1010272  PMID: 8882145

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