Design and rationale of the NetherLands registry of invasive Coronary vasomotor Function Testing (NL-CFT).

BACKGROUND: Angina without angiographic evidence of obstructive coronary artery disease (ANOCA) is a highly prevalent condition with insufficient pathophysiological knowledge and lack of evidence-based medical therapies. This affects ANOCA patients prognosis, their healthcare utilization and quality of life. In current guidelines, performing a coronary function test (CFT) is recommended to identify a specific vasomotor dysfunction endotype. The NetherLands registry of invasive Coronary vasomotor Function testing (NL-CFT) has been designed to collect data on ANOCA patients undergoing CFT in the Netherlands. METHODS: The NL-CFT is a web-based, prospective, observational registry including all consecutive ANOCA patients undergoing clinically indicated CFT in participating centers throughout the Netherlands. Data on medical history, procedural data and (patient reported) outcomes are gathered. The implementation of a common CFT protocol in all participating hospitals promotes an equal diagnostic strategy and ensures representation of the entire ANOCA population. A CFT is performed after ruling out obstructive coronary artery disease. It comprises of both acetylcholine vasoreactivity testing as well as bolus thermodilution assessment of microvascular function. Optionally, continuous thermodilution or Doppler flow measurements can be performed. Participating centers can perform research using own data, or pooled data will be made available upon specific request via a secure digital research environment, after approval of a steering committee. CONCLUSION: NL-CFT will be an important registry by enabling both observational and registry based (randomized) clinical trials in ANOCA patients undergoing CFT.

Diastolic dysfunction and sex-specific progression to HFpEF: current gaps in knowledge and future directions.

Diastolic dysfunction of the left ventricle (LVDD) is equally common in elderly women and men. LVDD is a condition that can remain latent for a long time but is also held responsible for elevated left ventricular filling pressures and high pulmonary pressures that may result in (exercise-induced) shortness of breath. This symptom is the hallmark of heart failure with preserved ejection fraction (HFpEF) which is predominantly found in women as compared to men within the HF spectrum. Given the mechanistic role of LVDD in the development of HFpEF, we review risk factors and mechanisms that may be responsible for this sex-specific progression of LVDD towards HFpEF from an epidemiological point-of-view and propose future research directions.

Plasma Testosterone Levels and Atherosclerotic Plaque Gene Expression in Men With Advanced Atherosclerosis.

Aims: Low plasma testosterone levels have been shown to predict worse outcome in men with severe atherosclerotic disease. We hypothesized that a low plasma testosterone level affects disease risk through changes in gene expression in atherosclerotic plaques. Therefore, we studied plasma testosterone levels in relation to gene expression levels in atherosclerotic plaque tissue of men with advanced atherosclerotic disease. Methods: Plasma testosterone levels were measured in 203 men undergoing carotid endarterectomy. The corresponding atherosclerotic plaque tissue was used for RNA sequencing. First, we assessed how often the androgen receptor gene was expressed in the plaque. Second, correlations between plasma testosterone levels and pre-selected testosterone-sensitive genes were assessed. Finally, differences within the RNA expression profile of the plaque as a whole, characterized into gene regulatory networks and at individual gene level were assessed in relation to testosterone levels. Results: Testosterone plasma levels were low with a median of 11.6 nmol/L (IQR: 8.6-13.8). RNA-seq of the plaque resulted in reliable expression data for 18,850 genes to be analyzed. Within the RNA seq data, the androgen-receptor gene was expressed in 189 out of 203 (93%) atherosclerotic plaques of men undergoing carotid endarterectomy. The androgen receptor gene expression was not associated with testosterone plasma levels. There were no significant differences in gene expression of atherosclerotic plaques between different endogenous testosterone levels. This remained true for known testosterone-sensitive genes, the complete transcriptomic profile, male-specific gene co-expression modules as well as for individual genes. Conclusion: In men with severe atherosclerotic disease the androgen receptor is highly expressed in plaque tissue. However, plasma testosterone levels were neither associated with pre-selected testosterone sensitive genes, gene expression profiles nor gene regulatory networks in late-stage atherosclerotic plaques. The effect of testosterone on gene expression of the late-stage atherosclerotic plaque appears limited, suggesting that alternate mechanisms explain its effect on clinical outcomes.

Evaluation of non-invasive imaging parameters in coronary microvascular disease: a systematic review.

BACKGROUND: Coronary microvascular dysfunction (CMD) is an important underlying cause of angina pectoris. Currently, no diagnostic tool is available to directly visualize the coronary microvasculature. Invasive microvascular reactivity testing is the diagnostic standard for CMD, but several non-invasive imaging techniques are being evaluated. However, evidence on reported non-invasive parameters and cut-off values is limited. Thus, we aimed to provide an overview of reported non-invasive parameters and corresponding cut-off values for CMD. METHODS: Pubmed and EMBASE databases were systematically searched for studies enrolling patients with angina pectoris without obstructed coronary arteries, investigating at least one non-invasive imaging technique to quantify CMD. Methodological quality assessment of included studies was performed using QUADAS-2. RESULTS: Thirty-seven studies were included. Ten cardiac magnetic resonance studies reported MPRI and nine positron emission tomography (PET) and transthoracic echocardiography (TTE) studies reported CFR. Mean MPRI ranged from 1.47 ± 0.36 to 2.01 ± 0.41 in patients and from 1.50 ± 0.47 to 2.68 ± 0.49 in controls without CMD. Reported mean CFR in PET and TTE ranged from 1.39 ± 0.31 to 2.85 ± 1.35 and 1.69 ± 0.40 to 2.40 ± 0.40 for patients, and 2.68 ± 0.83 to 4.32 ± 1.78 and 2.65 ± 0.65 to 3.31 ± 1.10 for controls, respectively. CONCLUSIONS: This systematic review summarized current evidence on reported parameters and cut-off values to diagnose CMD for various non-invasive imaging modalities. In current clinical practice, CMD is generally diagnosed with a CFR less than 2.0. However, due to heterogeneity in methodology and reporting of outcome measures, outcomes could not be compared and no definite reference values could be provided.

Vasomotor menopausal symptoms and cardiovascular disease risk in midlife: A longitudinal study.

OBJECTIVE: To ascertain the association between vasomotor menopausal symptoms (VSM), hot flushes and night sweats, and cardiovascular disease, coronary heart disease and cerebrovascular disease. STUDY DESIGN: The study sample comprised 8881 women (aged 45-50 years) with available hospital separation data from the 1946-51 cohort (1996-2016) of the ongoing Australian Longitudinal Study on Women's Health, a national prospective cohort study. MAIN OUTCOME MEASURES: First fatal or non-fatal cardiovascular disease, coronary heart disease, and cerebrovascular disease events were obtained through linkage with hospital admission data, the National Death Index, and Medicare Benefits Schedule. Hot flushes and night sweats were assessed via questionnaires at each main survey. Additionally, we calculated the duration of symptoms based on whether or not women reported vasomotor menopausal symptoms in each survey. RESULTS: There were 925 cardiovascular disease, 484 coronary heart disease and 154 cerebrovascular disease events. There was no consistent evidence of any association with vasomotor menopausal symptoms, hot flushes and night sweats. We did find marginally statistically significant associations between presence of night sweats and cardiovascular disease (Hazard Ratio = 1.18, 95 % Confidence Interval: 1.01-1.38), and between the duration of vasomotor menopausal symptoms [years] and coronary heart disease (Hazard Ratioper year = 1.03, 95 % Confidence Interval: 1.00-1.05). However, given the number of associations tested, these findings could very well have arisen by chance. CONCLUSION: In this large longitudinal study with 20 years of follow-up and clinical outcomes we did not find a convincing association between vasomotor menopausal symptoms, hot flushes, night sweats and cardiovascular disease, coronary heart disease and cerebrovascular disease.

Unraveling the associations of age and menopause with cardiovascular risk factors in a large population-based study.

BACKGROUND: Although the association between menopause and cardiovascular disease (CVD) risk has been studied extensively, the simultaneous role of chronological aging herein remains underexposed. This study aims to disentangle the relationships of menopausal status and chronological aging with CVD risk factors in the largest study population to date. METHODS: In this cross-sectional study, CVD risk factors were compared between women with a different menopausal status within the same yearly age strata. The study population comprised female participants of the baseline visit of the population-based LifeLines Cohort Study. A total of 63,466 women, aged between 18 and 65 years, was included. Of them, 39,379 women were considered to be premenopausal, 8669 were perimenopausal, 14,514 were naturally postmenopausal, and 904 were surgically postmenopausal. RESULTS: Compared to postmenopausal women aged 45 years, average total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) were 0.5 and 0.4 mmol/L higher, respectively, in postmenopausal women aged 50. Systolic and diastolic blood pressure levels were 4 and 1 mmHg higher, respectively. At all ages between 46 and 55 years, and after adjustment for confounders, naturally postmenopausal women had 0.2 to 0.4 mmol/L higher TC and 0.1 to 0.3 mmol/L higher LDL-c levels compared to premenopausal women in the same age range. Systolic blood pressure levels were up to 4 mmHg lower in naturally post- compared to premenopausal women at all ages between 29 and 52 years. Body mass index levels were up to 3.2 kg/m2 higher in women with surgical menopause compared to all other women between the ages 32 and 52 years. All aforementioned results were statistically significant. CONCLUSIONS: Chronological age and menopausal status are both independently associated with CVD risk factors. Based on the comparatively smaller observed differences associated with menopausal status than with chronological aging, the significance of a more unfavorable lipid profile in a later reproductive stage may be less obvious than previously thought.

Genetic variation in uncontrolled childhood asthma despite ICS treatment.

Genetic variation may partly explain asthma treatment response heterogeneity. We aimed to identify common and rare genetic variants associated with asthma that was not well controlled despite inhaled corticosteroid (ICS) treatment. Data of 110 children was collected in the Children Asthma Therapy Optimal trial. Associations of genetic variation with measures of lung function (FEV1%pred), airway hyperresponsiveness (AHR) to methacholine (Mch PD20) and treatment response outcomes were analyzed using the exome chip. The 17q12-21 locus (containing ORMDL3 and GSMDB) previously associated with childhood asthma was investigated separately. Single-nucleotide polymorphisms (SNPs) in the 17q12-21 locus were found nominally associated with the outcomes. The strongest association in this region was found for rs72821893 in KRT25 with FEV1%pred (P=3.75*10(-5)), Mch PD20 (P=0.00095) and Mch PD20-based treatment outcome (P=0.006). No novel single SNPs or burden tests were significantly associated with the outcomes. The 17q12-21 region was associated with FEV1%pred and AHR, and additionally with ICS treatment response.

Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis.

Background: We investigated causal effect of completed growth, measured by adult height, on coronary heart disease (CHD), stroke and cardiovascular traits, using instrumental variable (IV) Mendelian randomization meta-analysis. Methods: We developed an allele score based on 69 single nucleotide polymorphisms (SNPs) associated with adult height, identified by the IBCCardioChip, and used it for IV analysis against cardiovascular risk factors and events in 21 studies and 60 028 participants. IV analysis on CHD was supplemented by summary data from 180 height-SNPs from the GIANT consortium and their corresponding CHD estimates derived from CARDIoGRAMplusC4D. Results: IV estimates from IBCCardioChip and GIANT-CARDIoGRAMplusC4D showed that a 6.5-cm increase in height reduced the odds of CHD by 10% [odds ratios 0.90; 95% confidence intervals (CIs): 0.78 to 1.03 and 0.85 to 0.95, respectively],which agrees with the estimate from the Emerging Risk Factors Collaboration (hazard ratio 0.93; 95% CI: 0.91 to 0.94). IV analysis revealed no association with stroke (odds ratio 0.97; 95% CI: 0.79 to 1.19). IV analysis showed that a 6.5-cm increase in height resulted in lower levels of body mass index ( P < 0.001), triglycerides ( P < 0.001), non high-density (non-HDL) cholesterol ( P < 0.001), C-reactive protein ( P = 0.042), and systolic blood pressure ( P = 0.064) and higher levels of forced expiratory volume in 1 s and forced vital capacity ( P < 0.001 for both). Conclusions: Taller individuals have a lower risk of CHD with potential explanations being that taller people have a better lung function and lower levels of body mass index, cholesterol and blood pressure.

An epidemiologic risk prediction model for ovarian cancer in Europe: the EPIC study.

BACKGROUND: Ovarian cancer has a high case-fatality ratio, largely due to late diagnosis. Epidemiologic risk prediction models could help identify women at increased risk who may benefit from targeted prevention measures, such as screening or chemopreventive agents. METHODS: We built an ovarian cancer risk prediction model with epidemiologic risk factors from 202,206 women in the European Prospective Investigation into Cancer and Nutrition study. RESULTS: Older age at menopause, longer duration of hormone replacement therapy, and higher body mass index were included as increasing ovarian cancer risk, whereas unilateral ovariectomy, longer duration of oral contraceptive use, and higher number of full-term pregnancies were decreasing risk. The discriminatory power (overall concordance index) of this model, as examined with five-fold cross-validation, was 0.64 (95% confidence interval (CI): 0.57, 0.70). The ratio of the expected to observed number of ovarian cancer cases occurring in the first 5 years of follow-up was 0.90 (293 out of 324, 95% CI: 0.81-1.01), in general there was no evidence for miscalibration. CONCLUSION: Our ovarian cancer risk model containing only epidemiological data showed modest discriminatory power for a Western European population. Future studies should consider adding informative biomarkers to possibly improve the predictive ability of the model.

Diabetes and onset of natural menopause: results from the European Prospective Investigation into Cancer and Nutrition.

STUDY QUESTION: Do women who have diabetes before menopause have their menopause at an earlier age compared with women without diabetes? SUMMARY ANSWER: Although there was no overall association between diabetes and age at menopause, our study suggests that early-onset diabetes may accelerate menopause. WHAT IS KNOWN ALREADY: Today, more women of childbearing age are being diagnosed with diabetes, but little is known about the impact of diabetes on reproductive health. STUDY DESIGN, SIZE, DURATION: We investigated the impact of diabetes on age at natural menopause (ANM) in 258 898 women from the European Prospective Investigation into Cancer and Nutrition (EPIC), enrolled between 1992 and 2000. PARTICIPANTS/MATERIALS, SETTING, METHODS: Determinant and outcome information was obtained through questionnaires. Time-dependent Cox regression analyses were used to estimate the associations of diabetes and age at diabetes diagnosis with ANM, stratified by center and adjusted for age, smoking, reproductive and diabetes risk factors and with age from birth to menopause or censoring as the underlying time scale. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, no association between diabetes and ANM was found (hazard ratio (HR) = 0.94; 95% confidence interval (CI) 0.89-1.01). However, women with diabetes before the age of 20 years had an earlier menopause (10-20 years: HR = 1.43; 95% CI 1.02-2.01, <10 years: HR = 1.59; 95% CI 1.03-2.43) compared with non-diabetic women, whereas women with diabetes at age 50 years and older had a later menopause (HR = 0.81; 95% CI 0.70-0.95). None of the other age groups were associated with ANM. LIMITATIONS, REASONS FOR CAUTION: Strengths of the study include the large sample size and the broad set of potential confounders measured. However, results may have been underestimated due to survival bias. We cannot be sure about the sequence of the events in women with a late age at diabetes, as both events then occur in a short period. We could not distinguish between type 1 and type 2 diabetes. WIDER IMPLICATIONS OF THE FINDINGS: Based on the literature, an accelerating effect of early-onset diabetes on ANM might be plausible. A delaying effect of late-onset diabetes on ANM has not been reported before, and is not in agreement with recent studies suggesting the opposite association. STUDY FUNDING/COMPETING INTERESTS: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ) and Federal Ministry of Education and Research (BMMF) (Germany); Ministry of Health and Social Solidarity, Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC) and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skåne and Västerbotten (Sweden); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and Wellcome Trust (UK). None of the authors reported a conflict of interest.

Insulin-like growth factor I and risk of epithelial invasive ovarian cancer by tumour characteristics: results from the EPIC cohort.

BACKGROUND: Prospective studies on insulin-like growth factor I (IGF-I) and epithelial ovarian cancer (EOC) risk are inconclusive. Data suggest risk associations vary by tumour characteristics. METHODS: We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate IGF-I concentrations and EOC risk by tumour characteristics (n=565 cases). Multivariable conditional logistic regression models were used to estimate associations. RESULTS: We observed no association between IGF-I and EOC overall or by tumour characteristics. CONCLUSIONS: In the largest prospective study to date was no association between IGF-I and EOC risk. Pre-diagnostic serum IGF-I concentrations may not influence EOC risk.

Dietary intake of acrylamide and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort.

BACKGROUND: Three prospective studies have evaluated the association between dietary acrylamide intake and endometrial cancer (EC) risk with inconsistent results. The objective of this study was to evaluate the association between acrylamide intake and EC risk: for overall EC, for type-I EC, and in never smokers and never users of oral contraceptives (OCs). Smoking is a source of acrylamide, and OC use is a protective factor for EC risk. METHODS: Cox regression was used to estimate hazard ratios (HRs) for the association between acrylamide intake and EC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Acrylamide intake was estimated from the EU acrylamide monitoring database, which was matched with EPIC questionnaire-based food consumption data. Acrylamide intake was energy adjusted using the residual method. RESULTS: No associations were observed between acrylamide intake and overall EC (n=1382) or type-I EC risk (n=627). We observed increasing relative risks for type-I EC with increasing acrylamide intake among women who both never smoked and were non-users of OCs (HRQ5vsQ1: 1.97, 95% CI: 1.08-3.62; likelihood ratio test (LRT) P-value: 0.01, n=203). CONCLUSIONS: Dietary intake of acrylamide was not associated with overall or type-I EC risk; however, positive associations with type I were observed in women who were both non-users of OCs and never smokers.

The significance of fragile X mental retardation gene 1 CGG repeat sizes in the normal and intermediate range in women with primary ovarian insufficiency.

STUDY QUESTION: Are fragile X mental retardation gene 1 (FMR1) CGG repeats in the normal and intermediate range (up to 55 repeats) associated with primary ovarian insufficiency (POI) in a large case-control study? SUMMARY ANSWER: No association was found between CGG repeats of intermediate size and POI compared with controls. WHAT IS KNOWN ALREADY: CGG repeats in the FMR1 gene in the premutation range (55-200 repeats) have consistenly associated with POI. Intermediate range CGG repeats have been considered for a potential association with POI. STUDY DESIGN, SIZE: A case-control study in 375 well-phenotyped Dutch women diagnosed with POI and 3368 controls with natural menopause ≥40 years of age. PARTICIPANTS/MATERIALS, SETTING, METHODS: The FMR1 CGG repeat number was determined by PCR amplification in women diagnosed with POI and women with a known age at natural menopause ≥40 years. The prevalence of intermediate sized CGG repeats (45-54 repeats) was compared between POI cases and controls using Fisher's exact test. Differences in mean CGG repeat lengths on allele 1 and allele 2 between POI cases and controls were tested using analysis of variance. MAIN RESULTS AND THE ROLE OF CHANCE: The frequency of intermediate sized CGG repeats on the allele with the longest triple repeat number was not statistically significantly different between POI cases and controls (2.7 and 3.8%, respectively, odds ratio 0.72, 95% confidence interval: 0.38-1.39, P = 0.38). In women with POI, linear regression analysis for age at POI diagnosis and CGG repeat size also failed to show any association (ß = -0.018, P = 0.74). LIMITATIONS, REASONS FOR CAUTION: FMR1 CGG repeat lengths in POI cases and controls were genotyped in two different laboratories. The distributions of CGG repeats may vary among the different ethnic populations in our study. Also, in our study women with primary amenorrhea (N = 17) were included in the POI group. WIDER IMPLICATIONS OF THE FINDINGS: We found no association between intermediate sized CGG repeats and POI compared with controls. Therefore, a role for FMR1 CGG repeat sizes up to 55 repeats in the ovarian ageing process may be questioned. Moreover, there seems limited value in the evaluation of normal- and intermediate FMR1 repeat size in the diagnostic work-up of women affected by POI, or for prognostic purposes in women at risk of developing POI. STUDY FUNDING/COMPETING INTERESTS: The Prospect-EPIC study was funded by 'Europe Against Cancer' Program of the European Commission (SANCO); the Dutch Ministry of Health; the Dutch Cancer Society; ZonMW the Netherlands Organization for Health Research and Development; World Cancer Research Fund (WCRF) and the Dutch Heart Association.

Cholesteryl ester transfer protein polymorphisms, statin use, and their impact on cholesterol levels and cardiovascular events.

The association of nonfunctional variants of the cholesteryl ester transfer protein (CETP) with efficacy of statins has been a subject of debate. We evaluated whether three functional CETP variants influence statin efficacy. The effect of CETP genotype on achieved levels of high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), and total cholesterol during statin treatment was estimated by meta-analysis of the linear regression outcomes of three studies (11,021 individuals). The effect of these single-nucleotide polymorphisms (SNPs) on statin response in protecting against myocardial infarction (MI) was estimated by meta-analysis of statin × SNP interaction terms from logistic regression in five studies (16,570 individuals). The enhancer SNP rs3764261 significantly increased HDLc by 0.02 mmol/l per T allele (P = 6 × 10(-5)) and reduced protection against MI by statins (interaction odds ratio (OR) = 1.19 per T allele; P = 0.04). Focusing on functional CETP variants, we showed that in carriers of the rs3764261 T variant, HDLc increased more during statin treatment, and protection against MI by statins appeared to be reduced as compared with those in noncarriers.

Dietary patterns derived from principal component- and k-means cluster analysis: long-term association with coronary heart disease and stroke.

BACKGROUND AND AIMS: Studies comparing dietary patterns derived from different a posteriori methods in view of predicting disease risk are scarce. We aimed to explore differences between dietary patterns derived from principal component- (PCA) and k-means cluster analysis (KCA) in relation to their food group composition and ability to predict CHD and stroke risk. METHODS AND RESULTS: The study was conducted in the EPIC-NL cohort that consists of 40,011 men and women. Baseline dietary intake was measured using a validated food-frequency questionnaire. Food items were consolidated into 31 food groups. Occurrence of CHD and stroke was assessed through linkage with registries. After 13 years of follow-up, 1,843 CHD and 588 stroke cases were documented. Both PCA and KCA extracted a prudent pattern (high intakes of fish, high-fiber products, raw vegetables, wine) and a western pattern (high consumption of French fries, fast food, low-fiber products, other alcoholic drinks, soft drinks with sugar) with small variation between components and clusters. The prudent component was associated with a reduced risk of CHD (HR for extreme quartiles: 0.87; 95%-CI: 0.75-1.00) and stroke (0.68; 0.53-0.88). The western component was not related to any outcome. The prudent cluster was related with a lower risk of CHD (0.91; 0.82-1.00) and stroke (0.79; 0.67-0.94) compared to the western cluster. CONCLUSION: PCA and KCA found similar underlying patterns with comparable associations with CHD and stroke risk. A prudent pattern reduced the risk of CHD and stroke.

The association of CGG repeats in the FMR1 gene and timing of natural menopause.

STUDY QUESTION: Is there an association between the number of CGG repeats in the FMR1 gene in the normal and intermediate range and age at natural menopause? SUMMARY ANSWER: The number of CGG repeats in the normal and intermediate range in the FMR1 gene was not associated with age at natural menopause. WHAT IS KNOWN ALREADY: Excessive triple CGG repeats in the FMR1 gene have been widely associated with primary ovarian insufficiency. Recently, the number of CGG repeats in the normal and intermediate range (up to 55 repeats) was found to be associated with serum levels of anti-Müllerian hormone and follicle-stimulating hormone, as markers for ovarian ageing. This suggests that repeats in the normal and intermediate range could be involved in the rate of exhaustion of the ovarian primordial follicle pool and ultimately the timing of menopause. STUDY DESIGN, SIZE: Cross-sectional study in a population-based sample of 3611 Caucasian women with natural menopause. PARTICIPANTS/MATERIALS, SETTING, METHODS: The FMR1 CGG repeat number was determined by PCR amplification in 3611 women with a known age at natural menopause. A possible relation between CGG repeats in the normal and intermediate range (up to 55 repeats) and menopausal age were analysed in various ways, including linear regression analysis and analysis of variance. MAIN RESULTS AND THE ROLE OF CHANCE: The number of CGG repeats in the normal and intermediate range in the FMR1 gene was not associated with age at natural menopause. The mean age at menopause was 50.30 (± 4.2) years for women with <45 repeats and 50.64 (± 3.4) years for women with intermediate-sized repeats (P = 0.37). Linear regression analysis of the number of CGG repeats showed no association with menopausal age (ß = 0.019, P = 0.16). LIMITATIONS, REASONS FOR CAUTION: In our cohort, age at menopause was self-reported and determined retrospectively. WIDER IMPLICATIONS OF THE FINDINGS: Earlier observations suggesting that the number of CGG repeats in the normal and intermediate range is associated with the individual variation of the ovarian ageing process could not be confirmed in the current, large sample size study. A relation between the number of CGG repeats in the normal and intermediate range and age at natural menopause appeared to be absent. This finding questions the role of CGG repeat sizes in the ovarian ageing process.

Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: It is well established that parity and use of oral contraceptives reduce the risk of ovarian cancer, but the associations with other reproductive variables are less clear. METHODS: We examined the associations of oral contraceptive use and reproductive factors with ovarian cancer risk in the European Prospective Investigation into Cancer and Nutrition. Among 327,396 eligible women, 878 developed ovarian cancer over an average of 9 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models stratified by centre and age, and adjusted for smoking status, body mass index, unilateral ovariectomy, simple hysterectomy, menopausal hormone therapy, and mutually adjusted for age at menarche, age at menopause, number of full-term pregnancies and duration of oral contraceptive use. RESULTS: Women who used oral contraceptives for 10 or more years had a significant 45% (HR, 0.55; 95% CI, 0.41-0.75) lower risk compared with users of 1 year or less (P-trend, <0.01). Compared with nulliparous women, parous women had a 29% (HR, 0.71; 95% CI, 0.59-0.87) lower risk, with an 8% reduction in risk for each additional pregnancy. A high age at menopause was associated with a higher risk of ovarian cancer (>52 vs ≤ 45 years: HR, 1.46; 95% CI, 1.06-1.99; P-trend, 0.02). Age at menarche, age at first full-term pregnancy, incomplete pregnancies and breastfeeding were not associated with risk. CONCLUSION: This study shows a strong protective association of oral contraceptives and parity with ovarian cancer risk, a higher risk with a late age at menopause, and no association with other reproductive factors.

Genetic susceptibility to sporadic ovarian cancer: a systematic review.

Ovarian cancer is a highly lethal disease. Many researchers have, therefore, attempted to identify high risk populations. In this perspective, numerous genetic association studies have been performed to discover common ovarian cancer susceptibility variants. Accordingly, there is an increasing need to synthesize the evidence in order to identify true associations. A comprehensive and systematic assessment of all available data on genetic susceptibility to sporadic ovarian cancer was carried out. The evidence of statistically significant findings was evaluated based on the number of positive replications, the ratio of positive and negative studies, and the false-positive report probability (FPRP). The authors reviewed three genome-wide association studies (GWAS) and 147 candidate gene studies, published from 1990 to October 2010, including around 1100 genetic variants in more than 200 candidate genes and 20 intergenic regions. Genetic variants with the strongest evidence for an association with ovarian cancer include the rs2854344 in the RB1 gene and SNPs on chromosomes 9p22.2, 8q24, 2q31, and 19p13. Promising genetic pathways for ovarian cancer include the cell cycle, DNA repair, sex steroid hormone and oncogenic pathway. Concluding, this review shows that many genetic association studies have been performed, but only a few genetic variants show strong evidence for an association with ovarian cancer. More research is needed to elucidate causal genetic variants, taking into consideration gene-gene and gene-environment interactions, combined effects of common and rare variants, and differences between histological subtypes of this cancer.