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Background: Left ventricular ejection fraction (EF) is used to categorize heart failure (HF) into phenotypes but this information is often missing in electronic health records or non-HF registries. Methods: We tested the applicability of a simplified version of a multivariable algorithm, that was developed on data of the Swedish Heart Failure Registry to predict EF in patients with HF. We used data from 4,868 patients with HF from the Cardiology Centers of the Netherlands database, an organization of 13 cardiac outpatient clinics that operate between the general practitioner and the hospital cardiologist. The algorithm included 17 demographical and clinical variables. We tested model discrimination, model performance and calculated model sensitivity, specificity, positive and negative predictive values for EF ≥ vs. <50% and EF ≥ vs. <40%. We additionally performed a multivariable multinomial analysis for all three separate HF phenotypes (with reduced, mildly reduced and preserved EF) HFrEF vs. HFmrEF vs. HFpEF. Finally, we internally validated the model by using temporal validation. Results: Mean age was 66 ±12 years, 44% of patients were women, 68% had HFpEF, 17% had HFrEF, and 15% had HFmrEF. The C-statistic was of 0.71 for EF ≥/< 50% (95% CI: 0.69–0.72) and of 0.74 (95% CI: 0.73–0.75) for EF ≥/< 40%. The model had the highest sensitivities for EF ≥50% (0.72, 95% CI: 0.63–0.75) and for EF ≥40% (0.70, 95% CI: 0.65–0.71). Similar results were achieved by the multinomial model, but the C-statistics for predicting HFpEF vs HFrEF was lower (0.61, 95% CI 0.58–0.63). The internal validation confirmed good discriminative ability. Conclusions: A simple algorithm based on routine clinical characteristics can help discern HF phenotypes in non-cardiology datasets and research settings such as research on primary care data, where measurements of EF is often not available. [ABSTRACT FROM AUTHOR]

Background: A healthy diet is important for normal growth and development. Exposure to undernutrition during important developmental periods such as childhood and adolescence can have effects later in life. Inhabitants of the west of the Netherlands were exposed to severe undernutrition during the famine in the last winter of the second World War (1944–1945). Objective: We investigated if exposure of women to the Dutch famine during childhood and adolescence was associated with an unhealthy lifestyle later in life. Design: We studied 7,525 women from the Prospect-EPIC cohort, recruited in 1993–97 and aged 0–18 years during the Dutch famine. An individual famine score was calculated based on self-reported information about experience of hunger and weight loss. We investigated the association between famine exposure in early life and four lifestyle factors in adulthood: smoking, alcohol consumption, physical activity level and a Mediterranean-style diet. Results: Of the 7,525 included women, 46% were unexposed, 38% moderately exposed and 16% severely exposed to the Dutch famine. Moderately and severely exposed women were more often former or current smokers compared to women that did not suffer from the famine: adjusted prevalence ratio 1.10 (95% CI: 1.05; 1.14) and 1.18 (1.12; 1.25), respectively. They also smoked more pack years than unexposed women. Severely exposed women were more often physically inactive than unexposed women, adjusted prevalence ratio 1.32 (1.06; 1.64). Results did not differ between exposure age categories (0–9 and 10–17 years). We found no associations of famine exposure with alcohol consumption and no dose-dependent relations with diet. Conclusions: Exposure to famine early in female life may be associated with higher prevalence of smoking and physical inactivity later in life, but not with unhealthy diet and alcohol consumption. [ABSTRACT FROM AUTHOR]

The aim of our study was to relate four modifiable lifestyle factors (smoking status, body mass index, physical activity and diet) to health expectancy, using quality-adjusted life years (QALYs) in a prospective cohort study. Data of the prospective EPIC-NL study were used, including 33,066 healthy men and women aged 20–70 years at baseline (1993–7), followed until 31-12-2007 for occurrence of disease and death. Smoking status, body mass index, physical activity and adherence to a Mediterranean-style diet (excluding alcohol) were investigated separately and combined into a healthy lifestyle score, ranging from 0 to 4. QALYs were used as summary measure of healthy life expectancy, combining a person's life expectancy with a weight for quality of life when having a chronic disease. For lifestyle factors analyzed separately the number of years living longer in good health varied from 0.12 year to 0.84 year, after adjusting for covariates. A combination of the four lifestyle factors was positively associated with higher QALYs (P-trend <0.0001). A healthy lifestyle score of 4 compared to a score of 0 was associated with almost a 2 years longer life in good health (1.75 QALYs [95% CI 1.37, 2.14]). [ABSTRACT FROM AUTHOR]

Background: Disability-Adjusted Life Years (DALYs) have the advantage that effects on total health instead of on a specific disease incidence or mortality can be estimated. Our aim was to address several methodological points related to the computation of DALYs at an individual level in a follow-up study. Methods: DALYs were computed for 33,507 men and women aged 20–70 years when participating in the EPIC-NL study in 1993–7. DALYs are the sum of the Years Lost due to Disability (YLD) and the Years of Life Lost (YLL) due to premature mortality. Premature mortality was defined as death before the estimated date of individual Life Expectancy (LE). Different methods to compute LE were compared as well as the effect of different follow-up periods using a two-part model estimating the effect of smoking status on health as an example. Results: During a mean follow-up of 12.4 years, there were 69,245 DALYs due to years lived with a disease or premature death. Current-smokers had lost 1.28 healthy years of their life (1.28 DALYs 95%CI 1.10; 1.46) compared to never-smokers. The outcome varied depending on the method used for estimating LE, completeness of disease and mortality ascertainment and notably the percentage of extinction (duration of follow-up) of the cohort. Conclusion: We conclude that the use of DALYs in a cohort study is an appropriate way to assess total disease burden in relation to a determinant. The outcome is sensitive to the LE calculation method and the follow-up duration of the cohort. [ABSTRACT FROM AUTHOR]

The onset of menopause has important implications on women’s fertility and health. We previously identified genetic variants in genes involved in initial follicle recruitment as potential modifiers of age at natural menopause. The objective of this study was to extend our previous study, by searching for pairwise interactions between tagging single nucleotide polymorphisms (tSNPs) in the 5 genes previously selected (AMH, AMHR2, BMP15, FOXL2, GDF9). We performed a cross-sectional study among 3445 women with a natural menopause participating in the Prospect-EPIC study, a population-based prospective cohort study, initiated between 1993 and 1997. Based on the model-based multifactor dimensionality reduction (MB-MDR) test with a permutation-based maxT correction for multiple testing, we found a statistically significant interaction between rs10407022 in AMH and rs11170547 in AMHR2 (p = 0.019) associated with age at natural menopause. Rs10407022 did not have a statistically significant main effect. However, rs10407022 is an eQTL SNP that has been shown to influence mRNA expression levels in lymphoblastoid cell lines. This study provides additional insights into the genetic background of age at natural menopause and suggests a role of the AMH signaling pathway in the onset of natural menopause. However, these results remain suggestive and replication by independent studies is necessary. [ABSTRACT FROM AUTHOR]

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG 2106 concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8x10-106 ), PRMT6 (rs17496332, 1p13.3, 211 216 209 p= 1.4x10-11 ), GCKR (rs780093, 2p23.3,p= 2.2x10-16 ), ZBTB10 (rs440837, 8q21.13,p= 3.4x10-09 ), JMJD1C (rs7910927, 10q21.3, 235 208 212 p= 6.1x10-35 ), SLCO1B1 (rs4149056, 12p12.1,p = 1.9x10-08 ), NR2F2 (rs8023580, 15q26.2,p = 8.3x10-12 ), ZNF652 (rs2411984, 214 214 207 17q21.32,p = 3.5610 ), TDGF3 (rs1573036, Xq22.3,p = 4.1x10-14 ), LHCGR (rs10454142, 2p16.3,p = 1.3x10-07 ), BAIAP2L1 208 206 (rs3779195, 7q21.3,p= 2.7x10-08 ), and UGT2B15 (rs293428, 4q13.2,p= 5.5x10-06 ). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was 208 significant in men only (men p = 2.5x10-08, women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex- differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance. [ABSTRACT FROM AUTHOR]

While the risk of ovarian cancer clearly reduces with each full-term pregnancy, the effect of incomplete pregnancies is unclear. We investigated whether incomplete pregnancies (miscarriages and induced abortions) are associated with risk of epithelial ovarian cancer. This observational study was carried out in female participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 274,442 women were followed from 1992 until 2010. The baseline questionnaire elicited information on miscarriages and induced abortions, reproductive history, and lifestyle-related factors. During a median follow-up of 11.5 years, 1,035 women were diagnosed with incident epithelial ovarian cancer. Despite the lack of an overall association (ever vs. never), risk of ovarian cancer was higher among women with multiple incomplete pregnancies (HR≥4vs.0: 1.74, 95% CI: 1.20-2.70; number of cases in this category: n = 23). This association was particularly evident for multiple miscarriages (HR≥4vs.0: 1.99, 95% CI: 1.06-3.73; number of cases in this category: n = 10), with no significant association for multiple induced abortions (HR≥4vs.0: 1.46, 95% CI: 0.68-3.14; number of cases in this category: n = 7). Our findings suggest that multiple miscarriages are associated with an increased risk of epithelial ovarian cancer, possibly through a shared cluster of etiological factors or a common underlying pathology. These findings should be interpreted with caution as this is the first study to show this association and given the small number of cases in the highest exposure categories. [ABSTRACT FROM AUTHOR]

Background: Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients. Methodology: The KCNQ1 variants rs151290, rs2237892, and rs2237895 were genotyped in a total of 4620 type 2 diabetes patients and 5285 healthy controls from the Netherlands. Data on macrovascular complications, nephropathy and retinopathy were available in a subset of diabetic patients. Association between genotype and insulin secretion/action was assessed in the additional sample of 335 individuals who underwent a hyperglycaemic clamp. Principal Findings: We found that all the genotyped KCNQ1 variants were significantly associated with type 2 diabetes in our Dutch population, and the association of rs151290 was the strongest (OR 1.20, 95% CI 1.07-1.35, p = 0.002). The risk Callele of rs151290 was nominally associated with reduced first-phase glucose-stimulated insulin secretion, while the non-risk T-allele of rs2237892 was significantly correlated with increased second-phase glucose-stimulated insulin secretion (p = 0.025 and 0.0016, respectively). In addition, the risk C-allele of rs2237892 was associated with higher LDL and total cholesterol levels (p = 0.015 and 0.003, respectively). We found no evidence for an association of KCNQ1 with diabetic complications. Conclusions: Common variants in the KCNQ1 gene are associated with type 2 diabetes in a Dutch population, which can be explained at least in part by an effect on insulin secretion. Furthermore, our data suggest that KCNQ1 is also associated with lipid metabolism. [ABSTRACT FROM AUTHOR]

There is a large variation in caloric intake and macronutrient preference between individuals and between ethnic groups, and these food intake patterns show a strong heritability. The transition to new food sources during the agriculture revolution around 11,000 years ago probably created selective pressure and shaped the genome of modern humans. One major player in energy homeostasis is the appetite-stimulating hormone neuropeptide Y, in which the stimulatory capacity may be mediated by the neuropeptide Y receptors 1, 2 and 5 (NPY1R, NPY2R and NPY5R). We assess association between variants in the NPY1R, NPY2R and NPY5R genes and nutrient intake in a cross-sectional, single-center study of 400 men aged 40 to 80 years, and we examine whether genomic regions containing these genes show signatures of recent selection in 270 HapMap individuals (90 Africans, 90 Asians, and 90 Caucasians) and in 846 Dutch bloodbank controls. Our results show that derived alleles in NPY1R and NPY5R are associated with lower carbohydrate intake, mainly because of a lower consumption of mono- and disaccharides. We also show that carriers of these derived alleles, on average, consume meals with a lower glycemic index and glycemic load and have higher alcohol consumption. One of these variants shows the hallmark of recent selection in Europe. Our data suggest that lower carbohydrate intake, consuming meals with a low glycemic index and glycemic load, and/or higher alcohol consumption, gave a survival advantage in Europeans since the agricultural revolution. This advantage could lie in overall health benefits, because lower carbohydrate intake, consuming meals with a low GI and GL, and/or higher alcohol consumption, are known to be associated with a lower risk of chronic diseases. [ABSTRACT FROM AUTHOR]

Background. The TUB gene, encoding an evolutionary conserved protein, is highly expressed in the hypothalamus and might act as a transcription factor. Mutations in TUB cause late-onset obesity, insulin-resistance and neurosensory deficits in mice. An association of common variants in the TUB gene with body weight in humans has been reported. Methods/Findings. The aim was to investigate the relationship of single nucleotide polymorphisms (SNPs) of the TUB gene (rs2272382, rs2272383 and rs1528133) with both anthropometry and self-reported macronutrient intake from a validated food frequency questionnaire. These associations were studied in a population-based, cross-sectional study of 1680 middleaged Dutch women, using linear regression analysis. The minor allele C of the rs1528133 SNP was significantly associated with increased weight (+1.88 kg, P = 0.022) and BMI (+0.56 units, P = 0.05). Compared with non-carriers, both AG heterozygotes and AA homozygotes of the rs2272382 SNP derived less energy from fat (AG: -0.55±0.28%, P = 0.05, AA: -0.95±0.48%, P = 0.047). However, both genotypes were associated with an increased energy intake from carbohydrates (0.69±0.33%, P = 0.04 and 1.68±0.56%, P = 0.003, respectively), mainly because of a higher consumption of mono- and disaccharides. Both these SNPs, rs2272382 and rs1528133, were also associated with a higher glycemic load in the diet. The glycemic load was higher among those with AG and AA genotypes for the variant rs2272382 than among the wild types (+1.49 (95% CI: -0.27-3.24) and +3.89 (95% CI: 0.94-6.85) units, respectively). Carriers of the minor allele C of rs1528133 were associated with an increased glycemic load of 1.85 units compared with non-carriers. Conclusions. Genetic variation of the TUB gene was associated with both body composition and macronutrient intake, suggesting that TUB might influence eating behavior. [ABSTRACT FROM AUTHOR]

Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of ∼2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom ∼50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) \((p = 8.8×10^{−7} and p = 1.5×10^{−6}\) respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels \((p = 13.5×10^{−12})\). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report.

Background: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268)., Methods and Findings: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction)  = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio  = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio  = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents., Conclusions: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.