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1.  Maternal gestational vitamin D supplementation and offspring bone health: a multicentre randomised, double-blind, placebo-controlled trial (MAVIDOS) 
Background
Maternal vitamin D status has been associated with lower bone mass of the offspring in many, but not all, observational studies. However, proof that maternal vitamin D repletion during pregnancy improves offspring bone mass is lacking.
Methods
Between 06/10/2008 and 11/02/2014, we randomly assigned pregnant women with a serum 25-hydroxyvitamin D [25(OH)D] 25-100nmol/l at 12 weeks’ gestation to either 1000IU/day cholecalciferol or matched placebo from 14 weeks’ gestation until delivery. Serum 25(OH)D was measured at 14 and 34 weeks’ gestation. Neonatal whole body bone mineral, assessed within 2 weeks after birth (n=665) by dual-energy X-ray absorptiometry (DXA), was the primary outcome. Secondary pre-specified analyses explored interactions with study centre, maternal ethnicity, parity, compliance, protocol completion, baseline BMI, baseline 25(OH)D and change in 25(OH)D from 14 to 34 weeks; and offspring sex and season of birth.
Findings
We found no difference in neonatal whole body bone mineral content (BMC) of infants born to mothers randomised to 1000IU/day cholecalciferol compared with infants born to mothers randomised to placebo [61.6g (95%CI: 60.3, 62.8g) vs 60.5g (95%CI: 59.3, 61.7g) respectively, p=0.21].
Interpretation
Supplementation of mothers with 1000IU/day cholecalciferol during pregnancy did not lead to increased offspring whole body BMC compared with placebo.
doi:10.1016/S2213-8587(16)00044-9
PMCID: PMC4843969  PMID: 26944421
Vitamin D; cholecalciferol; supplementation; trial; osteoporosis; epidemiology; DXA; pregnancy; neonate
2.  Maternal serum retinol and β-carotene concentrations and neonatal bone mineralization: results from the Southampton Women’s Survey cohort1 
Background: Studies in older adults and animals have suggested contrasting relations between bone health and different vitamin A compounds. To our knowledge, the associations between maternal vitamin A status and offspring bone development have not previously been elucidated.
Objective: We examined the associations between maternal serum retinol and β-carotene concentrations during late pregnancy and offspring bone mineralization assessed at birth with the use of dual-energy X-ray absorptiometry.
Design: In the Southampton Women’s Survey mother-offspring birth cohort, maternal health, lifestyle, and diet were assessed prepregnancy and at 11 and 34 wk of gestation. In late pregnancy, maternal serum retinol and β-carotene concentrations were measured. Offspring total body bone mineral density (BMD), bone mineral content (BMC), and bone area (BA) were measured within 2 wk after birth.
Results: In total, 520 and 446 mother-offspring pairs had measurements of maternal serum retinol and β-carotene, respectively. Higher maternal serum retinol in late pregnancy was associated with lower offspring total body BMC (β = −0.10 SD/SD; 95% CI: −0.19, −0.02; P = 0.020) and BA (β = −0.12 SD/SD; 95% CI: −0.20, −0.03; P = 0.009) but not BMD. Conversely, higher maternal serum β-carotene concentrations in late pregnancy were associated with greater total body BMC (β = 0.12 SD/SD; 95% CI: 0.02, 0.21; P = 0.016) and BA (β = 0.12 SD/SD; 95% CI: 0.03, 0.22; P = 0.010) but not BMD.
Conclusions: Maternal serum retinol and β-carotene concentrations had differing associations with offspring bone size and growth at birth: retinol was negatively associated with these measurements, whereas β-carotene was positively associated. These findings highlight the need for further investigation of the effects of maternal retinol and carotenoid status on offspring bone development.
doi:10.3945/ajcn.116.130146
PMCID: PMC5039809  PMID: 27629051
bone development; epidemiology; pregnancy; vitamin A; retinol; β-carotene
3.  Clustering of lifestyle risk factors and poor physical function in older adults: The Hertfordshire Cohort Study 
OBJECTIVES
To examine the relationship between number of lifestyle risk factors (out of: low physical activity, poor diet, obesity and smoking) and physical function in older community-dwelling men and women.
DESIGN
Cross-sectional study, Hertfordshire, UK
PARTICIPANTS
1682 men and 1540 women aged 59-73 years
MEASUREMENTS
Physical activity was assessed by administered questionnaire and a score derived (0-100); low activity was defined as a score ≤50. Diet was assessed by food frequency questionnaire; diet quality was assessed according to a score for a principal component analysis-defined ‘healthy’ dietary pattern. Poor diet was categorised as a dietary pattern score in the lowest quarter of the distribution. Obesity was defined as BMI ≥30kg/m2. Physical function was assessed by self-report (SF-36 PF); poor function was defined as a score in lowest quarter of the distribution. A sub-group of participants had objective assessments of physical function (timed up-and-go, timed 3-m walk, chair rises, one-legged standing balance).
RESULTS
There were graded positive increases in prevalence of poor self-reported physical function in both men and women, in parallel with increasing number of risk factors (men: adjusted odds ratio for 3 or 4 risk factors in comparison with none: 3.79 (95% CI 2.31 to 6.21); women: adjusted odds ratio 5.37 (95% CI 2.66 to10.84). With the exception of balance, the objective assessments also showed graded relationships with increasing number of risk factors, such that a greater number of risk factors was associated with poorer physical function.
CONCLUSION
These modifiable lifestyle risk factors are linked to marked differences in risk of poorer physical function in older adults. Efforts to encourage healthy lifestyles have the potential to improve physical function and to promote healthier ageing.
doi:10.1111/jgs.12457
PMCID: PMC4930137  PMID: 24083502
older adults; SF-36; physical function; lifestyle; risk factor
4.  Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12 
Thorax  2016;71(6):501-509.
Background
Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants.
Objective
To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation.
Methods
3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10−5) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays.
Results
Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10−6, preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10−6). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10−6). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10−7).
Conclusions
This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.
doi:10.1136/thoraxjnl-2015-207876
PMCID: PMC4893124  PMID: 26917578
COPD epidemiology; Tobacco and the lung
5.  Lean mass and fat mass have differing associations with bone microarchitecture assessed by high resolution peripheral quantitative computed tomography in men and women from the Hertfordshire Cohort Study 
Bone  2015;81:145-151.
Understanding the effects of muscle and fat on bone is increasingly important in the optimisation of bone health. We explored relationships between bone microarchitecture and body composition in older men and women from the Hertfordshire Cohort Study. 175 men and 167 women aged 72-81 years were studied. High resolution peripheral quantitative computed tomography (HRpQCT) images (voxel size 82μm) were acquired from the non-dominant distal radius and tibia with a Scanco XtremeCT scanner. Standard morphological analysis was performed for assessment of macrostructure, densitometry, cortical porosity and trabecular microarchitecture. Body composition was assessed using dual energy x-ray absorptiometry (DXA) (Lunar Prodigy Advanced). Lean mass index (LMI) was calculated as lean mass divided by height squared and fat mass index (FMI) as fat mass divided by height squared. The mean (standard deviation) age in men and women was 76 (3) years. In univariate analyses, tibial cortical area (p<0.01), cortical thickness (p<0.05) and trabecular number (p<0.01) were positively associated with LMI and FMI in both men and women. After mutual adjustment, relationships between cortical area and thickness were only maintained with LMI [tibial cortical area, β(95% confidence interval (CI)): men 6.99 (3.97,10.01), women 3.59 (1.81,5.38)] whereas trabecular number and density were associated with FMI. Interactions by sex were found, including for the relationships of LMI with cortical area and FMI with trabecular area in both the radius and tibia (p<0.05). In conclusion, LMI and FMI appeared to show independent relationships with bone microarchitecture. Further studies are required to confirm the direction of causality and explore the mechanisms underlying these tissue-specific associations.
doi:10.1016/j.bone.2015.07.013
PMCID: PMC4641321  PMID: 26187195
muscle; bone microarchitecture; fat; HRpQCT; mechanostat; epidemiology
7.  Differences in childhood adiposity influence upper limb fracture site 
Bone  2015;79:88-93.
Introduction
Although it has been suggested that overweight and obese children have an increased risk of fracture, recent studies in post-menopausal women have shown that the relationship between obesity and fracture risk varies by fracture site. We therefore assessed whether adiposity and overweight/obesity prevalence differed by upper limb fracture site in children.
Methods
Height, weight, BMI, triceps and subscapular skinfold thickness (SFT) were measured in children aged 3-18 years with an acute upper limb fracture. Data was compared across three fracture sites (hand, forearm and upper arm/shoulder [UA]), and to published reference data.
Results
401 children (67.1% male, median age 11.71 years (range 3.54-17.27 years) participated. 34.2%, 50.6% and 15.2% had fractures of the hand, forearm and UA, respectively. Children with forearm fractures had higher weight, BMI and SFT z-scores than those with UA fractures (p<0.05 for all). SFT z-scores were also higher in children with forearm fractures compared to hand fractures, but children withor hand and UA fractures did not differ. Overweight and obesity prevalence was higher in children with forearm fractures (37.6%) than those with UA fractures (19.0%, p=0.009). This prevalence was also higher than the published United Kingdom population prevalence (27.9%, p=0.003), whereas that of children with either UA (p=0.13) or hand fractures (29.1%, p=0.76) did not differ. The differences in anthropometry and overweight/obesity were similar for boys, but not present in girls.
Conclusion
Measurements of adiposity and the prevalence of overweight/obesity differ by fracture site in children, and in particular boys, with upper limb fractures.
doi:10.1016/j.bone.2015.05.031
PMCID: PMC4521307  PMID: 26027507
fracture; adiposity; obesity; children
9.  How well do radiographic, clinical and self-reported diagnoses of knee osteoarthritis agree? Findings from the Hertfordshire cohort study 
SpringerPlus  2015;4:177.
Objective
Epidemiological studies of knee osteoarthritis (OA) have often used a radiographic definition. However, the clinical syndrome of OA is influenced by a broad range of factors in addition to the structural changes required for radiographic OA. Hence more recently several studies have adopted a clinical or self-reported approach to OA diagnosis rather than a radiographic approach. The aim of this study was to investigate agreement between radiographic OA and the clinical and self-reported diagnoses of OA.
Design
Data were available for 199 men and 196 women in the Hertfordshire Cohort Study (HCS), UK. Participants completed a questionnaire detailing self-reported OA. Clinical OA was defined based on American College of Rheumatology (ACR) criteria. Knee radiographs were taken and graded for overall Kellgren and Lawrence (K&L) score.
Results
The mean (standard deviation (SD)) age of study participants was 75.2 (2.6) years and almost identical proportions of men and women. The prevalence of knee OA differed depending on the method employed for diagnosis; 21% of the study participants self-reported knee OA, 18% of the participants had clinical knee OA and 42% of the participants had radiographic OA. Of those 72 study participants with a self-reported diagnosis of knee OA 52 (72%) had a radiographic diagnosis of knee OA, while 66% (39 out of 59) of study participants with clinical knee OA had a diagnosis of radiographic knee OA. However 58% of those participants diagnosed with radiographic OA did not have either self-reported knee OA or a diagnosis of clinical OA. Therefore in comparison with the radiographic definition of OA, both the clinical and self-report definitions had high specificity (91.5% & 91.5% respectively) and low sensitivity (24.5% and 32.7% respectively).
Conclusion
There is modest agreement between the radiographic, clinical and self-report methods of diagnosis of knee OA.
doi:10.1186/s40064-015-0949-z
PMCID: PMC4408304  PMID: 25932366
Osteoarthritis; Epidemiology; Agreement; Radiographic; Definition
10.  Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region 
Annals of the Rheumatic Diseases  2012;72(3):427-436.
Background and objectives
Chronic widespread pain (CWP) is a common disorder affecting ∼10% of the general population and has an estimated heritability of 48–52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP.
Methods
We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain.
Results
The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10−7) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10−8, I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10−4).
Conclusions
We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.
doi:10.1136/annrheumdis-2012-201742
PMCID: PMC3691951  PMID: 22956598
Gene Polymorphism; Fibromyalgis/Pain Syndromes; Epidemiology
11.  Understanding NHS hospital admissions in England: linkage of Hospital Episode Statistics to the Hertfordshire Cohort Study 
Age and ageing  2014;43(5):653-660.
Background
Concern over the sustainability of the National Health Service is often focussed on rising numbers of hospital admissions, particularly among older people. Hospital admissions are enumerated routinely by the Hospital Episode Statistics (HES) Service, but published data do not allow individual level service use to be explored. This study linked information on Hertfordshire Cohort Study (HCS) participants with HES inpatient data. with the objective of describing patterns and predictors of admissions among individuals.
Methods
2997 community-dwelling men and women aged 59-73 years completed a baseline HCS assessment between 1998 and 2004; HES and mortality data to 31/03/2010 were linked with the HCS database. This paper describes patterns of hospital use among the cohort at both the admission and individual person level.
Results
The cohort experienced 8741 admissions; rates were 391 per 1000 person-years among men (95%CI 380, 402) and 327 among women (95%CI 316,338), p<0.0001 for gender difference. 1187 men (75%) and 981 women (69%) were admitted to hospital at least once; among these, median numbers of admissions were 3 in men (IQR 1,6) and 2 in women (IQR 1,5). 48% of those ever admitted had experienced an emergency admission and 70% had been admitted overnight.
Discussion
It is possible to link routinely collected HES data with detailed information from a cohort study. Hospital admission is common among community dwelling ‘young-old’ men and women. These linked datasets will facilitate research into lifecourse determinants of hospital admission and inform strategies to manage demand on the National Health Service.
doi:10.1093/ageing/afu020
PMCID: PMC4151283  PMID: 24598084
hospital admissions; older people; hospital episode statistics; data linkage; healthcare burden
12.  Processed meat consumption and lung function: modification by antioxidants and smoking 
The European respiratory journal  2013;43(4):972-982.
Unhealthy dietary patterns are associated with poorer lung function. It is not known whether this is due to low consumption of antioxidant-rich fruit and vegetables, or is a consequence of higher intakes of harmful dietary constituents such as processed meat.
We examined the individual and combined associations of processed meat, fruit and vegetable consumption and dietary total antioxidant capacity (TAC) with lung function among 1551 men and 1391 women in the Hertfordshire Cohort Study, UK. Diet was assessed by food frequency questionnaire.
After controlling for confounders, processed meat consumption was negatively associated with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC in men and women, while fruit and vegetable consumption and dietary TAC were positively associated with FEV1 and FVC, but not FEV1/FVC. In men the negative association between processed meat consumption and FEV1 was more marked in those who had low fruit and vegetable consumption (Pinteraction=0.035), and low dietary TAC (Pinteraction=0.025). The deficit in FEV1/FVC associated with processed meat consumption was larger in men who smoked (Pinteraction=0.022).
Higher processed meat consumption is associated with poorer lung function, especially in men who have lower fruit and vegetable consumption or dietary TAC, and among current smokers.
doi:10.1183/09031936.00109513
PMCID: PMC3956622  PMID: 24176995
Dietary balance; total antioxidant capacity; fruit and vegetables; processed meat; lung function
13.  Fetal and infant growth predict hip geometry at six years old: Findings from the Southampton Women’s Survey 
Pediatric research  2013;74(4):450-456.
Background
We investigated relationships between early growth and proximal femoral geometry at age six years in a prospective population-based cohort, the Southampton Women’s Survey.
Methods
In 493 mother-offspring pairs we assessed linear size (individual measure dependent on developmental stage) using high-resolution ultrasound at 11, 19 and 34 weeks gestation (femur length) and at birth, 1, 2, 3, 4 and 6 years (crown-heel length/height). Standard deviation (SD)-scores were created and conditional regression modelling generated mutually independent growth variables. Children underwent hip DXA (Dual X-ray absorptiometry) at 6 years (Hologic Discovery, Hologic Inc., MA); hip structure analysis software yielded measures of geometry and strength.
Results
There were strong associations between early linear growth and femoral neck section modulus (Z) at 6 years, with the strongest relationships observed for femur growth from 19-34 weeks gestation (β=0.26 cm3/SD, p<0.0001), and for height growth from birth to 1 year (β=0.25 cm3/SD, p<0.0001) and 1-2 years (β=0.33 cm3/SD, p<0.0001), with progressively weaker relationships over years 3 (β=0.23 cm3/SD, p=0.0002) and 4 (β=0.10 cm3/SD, p=0.18).
Conclusions
These results demonstrate that growth before age 3 years predicts proximal femoral geometry at six years old. The data suggest critical periods in which there is capacity for long term influence on the later skeletal growth trajectory.
doi:10.1038/pr.2013.119
PMCID: PMC3797011  PMID: 23857297
14.  Different Indices of Fetal Growth Predict Bone Size and Volumetric Density at 4 Years of Age 
We have demonstrated previously that higher birth weight is associated with greater peak and later-life bone mineral content and that maternal body build, diet, and lifestyle influence prenatal bone mineral accrual. To examine prenatal influences on bone health further, we related ultrasound measures of fetal growth to childhood bone size and density. We derived Z-scores for fetal femur length and abdominal circumference and conditional growth velocity from 19 to 34 weeks’ gestation from ultrasound measurements in participants in the Southampton Women’s Survey. A total of 380 of the offspring underwent dual-energy X-ray absorptiometry (DXA) at age 4 years [whole body minus head bone area (BA), bone mineral content (BMC), areal bone mineral density (aBMD), and estimated volumetric BMD (vBMD)]. Volumetric bone mineral density was estimated using BMC adjusted for BA, height, and weight. A higher velocity of 19- to 34-week fetal femur growth was strongly associated with greater childhood skeletal size (BA: r = 0.30, p < .0001) but not with volumetric density (vBMD: r = 0.03, p = .51). Conversely, a higher velocity of 19- to 34-week fetal abdominal growth was associated with greater childhood volumetric density (vBMD: r = 0.15, p = .004) but not with skeletal size (BA: r = 0.06, p = .21). Both fetal measurements were positively associated with BMC and aBMD, indices influenced by both size and density. The velocity of fetal femur length growth from 19 to 34 weeks’ gestation predicted childhood skeletal size at age 4 years, whereas the velocity of abdominal growth (a measure of liver volume and adiposity) predicted volumetric density. These results suggest a discordance between influences on skeletal size and volumetric density.
doi:10.1359/jbmr.091022
PMCID: PMC3793299  PMID: 20437610
EPIDEMIOLOGY; OSTEOPOROSIS; PROGRAMMING; DEVELOPMENTAL ORIGINS
15.  Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region 
Annals of the rheumatic diseases  2012;72(3):427-436.
Objectives
Chronic widespread pain (CWP) is a common disorder affecting ~10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP.
Methods
We conducted a GWAS meta-analysis in 1,308 female CWP cases and 5,791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1,480 CWP cases and 7,989 controls (P<1×10−5). Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain.
Results
The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of CCT5 and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (MAF=43%; OR=1.30, 95%CI=1.19-1.42, P=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95%CI=1.10-1.24, P=4.7×10−7) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95%CI=1.14-1.32, P=3.4×10−8, I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (P>7.7×10−4).
Conclusions
We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.
doi:10.1136/annrheumdis-2012-201742
PMCID: PMC3691951  PMID: 22956598
Gene Polymorphism; Fibromyalgia/Pain Syndromes; Epidemiology
16.  The relationship between depression, anxiety and cardiovascular disease: findings from the Hertfordshire Cohort Study 
Journal of affective disorders  2013;150(1):84-90.
Background
Previous studies suggest a link between depression, anxiety and cardiovascular disease (CVD). The aim of the study was to determine the relationship between depressive and anxiety symptoms and CVD in a population based cohort.
Methods
1,578 men and 1,417 women from the Hertfordshire Cohort Study were assessed for CVD at baseline and after 5.9±1.4 years. Depressive and anxiety symptoms were measured using the HADS Scale.
Results
Baseline HAD-D score, but not HAD-A, was significantly associated with baseline plasma triglycerides, glucose and insulin resistance (men only) and HDL cholesterol (women only).
After adjustment for CVD risk factors, higher baseline HAD-D scores were associated with increased odds ratios for CVD (men: 1.162 [95% CI 1.096 - 1.231]; women: 1.107 [1.038 – 1.181]). Higher HAD-A scores associated with increased CVD in men only.
High HAD-D scores predicted incident CVD (adjusted OR 1.130 [1.034 - 1.235]), all-cause mortality (adjusted HR 1.081, [1.012 – 1.154]) and cardiovascular mortality (adjusted HR 1.109 [1.002 - 1.229]) in men but not in women.
Limitations
The use of a self-report measure of depressive and anxiety symptoms, ‘healthy’ responder bias and the low number of cardiovascular events are all limitations.
Conclusions
Depressive and anxiety symptoms are commoner in people with CVD. These symptoms are independent predictors of CVD in men. Although HAD-D score was significantly associated with several cardiovascular risk factors, this did not fully explain the association between HAD-D and CVD.
doi:10.1016/j.jad.2013.02.026
PMCID: PMC3729346  PMID: 23507368
Depression; anxiety; cardiovascular disease; epidemiology; population studies
17.  Symptoms of anxiety or depression and risk of fracture in older people: The Hertfordshire Cohort Study 
Archives of osteoporosis  2012;7(0):59-65.
Background
Use of psychotropic drugs has been linked with an increased risk of fracture in older people, but there are indications that the conditions for which these drugs were prescribed may themselves influence fracture risk.
Aim
To investigate the relation between symptoms of anxiety and depression and risk of fracture in older people.
Design
Prospective cohort study.
Methods
1087 men and 1050 women aged 59-73 years completed the Hospital Anxiety and Depression Scale (HADS). Data on incident fracture during an average follow-up period of 5.6 years was collected through interview and a postal questionnaire.
Results
Compared to men with no or few symptoms of anxiety (score ≤7 on the HADS anxiety subscale), men with probable anxiety (score ≥11) had an increased risk of fracture: after adjustment for age and potential confounding factors, the odds ratio (OR) (95% confidence interval) was 4.03 (1.55, 10.5). Men with possible anxiety (score 8-10) did not have an increased risk of fracture: multivariate-adjusted OR was 1.04 (0.36, 3.03). There were no associations between levels of anxiety and fracture risk in women. Few men or women had probable depression at baseline (score ≥11 on the HADS depression subscale). Among men with possible depression (score 8-10) there was an increased risk of fracture that was of borderline significance: multivariate-adjusted OR 3.57 (0.99, 12.9). There was no association between possible depression and fracture risk in women.
Conclusions
High levels of anxiety in older men may increase their risk of fracture. Future research needs to replicate this finding in other populations and investigate the underlying mechanisms.
doi:10.1007/s11657-012-0080-5
PMCID: PMC3736098  PMID: 23225282
anxiety; depression; fracture
18.  European project on osteoarthritis: design of a six-cohort study on the personal and societal burden of osteoarthritis in an older European population 
Background
Osteoarthritis (OA), the most common form of arthritis, is a major contributor to functional impairment and loss of independence in older persons. The European Project on OSteoArthritis (EPOSA) is a collaborative study involving six European cohort studies on ageing. This project focuses on the personal and societal burden and its determinants of osteoarthritis. This paper describes the design of the project, and presents some descriptive analyses on selected variables across countries.
Methods/design
EPOSA is an observational study including pre-harmonized data from European cohort studies (Germany, Italy, the Netherlands, Spain, Sweden and the United Kingdom) on older community-dwelling persons aged 65 to 85 years. In total, 2942 persons were included in the baseline study with a mean age of 74.2 years (SD 5.1), just over half were women (51,9%). The baseline assessment was conducted by a face-to-face interview followed by a clinical examination. Measures included physical, cognitive, psychological and social functioning, lifestyle behaviour, physical environment, wellbeing and care utilisation. The clinical examination included anthropometry, muscle strength, physical performance and OA exam. A follow-up assessment was performed 12–18 months after baseline.
Discussion
The EPOSA study is the first population-based study including a clinical examination of OA, using pre-harmonized data across European countries. The EPOSA study provides a unique opportunity to study the determinants and consequences of OA in general populations of older persons, including both care-seeking and non care-seeking persons.
doi:10.1186/1471-2474-14-138
PMCID: PMC3637520  PMID: 23597054
19.  Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture 
Estrada, Karol | Styrkarsdottir, Unnur | Evangelou, Evangelos | Hsu, Yi-Hsiang | Duncan, Emma L | Ntzani, Evangelia E | Oei, Ling | Albagha, Omar M E | Amin, Najaf | Kemp, John P | Koller, Daniel L | Li, Guo | Liu, Ching-Ti | Minster, Ryan L | Moayyeri, Alireza | Vandenput, Liesbeth | Willner, Dana | Xiao, Su-Mei | Yerges-Armstrong, Laura M | Zheng, Hou-Feng | Alonso, Nerea | Eriksson, Joel | Kammerer, Candace M | Kaptoge, Stephen K | Leo, Paul J | Thorleifsson, Gudmar | Wilson, Scott G | Wilson, James F | Aalto, Ville | Alen, Markku | Aragaki, Aaron K | Aspelund, Thor | Center, Jacqueline R | Dailiana, Zoe | Duggan, David J | Garcia, Melissa | Garcia-Giralt, Natàlia | Giroux, Sylvie | Hallmans, Göran | Hocking, Lynne J | Husted, Lise Bjerre | Jameson, Karen A | Khusainova, Rita | Kim, Ghi Su | Kooperberg, Charles | Koromila, Theodora | Kruk, Marcin | Laaksonen, Marika | Lacroix, Andrea Z | Lee, Seung Hun | Leung, Ping C | Lewis, Joshua R | Masi, Laura | Mencej-Bedrac, Simona | Nguyen, Tuan V | Nogues, Xavier | Patel, Millan S | Prezelj, Janez | Rose, Lynda M | Scollen, Serena | Siggeirsdottir, Kristin | Smith, Albert V | Svensson, Olle | Trompet, Stella | Trummer, Olivia | van Schoor, Natasja M | Woo, Jean | Zhu, Kun | Balcells, Susana | Brandi, Maria Luisa | Buckley, Brendan M | Cheng, Sulin | Christiansen, Claus | Cooper, Cyrus | Dedoussis, George | Ford, Ian | Frost, Morten | Goltzman, David | González-Macías, Jesús | Kähönen, Mika | Karlsson, Magnus | Khusnutdinova, Elza | Koh, Jung-Min | Kollia, Panagoula | Langdahl, Bente Lomholt | Leslie, William D | Lips, Paul | Ljunggren, Östen | Lorenc, Roman S | Marc, Janja | Mellström, Dan | Obermayer-Pietsch, Barbara | Olmos, José M | Pettersson-Kymmer, Ulrika | Reid, David M | Riancho, José A | Ridker, Paul M | Rousseau, François | Slagboom, P Eline | Tang, Nelson LS | Urreizti, Roser | Van Hul, Wim | Viikari, Jorma | Zarrabeitia, María T | Aulchenko, Yurii S | Castano-Betancourt, Martha | Grundberg, Elin | Herrera, Lizbeth | Ingvarsson, Thorvaldur | Johannsdottir, Hrefna | Kwan, Tony | Li, Rui | Luben, Robert | Medina-Gómez, Carolina | Palsson, Stefan Th | Reppe, Sjur | Rotter, Jerome I | Sigurdsson, Gunnar | van Meurs, Joyce B J | Verlaan, Dominique | Williams, Frances MK | Wood, Andrew R | Zhou, Yanhua | Gautvik, Kaare M | Pastinen, Tomi | Raychaudhuri, Soumya | Cauley, Jane A | Chasman, Daniel I | Clark, Graeme R | Cummings, Steven R | Danoy, Patrick | Dennison, Elaine M | Eastell, Richard | Eisman, John A | Gudnason, Vilmundur | Hofman, Albert | Jackson, Rebecca D | Jones, Graeme | Jukema, J Wouter | Khaw, Kay-Tee | Lehtimäki, Terho | Liu, Yongmei | Lorentzon, Mattias | McCloskey, Eugene | Mitchell, Braxton D | Nandakumar, Kannabiran | Nicholson, Geoffrey C | Oostra, Ben A | Peacock, Munro | Pols, Huibert A P | Prince, Richard L | Raitakari, Olli | Reid, Ian R | Robbins, John | Sambrook, Philip N | Sham, Pak Chung | Shuldiner, Alan R | Tylavsky, Frances A | van Duijn, Cornelia M | Wareham, Nick J | Cupples, L Adrienne | Econs, Michael J | Evans, David M | Harris, Tamara B | Kung, Annie Wai Chee | Psaty, Bruce M | Reeve, Jonathan | Spector, Timothy D | Streeten, Elizabeth A | Zillikens, M Carola | Thorsteinsdottir, Unnur | Ohlsson, Claes | Karasik, David | Richards, J Brent | Brown, Matthew A | Stefansson, Kari | Uitterlinden, André G | Ralston, Stuart H | Ioannidis, John P A | Kiel, Douglas P | Rivadeneira, Fernando
Nature genetics  2012;44(5):491-501.
Bone mineral density (BMD) is the most important predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and East Asian ancestry. We tested the top-associated BMD markers for replication in 50,933 independent subjects and for risk of low-trauma fracture in 31,016 cases and 102,444 controls. We identified 56 loci (32 novel)associated with BMD atgenome-wide significant level (P<5×10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal-stem-cell differentiation, endochondral ossification and the Wnt signalling pathways. However, we also discovered loci containing genes not known to play a role in bone biology. Fourteen BMD loci were also associated with fracture risk (P<5×10−4, Bonferroni corrected), of which six reached P<5×10−8 including: 18p11.21 (C18orf19), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
doi:10.1038/ng.2249
PMCID: PMC3338864  PMID: 22504420
20.  Epidemiology of hip fracture: Worldwide geographic variation 
Indian Journal of Orthopaedics  2011;45(1):15-22.
Osteoporosis is a major health problem, especially in elderly populations, and is associated with fragility fractures at the hip, spine, and wrist. Hip fracture contributes to both morbidity and mortality in the elderly. The demographics of world populations are set to change, with more elderly living in developing countries, and it has been estimated that by 2050 half of hip fractures will occur in Asia. This review conducted using the PubMed database describes the incidence of hip fracture in different regions of the world and discusses the possible causes of this wide geographic variation. The analysis of data from different studies show a wide geographic variation across the world, with higher hip fracture incidence reported from industrialized countries as compared to developing countries. The highest hip fracture rates are seen in North Europe and the US and lowest in Latin America and Africa. Asian countries such as Kuwait, Iran, China, and Hong Kong show intermediate hip fracture rates. There is also a north–south gradient seen in European studies, and more fractures are seen in the north of the US than in the south. The factors responsible of this variation are population demographics (with more elderly living in countries with higher incidence rates) and the influence of ethnicity, latitude, and environmental factors. The understanding of this changing geographic variation will help policy makers to develop strategies to reduce the burden of hip fractures in developing countries such as India, which will face the brunt of this problem over the coming decades.
doi:10.4103/0019-5413.73656
PMCID: PMC3004072  PMID: 21221218
Epidemiology; geographic variation; hip fracture; incidence rate; osteoporosis
21.  Six new loci associated with body mass index highlight a neuronal influence on body weight regulation 
Willer, Cristen J | Speliotes, Elizabeth K | Loos, Ruth J F | Li, Shengxu | Lindgren, Cecilia M | Heid, Iris M | Berndt, Sonja I | Elliott, Amanda L | Jackson, Anne U | Lamina, Claudia | Lettre, Guillaume | Lim, Noha | Lyon, Helen N | McCarroll, Steven A | Papadakis, Konstantinos | Qi, Lu | Randall, Joshua C | Roccasecca, Rosa Maria | Sanna, Serena | Scheet, Paul | Weedon, Michael N | Wheeler, Eleanor | Zhao, Jing Hua | Jacobs, Leonie C | Prokopenko, Inga | Soranzo, Nicole | Tanaka, Toshiko | Timpson, Nicholas J | Almgren, Peter | Bennett, Amanda | Bergman, Richard N | Bingham, Sheila A | Bonnycastle, Lori L | Brown, Morris | Burtt, Noël P | Chines, Peter | Coin, Lachlan | Collins, Francis S | Connell, John M | Cooper, Cyrus | Smith, George Davey | Dennison, Elaine M | Deodhar, Parimal | Elliott, Paul | Erdos, Michael R | Estrada, Karol | Evans, David M | Gianniny, Lauren | Gieger, Christian | Gillson, Christopher J | Guiducci, Candace | Hackett, Rachel | Hadley, David | Hall, Alistair S | Havulinna, Aki S | Hebebrand, Johannes | Hofman, Albert | Isomaa, Bo | Jacobs, Kevin B | Johnson, Toby | Jousilahti, Pekka | Jovanovic, Zorica | Khaw, Kay-Tee | Kraft, Peter | Kuokkanen, Mikko | Kuusisto, Johanna | Laitinen, Jaana | Lakatta, Edward G | Luan, Jian'an | Luben, Robert N | Mangino, Massimo | McArdle, Wendy L | Meitinger, Thomas | Mulas, Antonella | Munroe, Patricia B | Narisu, Narisu | Ness, Andrew R | Northstone, Kate | O'Rahilly, Stephen | Purmann, Carolin | Rees, Matthew G | Ridderstråle, Martin | Ring, Susan M | Rivadeneira, Fernando | Ruokonen, Aimo | Sandhu, Manjinder S | Saramies, Jouko | Scott, Laura J | Scuteri, Angelo | Silander, Kaisa | Sims, Matthew A | Song, Kijoung | Stephens, Jonathan | Stevens, Suzanne | Stringham, Heather M | Tung, Y C Loraine | Valle, Timo T | Van Duijn, Cornelia M | Vimaleswaran, Karani S | Vollenweider, Peter | Waeber, Gerard | Wallace, Chris | Watanabe, Richard M | Waterworth, Dawn M | Watkins, Nicholas | Witteman, Jacqueline C M | Zeggini, Eleftheria | Zhai, Guangju | Zillikens, M Carola | Altshuler, David | Caulfield, Mark J | Chanock, Stephen J | Farooqi, I Sadaf | Ferrucci, Luigi | Guralnik, Jack M | Hattersley, Andrew T | Hu, Frank B | Jarvelin, Marjo-Riitta | Laakso, Markku | Mooser, Vincent | Ong, Ken K | Ouwehand, Willem H | Salomaa, Veikko | Samani, Nilesh J | Spector, Timothy D | Tuomi, Tiinamaija | Tuomilehto, Jaakko | Uda, Manuela | Uitterlinden, André G | Wareham, Nicholas J | Deloukas, Panagiotis | Frayling, Timothy M | Groop, Leif C | Hayes, Richard B | Hunter, David J | Mohlke, Karen L | Peltonen, Leena | Schlessinger, David | Strachan, David P | Wichmann, H-Erich | McCarthy, Mark I | Boehnke, Michael | Barroso, Inês | Abecasis, Gonçalo R | Hirschhorn, Joel N
Nature genetics  2008;41(1):25-34.
Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 × 10−8): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
doi:10.1038/ng.287
PMCID: PMC2695662  PMID: 19079261
22.  The developmental origins of sarcopenia: using peripheral quantitative computed tomography to assess muscle size in older people 
Background
A number of studies have shown strong graded positive relationships between size at birth and grip strength and estimates of muscle mass in older people. However no studies to date have included direct measures of muscle size.
Methods
We studied 313 men and 318 women born in Hertfordshire UK between 1931 and 1939 who were still resident there and had historical records of growth in early life. Information on lifestyle was collected and participants underwent peripheral quantitative computed tomography to directly measure forearm and calf muscle size.
Results
Birth weight was positively related to forearm muscle area in the men (r = 0.24 p < 0.0001) and women (r = 0.17 p =0.003). There were similar but weaker associations between birth weight and calf muscle area in the men (r=0.13, p=0.03) and in the women (r=0.17, p=0.004). These relationships were all attenuated by adjustment for adult size.
Conclusion
We present first evidence that directly measured muscle size in older men and women is associated with size at birth. This may reflect tracking of muscle size and is important because it suggests that benefit may be gained from taking a life course approach both to understanding the aetiology of sarcopenia and to developing effective interventions.
PMCID: PMC2652118  PMID: 18772471
23.  Diet and its relationship with grip strength in community-dwelling older men and women: the Hertfordshire Cohort Study 
OBJECTIVES
To examine relationships between diet and grip strength in older men and women, and to determine whether these relationships are modified by prenatal growth.
DESIGN
Cross-sectional and retrospective cohort study
SETTING
Hertfordshire, UK
PARTICIPANTS
Two thousand, nine hundred and eighty three men and women aged 59 to 73 years who were born and still live in Hertfordshire, UK
MEASUREMENTS
Weight at birth recorded in Health Visitor ledgers. Current food and nutrient intake assessed using an administered food frequency questionnaire, grip strength was measured with a hand-held dynamometer.
RESULTS
Grip strength was positively associated with height and weight at birth, and inversely related to age (all P<0.001). Of the dietary factors considered in relation to grip strength, the most important was fatty fish consumption. An increase in grip strength of 0.43kg (95% CI 0.13 to 0.74) in men (P=0.005), and 0.48kg (95% CI 0.24 to 0.72) in women (P<0.001), was observed for each additional portion of fatty fish consumed per week. These relationships were independent of adult height, age and birth weight, each of which had additive effects on grip strength. There was no evidence of interactive effects of weight at birth and adult diet on grip strength.
CONCLUSION
These data suggest that fatty fish consumption can have an important influence on muscle function in older men and women. This raises the possibility that the anti-inflammatory actions of n-3 fatty acids may play a role in the prevention of sarcopenia.
doi:10.1111/j.1532-5415.2007.01478.x
PMCID: PMC2493054  PMID: 18005355
diet; sarcopenia; grip strength
24.  Lipid profile, obesity and bone mineral density: the Hertfordshire Cohort Study 
Background
Body mass index (BMI) and bone mineral density (BMD) are positively correlated in several studies, but few data are available relating bone density, lipid profile and anthropometric measures. We addressed these relationships in a large well-characterised cohort of men and women (The Hertfordshire Cohort Study, UK).
Methods
Four hundred and sixty five men and 448 women from Hertfordshire, UK were recruited. Information was available on demographic and lifestyle factors, anthropometric measurements, body fat percentage, fasting triglycerides, cholesterol (total, HDL, LDL), apolipoprotein (a) and apolipoprotein (b); bone mineral density (BMD) was recorded at the lumbar spine and total femur.
Results
BMD at the lumbar spine (males r=0.15, p=0.001; females r=0.14 p=0.003) and total femoral region (males r=0.18, p=0.0001; females r==0.16, p=0.0008) was related to serum triglyceride level, even after adjustment for waist hip ratio, age, social class and lifestyle factors, but not if body fat percentage was substituted for waist-hip ratio in the regression model. Fasting HDL cholesterol level was related to lumbar spine BMD in women (r=−0.15, p=0.001) and total femoral BMD (males r=−0.15, p=0.002; females r=−0.23, p<0.0001); these relationships were also attenuated by adjustment for body fat percentage but not waist hip ratio. No relationships were seen between total or LDL cholesterol with BMD.
Conclusions
We have demonstrated relationships between lipid profile and BMD that are robust to adjustment for one measure of central obesity (waist-hip ratio) but not total body fat.
doi:10.1093/qjmed/hcm023
PMCID: PMC2080690  PMID: 17449479
lipid; bone; cohort; anthropometry; obesity
25.  Growth in early life predicts bone strength in late adulthood 
Bone  2007;41(3):400-405.
Infant growth is a determinant of adult bone mass, and poor childhood growth is a risk factor for adult hip fracture. Peripheral quantitative computed tomography (pQCT) allows non-invasive assessment of bone strength. We utilised this technology to examine relationships between growth in early life and bone strength.
We studied 313 men and 318 women born in Hertfordshire between 1931-39 who were still resident there in adult life, for whom detailed early life records were available. Lifestyle factors were evaluated by questionnaire, anthropometric measurements made, and peripheral QCT examination of the radius and tibia performed (Stratec 4500).
Birthweight and conditional weight at one year were strongly related to radial and tibial length in both sexes (p<0.001), and to measures of bone strength [fracture load X, fracture load Y, polar strength strain index (SSI)] at both the radius and tibia. These relationships were robust to adjustment for age, body mass index (BMI), social class, cigarette and alcohol consumption, physical activity, dietary calcium intake, HRT use and menopausal status in women. Among men, BMI was strongly positively associated with radial (r=0.46, p=0.001) and tibial (r=0.24, p=0.006) trabecular bone mineral density (BMD). Current smoking was associated with lower cortical (radius: p=0.0002; tibia: p=0.08) and trabecular BMD (radius: p=0.08; tibia: p=0.04) in males. Similar trends of BMD with these anthropometric and lifestyle variables were seen in women but they were non-significant. Current HRT use was associated with greater female cortical (radius: p=0.0002; tibia: p=0.001) and trabecular (radius: p=0.008; tibia: p=0.04) BMD. Current HRT use was also associated with greater radial strength (polar SSI: p=0.006; fracture load x: p=0.005; fracture load y: p=0.02) in women. Women who had sustained any fracture since the age of 45 years had lower radial total (p=0.0001), cortical (p<0.005) and trabecular (p=0.0002) BMD, poorer forearm bone strength [polar SSI (p=0.006), fracture load X & Y (p=0.02)], and lower tibial total (p<0.001), cortical (p=0.008) and trabecular (p=0.0001) BMD.
We have shown that growth in early life is associated with bone size and strength in a UK population aged 65-73 years. Lifestyle factors were associated with volumetric bone density in this population.
doi:10.1016/j.bone.2007.05.007
PMCID: PMC2080691  PMID: 17599849
Bone; Strength; Density; Programming; Epidemiology

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