Prevalence of overweight and metabolic syndrome, and associated sociodemographic factors among adult Ecuadorian populations: the ENSANUT-ECU study.

BACKGROUND: Obesity and metabolic syndrome (MetS) are key risk factors for type 2 diabetes and cardiovascular disease. Little information exists on the prevalence of obesity and MetS in Latin America and specifically in Ecuador. We aimed to estimate the prevalence of overweight, obesity, and MetS among adults in Ecuador. METHODS: We analyzed data from a nation-wide population-based survey in Ecuador (ENSANUT-ECU) among 10,318 participants (3684 men, 6634 women; age range: 18-59 years) conducted in 2012. Data related to residential location (urban versus rural), altitude (< 500, 500-1500 or > 1500 m above sea level (MASL)), region (highland, coast, amazon, or Galápagos), and socioeconomic status were collected. BMI, waist circumference, blood lipids, glucose, and blood pressure were measured by trained fieldworkers following standardized procedures. RESULTS: The age-standardized prevalence of overweight was 39.5%; 22.3% was obese; and 31.2% had MetS. The prevalence of obesity, low HDL-cholesterol, and abdominal obesity were higher in women than in men, whereas men had a higher prevalence of hypertension (p < 0.05). Sex differences were not observed regarding the prevalence of combined MetS. Prevalence of both obesity and MetS was higher in urban areas, at low altitude regions (coast and Galapagos), and at high socioeconomic status (all p < 0.05). CONCLUSIONS: Prevalence of obesity and MetS in Ecuador are high. There are important demographic differences in the prevalence of MetS between Ecuadorian subpopulations that requires targeted research and prevention efforts, to hold and reduce the current public health problem of metabolic disorders.

Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms.

Despite a substantial genetic component, efforts to identify common genetic variation underlying depression have largely been unsuccessful. In the current study we aimed to identify rare genetic variants that might have large effects on depression in the general population. Using high-coverage exome-sequencing, we studied the exonic variants in 1265 individuals from the Rotterdam study (RS), who were assessed for depressive symptoms. We identified a missense Asn396Ser mutation (rs77960347) in the endothelial lipase (LIPG) gene, occurring with an allele frequency of 1% in the general population, which was significantly associated with depressive symptoms (P-value=5.2 × 10-08, ß=7.2). Replication in three independent data sets (N=3612) confirmed the association of Asn396Ser (P-value=7.1 × 10-03, ß=2.55) with depressive symptoms. LIPG is predicted to have enzymatic function in steroid biosynthesis, cholesterol biosynthesis and thyroid hormone metabolic processes. The Asn396Ser variant is predicted to have a damaging effect on the function of LIPG. Within the discovery population, carriers also showed an increased burden of white matter lesions (P-value=3.3 × 10-02) and a higher risk of Alzheimer's disease (odds ratio=2.01; P-value=2.8 × 10-02) compared with the non-carriers. Together, these findings implicate the Asn396Ser variant of LIPG in the pathogenesis of depressive symptoms in the general population.

Prevalence and determinants of seborrhoeic dermatitis in a middle-aged and elderly population: the Rotterdam Study.

BACKGROUND: Seborrhoeic dermatitis is a chronic relapsing inflammatory skin disease with unclear pathophysiological mechanisms. OBJECTIVES: To establish which lifestyle and physiological determinants are associated with seborrhoeic dermatitis. METHODS: Seborrhoeic dermatitis was diagnosed by a trained physician during a full-body skin examination within the Rotterdam Study, a prospective population-based cohort study in middle-aged and elderly people. The current design is a comparative cross-sectional study embedded in the Rotterdam Study. Potential factors were identified from the literature and analysed in a multivariable logistic regression, including: age, sex, obesity, skin colour, stress, depression, education level, hypertension, climate, xerosis cutis, alcohol and tobacco use. RESULTS: Of the 5498 participants, 788 participants were diagnosed with seborrhoeic dermatitis (14·3%). We found associations between seborrhoeic dermatitis and male sex [adjusted odds ratio (OR) 2·09, 95% confidence interval (CI) 1·77-2·47], darker skin (adjusted OR 0·39, 95% CI 0·22-0·69), season (summer vs. winter: adjusted OR 0·63, 95% CI 0·48-0·82) and generalized xerosis cutis (adjusted OR 1·41, 95% CI 1·11-1·80). CONCLUSIONS: Seborrhoeic dermatitis is one of the most common inflammatory dermatoses in middle-aged and elderly individuals, especially during winter. Men, and people with a light and dry skin were most likely to have seborrhoeic dermatitis.

Dietary acid load, trabecular bone integrity, and mineral density in an ageing population: the Rotterdam study.

We studied the relation between a diet that is high in acid-forming nutrients (e.g. proteins) and low in base-forming nutrients (e.g. potassium) and bone structure. We showed a negative relation, which was more prominent if proteins were of animal rather than of vegetable origin and if intake of dietary fibre was high. INTRODUCTION: Studies on dietary acid load (DAL) and fractures have shown inconsistent results. Associations between DAL, bone mineral density (BMD) and trabecular bone integrity might play a role in these inconsistencies and might be influenced by renal function and dietary fibre intake. Therefore, our aim was to study (1) associations of DAL with BMD and with the trabecular bone score (TBS) and (2) the potential influence of renal function and dietary fibre in these associations. METHODS: Dutch individuals aged 45 years and over (n = 4672) participating in the prospective cohort of the Rotterdam study were included. Based on food frequency questionnaires, three indices of DAL were calculated: the net endogenous acid production (NEAP) and the ratios of vegetable or animal protein and potassium (VegPro/K and AnPro/K). Data on lumbar spinal TBS and BMD were derived from dual-energy X-ray absorptiometry measurements. RESULTS: Independent of confounders, NEAP and AnPro/K, but not VegPro/K, were associated with low TBS (standardized ß (95%) = -0.04 (-0.07, -0.01) and -0.08 (-0.11, -0.04)) but not with BMD. Associations of AnPro/K and VegPro/K with TBS were non-linear and differently shaped. Unfavourable associations between NEAP, BMD and TBS were mainly present in subgroups with high fibre intake. CONCLUSIONS: High NEAP was associated with low TBS. Associations of AnPro/K and VegPro/K and TBS were non-linear and differently shaped. No significant associations of DAL with BMD were observed, nor was there any significant interaction between DAL and renal function. Mainly in participants with high intake of dietary fibre, DAL might be detrimental to bone.

Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans.

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

Obesity in older adults and life expectancy with and without cardiovascular disease.

BACKGROUND: The prevalence of overweight and obesity is increasing globally and is an established risk factor for cardiovascular disease (CVD). Our objective was to evaluate the impact of overweight and obesity on life expectancy and years lived with and without CVD in older adults. METHODS: The study included 6636 individuals (3750 women) aged 55 years and older from the population-based Rotterdam Study. We developed multistate life tables by using prevalence, incidence rate and hazard ratios (HR) for three transitions (free-of-CVD-to-CVD, free-of-CVD-to-death and CVD-to-death), stratifying by the categories of body mass index (BMI) at baseline and adjusting for confounders. RESULTS: During 12 years of follow-up, we observed 1035 incident CVD events and 1902 overall deaths. Obesity was associated with an increased risk of CVD among men (HR 1.57 (95% confidence interval (CI) 1.17, 2.11)) and women (HR 1.49 (95% CI 1.19, 1.86)), compared with normal weight individuals. Overweight and obesity were not associated with mortality in men and women without CVD. Among men with CVD, obesity compared with normal weight, was associated with a lower risk of mortality (HR 0.67 (95% CI 0.49, 0.90)). Overweight and obesity did not influence total life expectancy. However, obesity was associated with 2.6 fewer years (95% CI -4.8, -0.4) lived free from CVD in men and 1.9 (95% CI -3.3, -0.9) in women. Moreover, men and women with obesity lived 2.9 (95% CI 1.1, 4.8) and 1.7 (95% CI 0.6, 2.8) more years suffering from CVD compared with normal weight counterparts. CONCLUSIONS: Obesity had no effect on total life expectancy in older individuals, but increased the risk of having CVD earlier in life and consequently extended the number of years lived with CVD. Owing to increasing prevalence of obesity and improved treatment of CVD, we might expect more individuals living with CVD and for a longer period of time.

Protein intake in early childhood and body composition at the age of 6 years: The Generation R Study.

BACKGROUND: Previous studies suggest that high protein intake in infancy leads to a higher body mass index (BMI) in later childhood. We examined the associations of total, animal and vegetable protein intake in early childhood with detailed measures of body composition at the age of 6 years. METHODS: This study was performed in 2911 children participating in a population-based cohort study. Protein intake at the age of 1 year was assessed with a validated food-frequency questionnaire and was adjusted for total energy intake. At the children's age of 6 years, we measured their anthropometrics and body fat (with dual-energy X-ray absorptiometry). We calculated age- and sex-specific s.d. scores for BMI, fat mass index (FMI) and fat-free mass index (FFMI). RESULTS: After adjustment for confounders, a 10 g per day higher total protein intake at 1 year of age was associated with a 0.05 s.d. (95% confidence interval (CI) 0.00, 0.09) higher BMI at age 6. This association was fully driven by a higher FMI (0.06 s.d. (95%CI 0.01, 0.11)) and not FFMI (-0.01 s.d. (95%CI -0.06, 0.05)). The associations of protein intake with FMI at 6 years remained significant after adjustment for BMI at the age of 1 year. Additional analyses showed that the associations of protein intake with FMI were stronger in girls than in boys (P for interaction=0.03), stronger among children who had catch-up growth in the first year of life (P for interaction<0.01) and stronger for intake of animal protein (both dairy and non-dairy protein) than protein from vegetable sources. CONCLUSIONS: Our results suggest that high protein intake in early childhood is associated with higher body fat mass, but not fat-free mass. Future studies are needed to investigate whether these changes persist into adulthood and to examine the optimal range of protein intake for infants and young children.

Associations of maternal and fetal 25-hydroxyvitamin D levels with childhood lung function and asthma: the Generation R Study.

BACKGROUND: Exposure to low levels of vitamin D in fetal life might be a risk factor for childhood asthma. OBJECTIVE: We examined whether 25-hydroxyvitamin D levels in mid-gestation and at birth were associated with higher airway resistance and inflammation, and increased risks of wheezing and asthma in school-age children. METHODS: We performed a population-based prospective cohort study among 3130 mothers and their children. Maternal blood samples in mid-gestation and umbilical cord blood samples at birth were used to determine 25-hydroxyvitamin D levels. At age of 6, airway resistance (Rint) was measured by interrupter technique and airway inflammation by fractional exhaled nitric oxide (FENO) using NIOX chemiluminescence analyser. Wheezing and asthma were prospectively assessed by annual questionnaires until age 6. RESULTS: Maternal levels of 25-hydroxyvitamin D in mid-gestation were not associated with Rint, FeNO, wheezing patterns, or asthma. Children in the lowest tertile of 25-hydroxyvitamin D levels at birth had a higher Rint (Z-score (95% confidence interval [95% CI]): -0.42 (-0.84, -0.01), P-value for trend< 0.05), compared to those in the highest tertile group. The effect estimate attenuated when child's current 25-hydroxyvitamin D level was taken into account [Z-score (95% CI): -0.55 (-1.08, 0.01)]. CONCLUSION AND CLINICAL RELEVANCE: Low levels of 25-hydroxyvitamin D at birth were associated with a higher airway resistance in childhood. Additional adjustment for child's current 25-hydroxyvitamin D level reduced the effect size of the association. Further studies are needed to replicate these findings and to examine mechanisms underlying the observed association and the long-term consequences.

The long-term risk of recognized and unrecognized myocardial infarction for depression in older men.

BACKGROUND: The association between myocardial infarction (MI) and depression is well described. Yet, the underlying mechanisms are unclear and the contribution of psychological factors is uncertain. We aimed to determine the risk of recognized (RMI) and unrecognized (UMI) myocardial infections on depression, as both have a similar impact on cardiovascular health but differ in psychological epiphenomena. METHOD: Participants of the Rotterdam Study, 1823 men aged ⩾55 years, were followed for the occurrence of depression. RMI and UMI were ascertained using electrocardiography and medical history at baseline. We determined the strength of the association of RMI and UMI with mortality, and we studied the relationship of RMI and UMI with depressive symptoms and the occurrence of major depression. RESULTS: The risk of mortality was similar in men with RMI [adjusted hazard ratio (aHR) 1.71, 95% confidence interval (CI) 1.45-2.03] and UMI (aHR 1.58, 95% CI 1.27-1.97). Men with RMI had on average [unstandardized regression coefficient (B) 1.14, 95% CI 0.07-2.21] higher scores for depressive symptoms. By contrast, we found no clear association between UMI and depressive symptoms (B 0.55, 95% CI -0.51 to 1.62) in men. Analysis including occurrence of major depression as the outcome were consistent with the pattern of association. CONCLUSION: The discrepant association of RMI and UMI with mortality compared to depression suggests that the psychological burden of having experienced an MI contributes to the long-term risk of depression.

Migraine is associated with better cognition in the middle-aged and elderly: the Rotterdam Study.

BACKGROUND AND PURPOSE: Converging evidence suggests that migraine has, in part, a vascular basis. In turn, vascular pathology is a strong risk factor for cognitive decline. In this population-based study, we studied cognition amongst individuals with and without migraine. METHODS: In 6708 participants of the Rotterdam Study, migraine was assessed using a validated questionnaire. Cognition was assessed by the Mini Mental State Examination (MMSE) and a dedicated cognitive test battery. Participants were classified as non-migraineurs (n = 5399), migraineurs (n = 1021) or probable migraineurs (n = 288). Multivariable linear regression was used to cross-sectionally evaluate the association between migraine and cognition, adjusting for age, sex and cardiovascular risk factors. Additionally, we stratified the analysis by sex and by migraine subtype. RESULTS: Migraineurs had higher mean MMSE scores [unstandardized regression coefficient 0.21, (95% confidence interval, 0.08; 0.34)] and global cognition [0.10 (0.04; 0.15)] than non-migraineurs. This difference was particularly marked for migraineurs with aura [MMSE: 0.39 (0.13; 0.66); global cognition: 0.13 (0.01; 0.24)]. Migraineurs performed better on tests of executive function and fine motor skills amongst specific cognitive domains. The difference in MMSE between migraineurs and non-migraineurs was greater in women [0.25 (0.10; 0.40)] than in men [0.13 (-0.15; 0.40)], whereas the difference in global cognition was similar in men and women [0.15 (0.04; 0.27) and 0.09 (0.02; 0.15), respectively]. CONCLUSIONS: Migraineurs, particularly migraineurs with aura, tend to score higher in cognition tests than non-migraineurs. More studies are needed to corroborate these findings.

The role of global and regional DNA methylation and histone modifications in glycemic traits and type 2 diabetes: A systematic review.

BACKGROUND: New evidence suggests the potential involvement of epigenetic mechanisms in type 2 diabetes (T2D) as a crucial interface between the effects of genetic predisposition and environmental influences. AIM: To systematically review studies investigating the association between epigenetic marks (DNA methylation and histone modifications) with T2D and glycemic traits (glucose and insulin levels, insulin resistance measured by HOMA-IR). METHOD AND RESULTS: Six bibliographic databases (Embase.com, Medline (Ovid), Web-of-Science, PubMed, Cochrane Central and Google Scholar) were screened until 28th August 2015. We included randomized controlled trials, cohort, case-control and cross-sectional studies in humans that examined the association between epigenetic marks (global, candidate or genome-wide methylation of DNA and histone modifications) with T2D, glucose and insulin levels and insulin metabolism. Of the initially identified 3879 references, 53 articles, based on 47 unique studies met our inclusion criteria. Overall, data were available on 10,823 participants, with a total of 3358 T2D cases. There was no consistent evidence for an association between global DNA-methylation with T2D, glucose, insulin and insulin resistance. The studies reported epigenetic regulation of several candidate genes for diabetes susceptibility in blood cells, muscle, adipose tissue and placenta to be related with T2D without any general overlap between them. Histone modifications in relation to T2D were reported only in 3 observational studies. CONCLUSIONS AND RELEVANCE: Current evidence supports an association between epigenetic marks and T2D. However, overall evidence is limited, highlighting the need for further larger-scale and prospective investigations to establish whether epigenetic marks may influence the risk of developing T2D.

Intake of different types of dairy and its prospective association with risk of type 2 diabetes: The Rotterdam Study.

BACKGROUND AND AIMS: The prevalence of type 2 diabetes (T2DM) is increasing. Several studies have suggested a beneficial effect of several major dairy nutrients on insulin production and sensitivity. Conversely, harmful effects have been suggested as well. This study aimed to investigate the impact of the full-range of dairy products and its association with incidence T2DM in Dutch adults aged ≥55 years participating in the Rotterdam Study. METHODS AND RESULTS: Dairy intake was assessed with a validated FFQ, including total, skimmed, semi-skimmed, full-fat, fermented, and non-fermented dairy, and subclasses of these product groups. Verified prevalent and incident diabetes were documented. Cox proportional hazards regression and spline regression were used to analyse data, adjusting for age, sex, alcohol, smoking, education, physical activity, body mass index, intake of total energy, energy-adjusted meat, and energy-adjusted fish intake. Median total dairy intake was 398 g/day (IQR 259-559 g/day). Through 9.5 ± 4.1 years of follow-up, 393 cases of incident T2DM were reported. Cox and spline regression did not point towards associations of total dairy consumption, dairy consumption based on fat content, non-fermented or fermented dairy consumption, or individual dairy product consumption with incident T2DM. The HR for total dairy intake and T2DM was 0.93 (95% CI: 0.70-1.23) in the upper quartile (P-for trend 0.76). CONCLUSIONS: This prospective cohort study did not point towards an association between dairy consumption and T2DM.

Maternal weight gain in different periods of pregnancy and childhood cardio-metabolic outcomes. The Generation R Study.

BACKGROUND: Excessive gestational weight gain seems to be associated with offspring cardio-metabolic risk factors. Little is known about the critical periods of gestational weight gain. We examined the associations of maternal weight gain in different periods of pregnancy with childhood cardio-metabolic risk factors. METHODS: In a population-based prospective cohort study from early pregnancy onwards among 5908 mothers and their children, we obtained maternal prepregnancy weight and weight in early, mid and late pregnancy. At the age of 6 years (median: 72.6 months; 95% range: 67.9, 95.8), we measured childhood body mass index (BMI), total body and abdominal fat distribution, blood pressure and blood levels of lipids, insulin and c-peptide. RESULTS: Overall, the associations of maternal prepregnancy weight with childhood outcomes were stronger than the associations of maternal gestational weight gain. Independent from maternal prepregnancy weight and weight gain in other periods, higher weight gain in early pregnancy was associated with higher childhood BMI, total fat mass, android/gynoid fat mass ratio, abdominal subcutaneous fat mass and systolic blood pressure (P-values<0.05). Independent associations of maternal weight gain in early pregnancy with childhood abdominal preperitoneal fat mass, insulin and c-peptide were of borderline significance. Higher weight gain in mid pregnancy was independently associated with higher childhood BMI, total and abdominal subcutaneous fat mass and systolic blood pressure (P-values<0.05). The associations for childhood cardio-metabolic outcomes attenuated after adjustment for childhood BMI. Weight gain in late pregnancy was not associated with childhood outcomes. Higher weight gain in early, but not in mid or late pregnancy, was associated with increased risks of childhood overweight and clustering of cardio-metabolic risk factors (odds ratio (OR) 1.19 (95% confidence interval (CI): 1.10, 1.29) and OR 1.20 (95% CI: 1.07, 1.35) per standard deviation increase in early gestational weight gain, respectively). CONCLUSIONS: Higher weight gain in early pregnancy is associated with an adverse cardio-metabolic profile in offspring. This association is largely mediated by childhood adiposity.

Cross-sectional population associations between detailed adiposity measures and C-reactive protein levels at age 6 years: the Generation R Study.

OBJECTIVES: High body mass index is associated with increased C-reactive protein levels in childhood and adulthood. Little is known about the associations of detailed adiposity measures with C-reactive protein levels in childhood. We examined the associations of general and abdominal adiposity measures with C-reactive protein levels at school age. To gain insight into the direction of causality, we used genetic risk scores based on known genetic variants in adults as proxies for child adiposity measures and C-reactive protein levels. METHODS: Within a population-based cohort study among 4338 children at the median age of 6.2 years, we measured body mass index, fat mass percentage, android/gynoid fat mass ratio and preperitoneal abdominal fat mass. We also measured C-reactive protein blood levels and defined increased levels as ⩾3.0 mg l(-1). Single-nucleotide polymorphisms (SNPs) for the weighted genetic risk scores were extracted from large genome-wide association studies on adult body mass index, waist-hip ratio and C-reactive protein levels. RESULTS: All fat mass measures were associated with increased C-reactive protein levels, even after adjusting for multiple confounders. Fat mass percentage was most strongly associated with increased C-reactive protein levels (odds ratio 1.46 (95% confidence interval 1.30-1.65) per increase standard deviation scores in fat mass percentage). The association was independent of body mass index. The genetic risk score based on adult body mass index SNPs, but not adult waist-hip ratio SNPs, tended to be associated with increased C-reactive protein levels at school age. The genetic risk score based on adult C-reactive protein level SNPs was not associated with adiposity measures at school age. CONCLUSION: Our results suggest that higher general and abdominal fat mass may lead to increased C-reactive protein levels at school age. Further studies are needed to replicate these results and explore the causality and long-term consequences.

Disability and not osteoarthritis predicts cardiovascular disease: a prospective population-based cohort study.

BACKGROUND: Previous studies found an association between osteoarthritis (OA) and risk of cardiovascular disease (CVD) and therefore suggested intensive treatment of cardiovascular risk factors in OA patients. However, prospective population-based data is lacking. OBJECTIVES: To investigate the association between OA and CVD longitudinally in a general population and examine the role of disability in this association. METHODS: This study was embedded in the Rotterdam Study, a prospective population-based cohort study in Rotterdam, the Netherlands that started in 1989. At baseline 4648 persons aged ≥55, free of CVD were classified into those with and those without radiographic or clinical OA. HRs adjusted for traditional cardiovascular risk factors for developing CVD (a composite of fatal and non-fatal coronary heart disease and stroke) were calculated. RESULTS: During a median follow-up of 14.4 years, 1230 cardiovascular events occurred, of which 101 were in participants with clinical OA. Presence of radiographic OA at baseline was not related to future CVD (HR 0.99, 95% CI 0.86 to 1.15), neither was presence of clinical OA (HR 1.09, 95% CI 0.88 to 1.34). However, persons with increasing disability were more likely to suffer a cardiovascular event compared with non-disabled persons (HR 1.26, 95% CI 1.12 to 1.42); this was independent of the presence of OA. CONCLUSIONS: In this large population-based study, participants with OA were not at increased risk of CVD. The close relation between disability and osteoarthritis may explain previous findings. Further studies are required in order to clarify whether OA patients need more intensive treatment of their cardiovascular risk factors.

Androgen levels in women with various forms of ovarian dysfunction: associations with cardiometabolic features.

STUDY QUESTION: Are differences in androgen levels among women with various forms of ovarian dysfunction associated with cardiometabolic abnormalities? SUMMARY ANSWER: Androgen levels differed substantially between women with and without ovarian dysfunction, and increased androgen levels were associated with impaired cardiometabolic features in all women irrespective of their clinical condition. WHAT IS KNOWN ALREADY: Sex steroid hormones play important roles in the development of cardiovascular diseases (CVD). Extremes of low as well as high androgen levels have been associated with increased CVD risk in both men and women. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included 680 women with polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), natural post-menopausal women (NM), or regular menstrual cycles (RC) (170 women per group). PARTICIPANTS/MATERIALS, SETTING, METHODS: Measurements of serum testosterone, androstenedione and dehydroepiandrosterone sulfate were performed using liquid chromatography-tandem mass spectrometry. Assessments were taken of body mass index (BMI), blood pressure, lipid profiles, glucose, insulin and SHBG, and the bioactive fraction of circulating testosterone was calculated using the free androgen index (FAI). MAIN RESULTS AND THE ROLE OF CHANCE: PCOS women were hyperandrogenic [median FAI = 4.9 (IQR 3.6-7.4)], and POI women were hypoandrogenic [FAI = 1.2 (0.8-1.7)], compared with RC women [FAI = 1.7 (1.1-2.8)], after adjustment for age, ethnicity, smoking and BMI (P < 0.001). After adjustment for age, there were no significant differences in androgens between POI and NM (P = 0.15) women and between NM and RC (P = 0.27) women, the latter indicating that chronological aging rather than ovarian aging influences the differences between pre- and post-menopausal women. A high FAI was associated with elevated triglycerides (ß log FAI for PCOS: 0.45, P < 0.001, POI: 0.25, P < 0.001, NM: 0.20, P = 0.002), insulin (ß log FAI for PCOS: 0.77, POI: 0.44, NM: 0.40, all P < 0.001), HOMA-IR (ß log FAI for PCOS: 0.82, POI: 0.46, NM: 0.47, all P < 0.001) and mean arterial pressure (ß log FAI for PCOS: 0.05, P = 0.002, POI: 0.07, P < 0.001, NM: 0.04, P = 0.04) in all women; with increased glucose (ß log FAI for PCOS: 0.05, P = 0.003, NM: 0.07, P < 0.001) and decreased high-density lipoprotein (ß log FAI for PCOS: -0.23, P < 0.001, NM: -0.09, P = 0.03) in PCOS and NM women; and with increased low-density lipoprotein (ß log FAI for POI: 0.083, P = 0.041) in POI women. Adjustment for BMI attenuated the observed associations. Associations between FAI and cardiometabolic features were the strongest in PCOS women, even after adjustment for BMI. LIMITATIONS, REASONS FOR CAUTION: Associations between androgen levels and cardiometabolic features were assessed in PCOS, POI and NM women only, due to a lack of available data in RC women. Due to the cross-sectional design of the current study, the potential associations between androgen levels and actual future cardiovascular events could not be assessed. WIDER IMPLICATIONS OF THE FINDINGS: This study affirms the potent effect of androgens on cardiometabolic features, indicating that androgens should indeed be regarded as important denominators of women's health. Future research regarding the role of androgens in the development of CVD and potential modulatory effects of BMI is required. STUDY FUNDING/COMPETING INTERESTS: N.M.P.D. is supported by the Dutch Heart Foundation (grant number 2013T083). L.J. and O.H.F. work in ErasmusAGE, a center for aging research across the life course, funded by Nestlé Nutrition (Nestec Ltd), Metagenics Inc. and AXA. M.K. is supported by the AXA Research Fund. Nestlé Nutrition (Nestec Ltd), Metagenics Inc. and AXA had no role in the design and conduct of the study; the collection, management, analysis and interpretation of the data; or the preparation, review or approval of the manuscript. J.S.E.L. has received fees and grant support from the following companies (in alphabetical order): Ferring, Merck-Serono, Merck Sharpe & Dome, Organon, Schering Plough and Serono. In the last 5 years, B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order); Actavis, COGI, Euroscreen, Ferring, Finox, Genovum, Gedeon-Richter, Merck-Serono, OvaScience, Pantharei Bioscience, PregLem, Roche, Uteron and Watson laboratories. With regard to potential conflicts of interest, there is nothing further to disclose.

Infant dietary patterns and bone mass in childhood: the Generation R Study.

UNLABELLED: Early life nutrition affects peak bone mass attainment. In this prospective cohort study, children with high adherence to a "dairy and whole grains" pattern in infancy had higher bone mineral density at the age of 6 years. Although the observed effects are small, our study provides insight into mechanisms linking early nutrition to bone acquisition in childhood. INTRODUCTION: Nutrition in early life may affect peak bone mass attainment. Previous studies on childhood nutrition and skeletal health mainly focused on individual nutrients, which does not consider the cumulative effects of nutrients. We investigated the associations between dietary patterns in infancy and childhood bone health. METHODS: This study included 2850 children participating in a population-based prospective cohort study. Dietary information was obtained from a food frequency questionnaire at the age of 13 months. Using principal component analysis, three major dietary patterns were extracted, explaining in total 30% of the variation in dietary intake. At the age of 6 years, a total body dual-energy X-ray absorptiometry (DXA) scan was performed, and bone mineral density (BMD), bone mineral content (BMC), area-adjusted BMC (aBMC), and bone area (BA) were analyzed. RESULTS: Higher adherence score to a "dairy and whole grains" pattern was positively associated with BMD and aBMC, but not with BMC and BA. Accordingly, children in the highest quartile of the "dairy and whole grains" pattern had higher BMD (difference 3.98 mg/cm(2), 95% confidence interval (CI) 0.36 to 7.61) and aBMC (difference 4.96 g, 95% CI 1.27 to 8.64) than children in the lowest quartile. Stratification for vitamin D supplementation showed that the positive associations between the "dairy and whole grains" pattern and bone outcomes were only observed in children who did not receive vitamin D supplementation. A "potatoes, rice, and vegetables" and a "refined grains and confectionery" pattern were not consistently associated with bone outcomes. CONCLUSIONS: An infant dietary pattern characterized by high intakes of dairy and cheese, whole grains, and eggs is positively associated with bone development in childhood. Further research is needed to investigate the consequences for bone health in later life.

N-terminal pro-B-type natriuretic peptide and the risk of stroke and transient ischaemic attack: the Rotterdam Study.

BACKGROUND AND PURPOSE: Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is a predictor of heart disease. It has also been related to stroke, but its association with transient ischaemic attacks (TIAs) is unclear. Moreover, it is unknown how clinical heart disease influences this relation. Within the prospective population-based Rotterdam Study, the association of NT-proBNP with stroke and TIA was examined and the role of heart disease on this association was investigated. METHODS: NT-proBNP was measured in 1997-2001 in 5611 participants (mean age 68.7 years; 57.7% women) without a history of stroke, TIA or heart failure. Follow-up for stroke and TIA finished in 2012. Models were adjusted for age and cardiovascular risk factors, and were stratified by sex. RESULTS: During 22 058 person-years 195 men suffered a stroke and 118 a TIA. During 31 825 person-years 230 women suffered a stroke and 187 a TIA. Higher NT-proBNP was associated with a higher risk of stroke in men [hazard ratio (HR) per SD increase 1.50; 95% confidence interval (CI) 1.29-1.76] and in women (HR 1.24; 95% CI 1.05-1.46). Associations with TIA were only present in women (HR 1.51; 95% CI 1.26-1.82) but not in men (HR 1.02; 95% CI 0.83-1.26). Excluding persons with a history of clinical coronary heart disease, heart failure or atrial fibrillation and censoring for clinical heart disease during follow-up did not change the associations. CONCLUSIONS: Higher NT-proBNP is associated with incident stroke in men and women and with incident TIA only in women. These associations are independent of clinical heart disease preceding cerebrovascular disease.

Dissecting the relationship between high-sensitivity serum C-reactive protein and increased fracture risk: the Rotterdam Study.

UNLABELLED: Serum high-sensitivity C-reactive protein (CRP) is an inflammatory biomarker. We investigated the relationship between CRP and bone health in the Rotterdam Study. Serum high-sensitivity CRP was associated with fracture risk and lower femoral neck bending strength. Mendelian randomization analyses did not yield evidence for this relationship being causal. INTRODUCTION: Inflammatory diseases are associated with bone pathology, reflected in a higher fracture risk. Serum high-sensitivity CRP is an inflammatory biomarker. We investigated the relationship between CRP and bone mineral density (BMD), hip bone geometry, and incident fractures in the Rotterdam Study, a prospective population-based cohort. METHODS: At baseline, serum high-sensitivity CRP was measured. A weighted genetic risk score was compiled for CRP based on published studies (29 polymorphisms; Illumina HumanHap550 Beadchip genotyping and HapMap imputation). Regression models were reported per standard deviation increase in CRP adjusted for sex, age, and BMI. Complete data was available for 6,386 participants, of whom 1,561 persons sustained a fracture (mean follow-up, 11.6 years). RESULTS: CRP was associated with a risk for any type of fracture [hazard ratio (HR) = 1.06; 95 % confidence interval (CI), 1.02-1.11], hip fractures (HR = 1.09; 1.02-1.17) and vertebral fractures [odds ratio (OR) = 1.34; 1.14-1.58]. An inverse relationship between CRP levels and section modulus (-0.011 cm(3); -0.020 to -0.003 cm(3)) was observed. The combined genetic risk score of CRP single nucleotide polymorphisms (SNPs) was associated with serum CRP levels (p = 9 × 10(-56)), but not with fracture risk (HR = 1.00; 0.99-1.00; p = 0.23). CONCLUSIONS: Serum high-sensitivity CRP is associated with fracture risk and lower bending strength. Mendelian randomization analyses did not yield evidence for this relationship being causal. Future studies might reveal what factors truly underlie the relationship between CRP and fracture risk.