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1.  Grip Strength across the Life Course: Normative Data from Twelve British Studies 
PLoS ONE  2014;9(12):e113637.
Introduction
Epidemiological studies have shown that weaker grip strength in later life is associated with disability, morbidity, and mortality. Grip strength is a key component of the sarcopenia and frailty phenotypes and yet it is unclear how individual measurements should be interpreted. Our objective was to produce cross-sectional centile values for grip strength across the life course. A secondary objective was to examine the impact of different aspects of measurement protocol.
Methods
We combined 60,803 observations from 49,964 participants (26,687 female) of 12 general population studies in Great Britain. We produced centile curves for ages 4 to 90 and investigated the prevalence of weak grip, defined as strength at least 2.5 SDs below the gender-specific peak mean. We carried out a series of sensitivity analyses to assess the impact of dynamometer type and measurement position (seated or standing).
Results
Our results suggested three overall periods: an increase to peak in early adult life, maintenance through to midlife, and decline from midlife onwards. Males were on average stronger than females from adolescence onwards: males’ peak median grip was 51 kg between ages 29 and 39, compared to 31 kg in females between ages 26 and 42. Weak grip strength, defined as strength at least 2.5 SDs below the gender-specific peak mean, increased sharply with age, reaching a prevalence of 23% in males and 27% in females by age 80. Sensitivity analyses suggested our findings were robust to differences in dynamometer type and measurement position.
Conclusion
This is the first study to provide normative data for grip strength across the life course. These centile values have the potential to inform the clinical assessment of grip strength which is recognised as an important part of the identification of people with sarcopenia and frailty.
doi:10.1371/journal.pone.0113637
PMCID: PMC4256164  PMID: 25474696
2.  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
3.  Self-perceived weather sensitivity and joint pain in older people with osteoarthritis in six European countries: results from the European Project on OSteoArthritis (EPOSA) 
Background
People with osteoarthritis (OA) frequently report that their joint pain is influenced by weather conditions. This study aimed to examine whether there are differences in perceived joint pain between older people with OA who reported to be weather-sensitive versus those who did not in six European countries with different climates and to identify characteristics of older persons with OA that are most predictive of perceived weather sensitivity.
Methods
Baseline data from the European Project on OSteoArthritis (EPOSA) were used. ACR classification criteria were used to determine OA. Participants with OA were asked about their perception of weather as influencing their pain. Using a two-week follow-up pain calendar, average self-reported joint pain was assessed (range: 0 (no pain)-10 (greatest pain intensity)). Linear regression analyses, logistic regression analyses and an independent t-test were used. Analyses were adjusted for several confounders.
Results
The majority of participants with OA (67.2%) perceived the weather as affecting their pain. Weather-sensitive participants reported more pain than non-weather-sensitive participants (M = 4.1, SD = 2.4 versus M = 3.1, SD = 2.4; p < 0.001). After adjusting for several confounding factors, the association between self-perceived weather sensitivity and joint pain remained present (B = 0.37, p = 0.03). Logistic regression analyses revealed that women and more anxious people were more likely to report weather sensitivity. Older people with OA from Southern Europe were more likely to indicate themselves as weather-sensitive persons than those from Northern Europe.
Conclusions
Weather (in)stability may have a greater impact on joint structures and pain perception in people from Southern Europe. The results emphasize the importance of considering weather sensitivity in daily life of older people with OA and may help to identify weather-sensitive older people with OA.
doi:10.1186/1471-2474-15-66
PMCID: PMC3996041  PMID: 24597710
Europe; Joint pain; Older people; Osteoarthritis; Weather sensitivity
4.  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
5.  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
6.  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
7.  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
8.  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
9.  No Interactions Between Previously Associated 2-Hour Glucose Gene Variants and Physical Activity or BMI on 2-Hour Glucose Levels 
Scott, Robert A. | Chu, Audrey Y. | Grarup, Niels | Manning, Alisa K. | Hivert, Marie-France | Shungin, Dmitry | Tönjes, Anke | Yesupriya, Ajay | Barnes, Daniel | Bouatia-Naji, Nabila | Glazer, Nicole L. | Jackson, Anne U. | Kutalik, Zoltán | Lagou, Vasiliki | Marek, Diana | Rasmussen-Torvik, Laura J. | Stringham, Heather M. | Tanaka, Toshiko | Aadahl, Mette | Arking, Dan E. | Bergmann, Sven | Boerwinkle, Eric | Bonnycastle, Lori L. | Bornstein, Stefan R. | Brunner, Eric | Bumpstead, Suzannah J. | Brage, Soren | Carlson, Olga D. | Chen, Han | Chen, Yii-Der Ida | Chines, Peter S. | Collins, Francis S. | Couper, David J. | Dennison, Elaine M. | Dowling, Nicole F. | Egan, Josephine S. | Ekelund, Ulf | Erdos, Michael R. | Forouhi, Nita G. | Fox, Caroline S. | Goodarzi, Mark O. | Grässler, Jürgen | Gustafsson, Stefan | Hallmans, Göran | Hansen, Torben | Hingorani, Aroon | Holloway, John W. | Hu, Frank B. | Isomaa, Bo | Jameson, Karen A. | Johansson, Ingegerd | Jonsson, Anna | Jørgensen, Torben | Kivimaki, Mika | Kovacs, Peter | Kumari, Meena | Kuusisto, Johanna | Laakso, Markku | Lecoeur, Cécile | Lévy-Marchal, Claire | Li, Guo | Loos, Ruth J.F. | Lyssenko, Valeri | Marmot, Michael | Marques-Vidal, Pedro | Morken, Mario A. | Müller, Gabriele | North, Kari E. | Pankow, James S. | Payne, Felicity | Prokopenko, Inga | Psaty, Bruce M. | Renström, Frida | Rice, Ken | Rotter, Jerome I. | Rybin, Denis | Sandholt, Camilla H. | Sayer, Avan A. | Shrader, Peter | Schwarz, Peter E.H. | Siscovick, David S. | Stančáková, Alena | Stumvoll, Michael | Teslovich, Tanya M. | Waeber, Gérard | Williams, Gordon H. | Witte, Daniel R. | Wood, Andrew R. | Xie, Weijia | Boehnke, Michael | Cooper, Cyrus | Ferrucci, Luigi | Froguel, Philippe | Groop, Leif | Kao, W.H. Linda | Vollenweider, Peter | Walker, Mark | Watanabe, Richard M. | Pedersen, Oluf | Meigs, James B. | Ingelsson, Erik | Barroso, Inês | Florez, Jose C. | Franks, Paul W. | Dupuis, Josée | Wareham, Nicholas J. | Langenberg, Claudia
Diabetes  2012;61(5):1291-1296.
Gene–lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13–0.31], P = 1.63 × 10−6). All SNPs were associated with 2-h glucose (β = 0.06–0.12 mmol/allele, P ≤ 1.53 × 10−7), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene–lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.
doi:10.2337/db11-0973
PMCID: PMC3331745  PMID: 22415877
10.  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
11.  The high bone mass phenotype is characterised by a combined cortical and trabecular bone phenotype: Findings from a pQCT case–control study☆ 
Bone  2013;52(1):380-388.
High bone mass (HBM), detected in 0.2% of DXA scans, is characterised by a mild skeletal dysplasia largely unexplained by known genetic mutations. We conducted the first systematic assessment of the skeletal phenotype in unexplained HBM using pQCT in our unique HBM population identified from screening routine UK NHS DXA scans.
pQCT measurements from the mid and distal tibia and radius in 98 HBM cases were compared with (i) 65 family controls (constituting unaffected relatives and spouses), and (ii) 692 general population controls.
HBM cases had substantially greater trabecular density at the distal tibia (340 [320, 359] mg/cm3), compared to both family (294 [276, 312]) and population controls (290 [281, 299]) (p < 0.001 for both, adjusted for age, gender, weight, height, alcohol, smoking, malignancy, menopause, steroid and estrogen replacement use). Similar results were obtained at the distal radius. Greater cortical bone mineral density (cBMD) was observed in HBM cases, both at the midtibia and radius (adjusted p < 0.001). Total bone area (TBA) was higher in HBM cases, at the distal and mid tibia and radius (adjusted p < 0.05 versus family controls), suggesting greater periosteal apposition. Cortical thickness was increased at the mid tibia and radius (adjusted p < 0.001), implying reduced endosteal expansion. Together, these changes resulted in greater predicted cortical strength (strength strain index [SSI]) in both tibia and radius (p < 0.001). We then examined relationships with age; tibial cBMD remained constant with increasing age amongst HBM cases (adjusted β − 0.01 [− 0.02, 0.01], p = 0.41), but declined in family controls (− 0.05 [− 0.03, − 0.07], p < 0.001) interaction p = 0.002; age-related changes in tibial trabecular BMD, CBA and SSI were also divergent. In contrast, at the radius HBM cases and controls showed parallel age-related declines in cBMD and trabecular BMD.
HBM is characterised by increased trabecular BMD and by alterations in cortical bone density and structure, leading to substantial increments in predicted cortical bone strength. In contrast to the radius, neither trabecular nor cortical BMD declined with age in the tibia of HBM cases, suggesting attenuation of age-related bone loss in weight-bearing limbs contributes to the observed bone phenotype.
Highlights
► High Bone Mass (HBM) is characterised by increased bone size, cortical BMD, cortical thickness and increased strength strain index. ► In HBM, trabecular density is also increased at both the distal radius and tibia. ► Tibial cortical and trabecular BMD decline with age in controls, but not in HBM implying attenuation of age-related loss. ► Similar differences in age-related bone loss are not seen at the radius, suggesting a possible interaction with weight-bearing.
doi:10.1016/j.bone.2012.10.021
PMCID: PMC3526774  PMID: 23103330
HBM, high bone mass; NHS, National Health Service; pQCT, peripheral quantitative computed tomography; OA, osteoarthritis; L1, 1st lumbar vertebra; cBMD, cortical bone mineral density; tBMD, trabecular bone mineral density; TBA, total bone area; CBA, cortical bone area; SSI, strength strain index; SD, standard deviation; PVE, partial volume effect; High bone mass; pQCT; Cortical; Trabecular; Age; BMD
12.  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
13.  Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes 
Strawbridge, Rona J. | Dupuis, Josée | Prokopenko, Inga | Barker, Adam | Ahlqvist, Emma | Rybin, Denis | Petrie, John R. | Travers, Mary E. | Bouatia-Naji, Nabila | Dimas, Antigone S. | Nica, Alexandra | Wheeler, Eleanor | Chen, Han | Voight, Benjamin F. | Taneera, Jalal | Kanoni, Stavroula | Peden, John F. | Turrini, Fabiola | Gustafsson, Stefan | Zabena, Carina | Almgren, Peter | Barker, David J.P. | Barnes, Daniel | Dennison, Elaine M. | Eriksson, Johan G. | Eriksson, Per | Eury, Elodie | Folkersen, Lasse | Fox, Caroline S. | Frayling, Timothy M. | Goel, Anuj | Gu, Harvest F. | Horikoshi, Momoko | Isomaa, Bo | Jackson, Anne U. | Jameson, Karen A. | Kajantie, Eero | Kerr-Conte, Julie | Kuulasmaa, Teemu | Kuusisto, Johanna | Loos, Ruth J.F. | Luan, Jian'an | Makrilakis, Konstantinos | Manning, Alisa K. | Martínez-Larrad, María Teresa | Narisu, Narisu | Nastase Mannila, Maria | Öhrvik, John | Osmond, Clive | Pascoe, Laura | Payne, Felicity | Sayer, Avan A. | Sennblad, Bengt | Silveira, Angela | Stančáková, Alena | Stirrups, Kathy | Swift, Amy J. | Syvänen, Ann-Christine | Tuomi, Tiinamaija | van 't Hooft, Ferdinand M. | Walker, Mark | Weedon, Michael N. | Xie, Weijia | Zethelius, Björn | Ongen, Halit | Mälarstig, Anders | Hopewell, Jemma C. | Saleheen, Danish | Chambers, John | Parish, Sarah | Danesh, John | Kooner, Jaspal | Östenson, Claes-Göran | Lind, Lars | Cooper, Cyrus C. | Serrano-Ríos, Manuel | Ferrannini, Ele | Forsen, Tom J. | Clarke, Robert | Franzosi, Maria Grazia | Seedorf, Udo | Watkins, Hugh | Froguel, Philippe | Johnson, Paul | Deloukas, Panos | Collins, Francis S. | Laakso, Markku | Dermitzakis, Emmanouil T. | Boehnke, Michael | McCarthy, Mark I. | Wareham, Nicholas J. | Groop, Leif | Pattou, François | Gloyn, Anna L. | Dedoussis, George V. | Lyssenko, Valeriya | Meigs, James B. | Barroso, Inês | Watanabe, Richard M. | Ingelsson, Erik | Langenberg, Claudia | Hamsten, Anders | Florez, Jose C.
Diabetes  2011;60(10):2624-2634.
OBJECTIVE
Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.
RESEARCH DESIGN AND METHODS
We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.
RESULTS
Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.
CONCLUSIONS
We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.
doi:10.2337/db11-0415
PMCID: PMC3178302  PMID: 21873549
14.  WNT16 Influences Bone Mineral Density, Cortical Bone Thickness, Bone Strength, and Osteoporotic Fracture Risk 
PLoS Genetics  2012;8(7):e1002745.
We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of −0.11 standard deviations [SD] per C allele, P = 6.2×10−9). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (−0.14 SD per C allele, P = 2.3×10−12, and −0.16 SD per G allele, P = 1.2×10−15, respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3×10−9), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9×10−6 and rs2707466: OR = 1.22, P = 7.2×10−6). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16−/− mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%–61% (6.5×10−13
Author Summary
Bone traits are highly dependent on genetic factors. To date, numerous genetic loci for bone mineral density (BMD) and only one locus for osteoporotic fracture have been previously identified to be genome-wide significant. Cortical bone has been reported to be an important determinant of bone strength; so far, no genome-wide association studies (GWAS) have been performed for cortical bone thickness (CBT) of the tibial and radial diaphysis or BMD at forearm, a skeletal site rich in cortical bone. Therefore, we performed two separated meta-analyses of GWAS for cortical thickness of the tibia in 3 independent cohorts of 5,878 men and women, and for forearm BMD in 5 cohorts of 5,672 individuals. We identified the 7q31 locus, which contains WNT16, to be associated with CBT and BMD. Four SNPs from this locus were then tested in 2,023 osteoporotic fracture cases and 3,740 controls. One of these SNPs was genome-wide significant, and two were genome-wide suggestive, for forearm fracture. Generating a mouse with targeted disruption of Wnt16, we also demonstrated that mice lacking this protein had substantially thinner bone cortices and reduced bone strength than their wild-type littermates. These findings highlight WNT16 as a clinically relevant member of the Wnt signaling pathway and increase our understanding of the etiology of osteoporosis-related phenotypes and fracture.
doi:10.1371/journal.pgen.1002745
PMCID: PMC3390364  PMID: 22792071
Background
The European Project on OSteoArthritis (EPOSA), here presented for the first time, is a collaborative study involving five European cohort studies on aging. This project focuses on the personal and societal burden and its determinants of osteoarthritis (OA). The aim of the current report is to describe the purpose of the project, the post harmonization of the cross-national data and methodological challenges related to the harmonization process
Methods
The study includes data from cohort studies in five European countries (Germany, Italy, the Netherlands, Spain and the United Kingdom) on older community-dwelling persons aged ≥ 59 years. The study design and main characteristics of the five cohort studies are described. Post harmonization algorithms are developed by finding a "common denominator" to merge the datasets and weights are calculated to adjust for differences in age and sex distribution across the datasets.
Results
A harmonized database was developed, consisting of merged data from all participating countries. In total, 10107 persons are included in the harmonized dataset with a mean age of 72.8 years (SD 6.1). The female/male ratio is 53.3/46.7%. Some variables were difficult to harmonize due to differences in wording and categories, differences in classifications and absence of data in some countries. The post harmonization algorithms are described in detail in harmonization guidelines attached to this paper.
Conclusions
There was little evidence of agreement on the use of several core data collection instruments, in particular on the measurement of OA. The heterogeneity of OA definitions hampers comparing prevalence rates of OA, but other research questions can be investigated using high quality harmonized data. By publishing the harmonization guidelines, insight is given into (the interpretation of) all post harmonized data of the EPOSA study.
doi:10.1186/1471-2474-12-272
PMCID: PMC3257208  PMID: 22122831
PLoS ONE  2011;6(8):e23371.
Osteoarthritis (OA) is the most common form of arthritis and a major cause of disability. This study evaluates the association in Caucasian populations of two single nucleotide polymorphisms (SNPs) mapping to the Human Leukocyte Antigen (HLA) region and deriving from a genome wide association scan (GWAS) of knee OA in Japanese populations. The frequencies for rs10947262 were compared in 36,408 controls and 5,749 knee OA cases from European-descent populations. rs7775228 was tested in 32,823 controls and 1,837 knee OA cases of European descent. The risk (major) allele at rs10947262 in Caucasian samples was not significantly associated with an odds ratio (OR)  = 1.07 (95%CI 0.94 -1.21; p = 0.28). For rs7775228 the meta-analysis resulted in OR = 0.94 (95%CI 0.81-1.09; p = 0.42) for the allele associated with risk in the Japanese GWAS. In Japanese individuals these two SNPs are in strong linkage disequilibrium (LD) (r2 = 0.86) with the HLA class II haplotype DRB1*1502 DQA1*0103 DQB1*0601 (frequency 8%). In Caucasian and Chinese samples, using imputed data, these SNPs appear not to be in LD with that haplotype (r2<0.07). The rs10947262 and rs7775228 variants are not associated with risk of knee OA in European descent populations and they do not appear tag the same HLA class II haplotype as they do in Japanese individuals.
doi:10.1371/journal.pone.0023371
PMCID: PMC3154440  PMID: 21853121
Diabetes  2010;59(5):1266-1275.
OBJECTIVE
Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action.
RESEARCH DESIGN AND METHODS
We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084).
RESULTS
The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 × 10−71). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction.
CONCLUSIONS
Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.
doi:10.2337/db09-1568
PMCID: PMC2857908  PMID: 20185807
PLoS Genetics  2011;7(4):e1001372.
Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55–85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or −4.0 to −1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD–associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies.
Author Summary
Osteoporotic fracture is a major cause of early mortality and morbidity in the community. To identify genes associated with osteoporosis, we have performed a genome-wide association study. In order to improve study power and to address the demographic group of highest risk from osteoporotic fracture, we have used a unique study design, studying 1,955 postmenopausal women with either extreme high or low hip bone mineral density. We then confirmed our findings in 20,898 women from the general population. Our study replicated 21 of 26 known osteoporosis genes, and it identified a further six novel loci (in or nearby CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4). For one of these loci, GALTN3, we demonstrate in a mouse model that a loss-of-function genetic mutation in GALNT3 causes high bone mass. These findings report novel mechanisms by which osteoporosis can arise, and they significantly add to our understanding of the aetiology of the disease.
doi:10.1371/journal.pgen.1001372
PMCID: PMC3080863  PMID: 21533022
Quality of Life Research  2011;20(7):1005-1010.
Purpose
To evaluate two psychometric properties of SF-36, namely unidimensionality and reliability.
Methods
The data are from three cohorts in the HALCyon collaborative research programme into healthy ageing: Aberdeen Birth Cohort 1936 (n = 428), Hertfordshire Ageing Study (n = 358) and Hertfordshire Cohort Study (n = 3,216). The Mokken scaling model was applied to each sub-scale of SF-36 to evaluate unidimensionality as indicated by scalability. The lower bound for internal consistency reliability was determined by Cronbach’s alpha.
Results
All six sub-scales of SF-36, with the exception of general health (GH) and mental health (MH), demonstrated strong scalability (0.5 ≤ H < 1). The results were consistent across all 3 cohorts. Both GH and MH showed medium scalability (0.4 ≤ H <0.55), although individual items ‘sick easier..’, ‘as healthy as..’ and ‘expect to get worse’ of the GH sub-scale and ‘nervous’, ‘happy’ in the MH sub-scale had low scalability (H < 0.4) in the oldest cohort (aged 73–83). Cronbach’s alphas for all sub-scales were between 0.70 and 0.92.
Conclusions
The unidimensionality and reliability of the sub-scales of SF-36 are sufficient to make this a useful measure of health-related quality of life in older people. Caution is needed when interpreting the results for GH and MH in the oldest cohort due to the poor unidimensionality.
doi:10.1007/s11136-010-9838-7
PMCID: PMC3161183  PMID: 21225350
SF-36; Psychometric properties; Unidimensionality; Reliability; Cronbach’s alpha; Mokken scaling
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
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
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
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
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
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

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