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Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17 000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P

Introduction: To establish an up-to-date and comprehensive set of normal values for the clinically current measurements in the adult ECG, covering all ages for both sexes.Methods: The study population included 13,354 individuals, taken from four population studies in The Netherlands, ranging in age from 16 to 90 years (55% men) and cardiologically healthy by commonly accepted criteria. Standard 12-lead ECGs were available for all participants. The ECGs were processed by a well-validated computer program. Normal limits were taken as the 2nd and 98th percentiles of the measurement distribution per age group.Results: Our study corroborates many findings of previous studies, but also provides more differentiated results, in particular for the older age groups. Age trends were apparent for the QTc interval, QRS axis, and indices of left ventricular hypertrophy. Amplitudes in the left precordial leads showed a substantial increase in the older age groups for women, but not for men. Sex-dependent differences were apparent for most ECG parameters. All results are available on the Website www.normalecg.org, both in tabular and in graphical format.Conclusions: We determined age- and sex-dependent normal values of the adult ECG. Our study distinguishes itself from other studies by the large size of the study population, comprising both sexes, the broad range of ages, and the exhaustive set of measurements. Our results emphasize that most diagnostic ECG criteria should be age- and sex-specific. (C) 2014 Elsevier Inc. All rights reserved.

There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000. ispartof: Nature vol:490 issue:7419 pages:267-272 ispartof: location:England status: published

Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 × 10⁻⁸): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity. © 2009 Nature America, Inc. All rights reserved.

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

Contains fulltext : 110955.pdf (Publisher’s version ) (Closed access) It has been demonstrated that aortic stiffness is an independent predictor of cardiovascular disease. We investigated whether this measure is of use in cardiovascular risk stratification in clinical practice for elderly subjects (mean age 71.5 years). Within the framework of the Rotterdam Study, we stratified subjects free of coronary heart disease (CHD) at baseline into categories of low (20%) 10-year risk of CHD based on Framingham risk factors. Within each risk category, we determined the percentages of subjects moving into a higher or lower risk category when adding aortic stiffness to the Framingham risk factors. Among 2849 participants, 223 CHD events occurred during a median follow-up of 7.9 years. In the low risk group, 5% of the subjects could be reclassified and in the high-risk group, 6% of the subjects could be reclassified to the intermediate-risk group. In the intermediate-risk group 3% could be reclassified to the high-risk group and 6% to the low-risk group. In a population of elderly subjects, aortic stiffness measurement in addition to Framingham risk factors leads to a limited reclassification of subjects in 10-year cardiovascular disease-risk categories. Therefore, aortic stiffness is associated with the risk of CHD in elderly, but provides no additional value in cardiovascular risk stratification. 01 januari 2012

Summary Background Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4–38·2) and of interleukin 6 by 14·6% (10·7–18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9–9·1) and of fibrinogen by 1·0% (0·7–1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8–5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. Funding British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

OBJECTIVES: To clarify the association between cholesterol and noncardiovascular mortality and to evaluate how this association varies across age groups. DESIGN: Prospective population-based cohort study. SETTING: Rotterdam, the Netherlands. PARTICIPANTS: Adults aged 55 to 99 (N = 5,750). MEASUREMENTS: Participants were evaluated for total cholesterol and subfractions and followed for mortality for a median of 13.9 years. Total cholesterol and its subfractions were evaluated in relation to noncardiovascular mortality. Cox regression analyses were conducted in the total sample and within age-groups (55 64, 65 74, 75 84, >= 85). RESULTS: Age- and sex-adjusted analyses showed that each 1-mmol/L increase in total cholesterol was associated with an approximately 12% lower risk of noncardiovascular mortality (hazard ratio (HR) = 0.88, 95% confidence interval (CI) = 0.84-0.92, P < .001). Age group-specific analyses demonstrated that this association reached significance after the age of 65 and increased in magnitude across each subsequent decade. This was driven largely by non-high-density lipoprotein cholesterol (non-HDL-C) (HR = 0.89, 95% CI 0.85-0.93, P < .001) and was partly attributable to cancer mortality. Conversely, HDL-C was not significantly associated with noncardiovascular mortality (HR = 0.92, 95% CI 0.79-1.07, P = .26). CONCLUSION: Higher total cholesterol was associated with a lower risk of noncardiovascular mortality in older adults. This association varied across the late-life span and was stronger in older age groups. Further research is required to examine the mechanisms underlying this association. J Am Geriatr Soc 59:1779-1785, 2011.

OBJECTIVES: To identify the main age-related factors responsible for cardiomyopathy in people with end-stage renal disease (ESRD). DESIGN: Cross-sectional. SETTING: Dialysis unit. PARTICIPANTS: Two hundred fifty-four individuals undergoing chronic dialysis. MEASUREMENTS: Left ventricular (LV) systolic function (assessed according to midwall fractional shortening (mwFS)) and LV mass index (LVMI). RESULTS: At echocardiography, 196 (77%) participants displayed LV hypertrophy (LVH) and 123 (48%) had LV systolic dysfunction. On univariate analysis, age was related directly to LVMI (correlation coefficient (r)=0.33, P

Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels. European Journal of Human Genetics (2011) 19, 813-819; doi:10.1038/ejhg.2011.21; published online 30 March 2011

Background— Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search. Methods and Results— A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log–transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 ( P =6.4×10 −52 ) was 46.0 kb upstream from F3 , coagulation factor III (tissue factor). At 1q24, rs6687813 ( P =2.4×10 −14 ) was 79.7 kb downstream of F5 , coagulation factor V. At 4q32, rs13109457 ( P =2.9×10 −18 ) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA . Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log–transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus. Conclusions— Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.

The incidence of heart failure increases with aging. Aim of the present, study was to determine whether measures body composition predict incident heart failure in older adults. Prospective community-based cohort study. 5, 868 men and women aged 55 years and older participating the Rotterdam study. Measures of body mass index and waist circumference were obtained at baseline. Information on incident heart failure was obtained during follow-up. Cox regression analyses were performed to investigate the possible association between measure of body composition and incident heart failure. During a mean follow up of 10.9 (SD +/- 4.4) years, 765 participants had heart failure. After adjustment for age and gender, 1-standard deviation of body mass index, waist circumference and the waist-hip ratio predicted heart failure (HR 1.25; 95% CI 1.17-1.34; HR 1.26; 95% CI 1.18-1.36; and HR 1.17; 95% CI 1.08-1.27), respectively. In age-stratified analyses, 1-standard deviation of body mass index (1.17; 95% CI 1.06-1.29) and waist circumference (1.16; 95% CI 1.05-1.29) were still associated with the risk of heart failure in the oldest participants, whereas the waist-hip ratio was not (1.06; 95% CI 0.945-1.18). Although estimates decrease with age, measures of overall and central adiposity predict incident heart failure among community dwelling older adults.

Reclassification is observed even when there is no or minimal improvement in the area under the receiver operating characteristic curve (AUC), and it is unclear whether it indicates improved clinical utility. The authors investigated total reclassification, net reclassification improvement, and integrated discrimination improvement for different delta AUC using empirical and simulated data. Empirical analyses compared prediction of type 2 diabetes risk based on age, sex, and body mass index with prediction updated with 18 established genetic risk factors. Simulated data were used to investigate measures of reclassification against delta AUCs of 0.005, 0.05, and 0.10. Total reclassification and net reclassification improvement were calculated for all possible cutoff values. The AUC of type 2 diabetes risk prediction improved from 0.63 to 0.66 when 18 polymorphisms were added, whereas total reclassification ranged from 0% to 22.5% depending on the cutoff value chosen. In the simulation study, total reclassification, net reclassification improvement, and integrated discrimination improvement increased with higher delta AUC. When delta AUC was low (0.005), net reclassification improvement values were close to zero, integrated discrimination improvement was 0.08% (P > 0.05), but total reclassification ranged from 0 to 6.7%. Reclassification increases with increasing AUC but predominantly varies with the cutoff values chosen. Reclassification observed in the absence of AUC increase is unlikely to improve clinical utility.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P-8), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD. © 2010 Macmillan Publishers Limited. All rights reserved.

Background: Little is known about the effect of different types of dairy food products on the development of hypertension. Objective: The objective was to determine whether the incidence of hypertension in older Dutch subjects is associated with intake of dairy products. Design: We examined the relation between dairy intake and incident hypertension in 2245 participants of the Rotterdam Study aged >= 55 y with complete dietary and blood pressure data, who were free of hypertension at baseline (1990-1993). Blood pressure was reexamined in 1993-1995 and in 1997-1999. Hazard ratios (HRs) with 95% CIs for 2-and 6-y incidence of hypertension were obtained in quartiles of energy-adjusted dairy intake, with adjustment for age, sex, BMI, smoking, educational level, dietary factors, and intake of alcohol and total energy. Results: Risk of hypertension after 2 y of follow-up (664 incident cases) was inversely associated with dairy product intake. After adjustment for confounders, HRs (95% CIs) were 1.00, 0.82 (0.67, 1.02), 0.67 (0.54, 0.84), and 0.76 (0.61, 0.95) in consecutive quartiles of total dairy product intake (P for trend = 0.008). Corresponding HRs for low-fat dairy products were 1.00, 0.75 (0.60, 0.92), 0.77 (0.63, 0.96), and 0.69 (0.56, 0.86) (P for trend = 0.003). Analysis of specific types of dairy products showed an inverse association with milk and milk products (P for trend = 0.07) and no association with high-fat dairy or cheese (P > 0.6). After 6 y of follow-up (984 incident cases), the associations with hypertension were attenuated to risk reductions of approximate to 20% for both total and low-fat dairy products between the extreme quartiles of intake (P for trend = 0.07 and 0.09, respectively). Conclusion: Intake of low-fat dairy products may contribute to the prevention of hypertension at an older age. Am J Clin Nutr 2009; 89: 1877-83.

OBJECTIVES: To determine the prognostic role of orthostatic hypotension for cardiovascular disease (CVD) and all-cause mortality in elderly people. DESIGN: Prospective study. SETTING: Community based. PARTICIPANTS: Five thousand sixty-four subjects from the Rotterdam study aged 55 and older. MEASUREMENTS: Orthostatic hypotension was measured using a Dinamap automatic blood pressure recorder. Orthostatic hypotension is defined as a decline in systolic blood pressure of 20mmHg or more or a decline in diastolic blood pressure of 10mmHg or more from supine to standing position at any of three measurements taken 1, 2, and 3 minutes after standing. RESULTS: At baseline, 901 subjects had orthostatic hypotension. During follow-up, 668 subjects had coronary heart disease (CHD) (mean follow-up 6.0 � 3.5 years), and 1,835 subjects died (mean follow-up period 7.8 � 3.8 years). Orthostatic hypotension increased the risk of CHD (hazard ratio (HR) 51.31, 95% confidence interval (CI) 51.08‐ 1.57) and all-cause mortality (HR 51.22, 95% CI 51.09‐ 1.36), in models adjusted for age and sex. The risk was slightly lower after additional adjustment for cardiovascular risk factors. In analyses stratified for age, the HRs for all-cause mortality were 1.80 (95% CI 1.25‐2.60), 1.13 (0.89‐1.42), and 1.27 (95% CI 51.11‐1.44), in the first, second, and third tertile of age, respectively. CONCLUSION: Orthostatic hypotension increases the risk of CHD and all-cause mortality in elderly people. The risk of CVD and mortality is strongest in younger and very old subjects. J Am Geriatr Soc 56:1816–1820, 2008.

OBJECTIVE The assessment of blood pressure (BP) in individuals is traditionally based on a few BP readings obtained at intervals of just a few minutes. We examined if increasing intervals between BP readings on one visit would have an impact on the BP estimates. METHODS We conducted an examination survey of cardiovascular risk factors in the general population aged 25-64 years in Seychelles (Indian Ocean), attended by 1255 of 1565 eligible participants. BP was measured once shortly after participants' arrival to the study centers (BP1) and twice before discharge, 15-351 min later (BP2, BP3; separated by 2 min). RESULTS Mean (standard error) BP1 was 135.1 (0.7)/87.9 (0.4) mmHg, BP2: 130.7 (0.6)/85.1 (0.4) mmHg and BP3: 128.4 (0.6)/83.9 (0.3) mmHg. The difference in BP between the first and the last measurements (DeltaBP1-BP3) was, respectively, 5.8 (1.3)/2.6 (0.9) mmHg for a time interval between BP1 and BP3 of 15-60 min, 6.3 (0.5)/3.9 (0.3) mmHg for 61-120 min, 6.9 (0.6)/4.1 (0.4) mmHg for 121-240 min and 7.4 (0.7)/4.3 (0.5) mmHg for 241-351 min (P-trend for systolic/diastolic BP: 0.15/0.49). In multivariate analysis, both systolic and diastolic DeltaBP were associated with the initial BP level and the female sex but not with time (in minutes) between BP readings (for systolic/diastolic BP, P=0.12/0.34). CONCLUSION The decrease in subsequent BP readings obtained did not differ whether the time interval between BP measurements was larger or smaller than 1 h. This indirectly suggests that extending the time interval between repeated BP readings on one single visit is unlikely to be a valid, alternative strategy to the recommendation of gathering BP readings on several, separate visits to define hypertension.

OBJECTIVES: To investigate whether higher circulating levels of C-reactive protein (CRP), interleukin-6 (IL-6), and a1-antichymotrypsin (ACT) are associated with worse cognitive function and decline in old age. DESIGN: Two independent population-based cohort studies. SETTING: The Rotterdam Study (mean follow-up 4.6 years) and the Leiden 85-plus Study (maximal follow-up 5 years). PARTICIPANTS: Three thousand eight hundred seventyfour individuals, mean age 72, from the Rotterdam Study, and 491 individuals, all aged 85, from the Leiden 85-plus Study. MEASUREMENTS: Both studies assessed global cognition, executive function, and memory. Linear regression analyses were used in the current study to investigate the associations between inflammatory markers and cognitive function and decline. RESULTS: In the Rotterdam Study, higher levels of CRP and IL-6 were cross-sectionally associated with worse global cognition and executive function (Po.05). ACT was not associated with cognitive function. In the Leiden 85-plus Study, estimates were similar for CRP, although not statistically significant. Higher IL-6 levels were related to a steeper annual decline in memory function in the longitudinal analysis in the Leiden 85-plus Study (Po.05). The effect of higher IL-6 levels on global and memory function decline was stronger in apolipoprotein E (APOE) e4 carriers (P-interaction 5.01) than in those who were not (P-interaction 5.05). In the Rotterdam Study, higher IL-6 levels were related to a steeper annual decline in global cognition in APOE e4 carriers only. CONCLUSION: Systemic markers of inflammation are only moderately associated with cognitive function and decline and tend to be stronger in carriers of the APOE e4 allele. Systemic markers of inflammation are not suitable for risk stratification. J Am Geriatr Soc 55:708‐716, 2007.

Contains fulltext : 52445.pdf (Publisher’s version ) (Closed access) TGF-beta1 has a dual role in carcinogenesis. In this gene, a leucine to proline substitution in codon 10 leads to higher circulating levels of TGF-beta1. This variant has been studied in relationship to the risk for breast cancer yielding contradicting results. We aim to unravel the relationship of this polymorphism and the risk of breast cancer. Women participating in the Rotterdam Study including 143 patients with incident breast cancer were genotyped for this polymorphism. We carried out a logistic regression and a survival analysis using age as the time variable. The logistic regression analysis showed an increased risk of breast cancer for Proline carriers (OR=1.4; 95% confidence interval (CI)=1.1-2.0) versus non-carriers. The survival analysis showed that carriers of the same allele had an increased risk of breast cancer (HR=1.4, 95% CI=1.1-2.0) against non-carriers. Our data suggest that the TGF-beta1 Leu10Pro polymorphism might play a role in breast cancer risk.

Electrocardiogram (ECG) measurements are a powerful tool for evaluating cardiac function and are widely used for the diagnosis and prediction of a variety of conditions, including myocardial infarction, cardiac arrhythmias, and sudden cardiac death. Recently, genome-wide association studies (GWASs) identified a large number of genes related to ECG parameter variability, specifically for the QT, QRS, and PR intervals. The aims of this study were to establish the heritability of ECG traits, including indices of left ventricular hypertrophy, and to directly assess the proportion of those heritabilities explained by GWAS variants. These analyses were conducted in a large, Dutch family-based cohort study, the Erasmus Rucphen Family study using variance component methods implemented in the SOLAR (Sequential Oligogenic Linkage Analysis Routines) software package. Heritability estimates ranged from 34 % for QRS and Cornell voltage product to 49 % for 12-lead sum. Trait-specific GWAS findings for each trait explained a fraction of their heritability (17 % for QRS, 4 % for QT, 2 % for PR, 3 % for Sokolow–Lyon index, and 4 % for 12-lead sum). The inclusion of all ECG-associated single nucleotide polymorphisms explained an additional 6 % of the heritability of PR. In conclusion, this study shows that, although GWAS explain a portion of ECG trait variability, a large amount of heritability remains to be explained. In addition, larger GWAS for PR are likely to detect loci already identified, particularly those observed for QRS and 12-lead sum. Electronic supplementary material The online version of this article (doi:10.1007/s00439-015-1595-9) contains supplementary material, which is available to authorized users.

11 Perrier A, Desmarais S, Miron MJ, de Moerloose P, Lepage R,Slosman D, Didier D, Unger PF, Patenaude JV, Bounameaux H.Non-invasive diagnosis of venous thromboembolism in outpatients.Lancet 1999; 353: 190–5.12 Le Gal G, Righini M, Parent F, van Strijen M, Couturaud F. Diag-nosis and management of subsegmental pulmonary embolism.J Thromb Haemost 2006; 4: 724–31.13 Donato AA, Khoche S, Santora J, Wagner B. Clinical outcomes inpatients with isolated subsegmental pulmonary emboli diagnosed bymultidetector CT pulmonary angiography. Thromb Res 2010; 126:e266–70.14 CarrierM,LeGalG,WellsPS,RodgerMA.Systematicreview:case-fatality rates of recurrent venous thromboembolism and majorbleeding events among patients treated for venous thromboembolism.AnnInternMed2010; 152: 578–89.

Item does not contain fulltext AIMS/HYPOTHESIS: The aim of this work was to investigate whether measurement of the mean common carotid intima-media thickness (CIMT) improves cardiovascular risk prediction in individuals with diabetes. METHODS: We performed a subanalysis among 4,220 individuals with diabetes in a large ongoing individual participant data meta-analysis involving 56,194 subjects from 17 population-based cohorts worldwide. We first refitted the risk factors of the Framingham heart risk score on the individuals without previous cardiovascular disease (baseline model) and then expanded this model with the mean common CIMT (CIMT model). The absolute 10 year risk for developing a myocardial infarction or stroke was estimated from both models. In individuals with diabetes we compared discrimination and calibration of the two models. Reclassification of individuals with diabetes was based on allocation to another cardiovascular risk category when mean common CIMT was added. RESULTS: During a median follow-up of 8.7 years, 684 first-time cardiovascular events occurred among the population with diabetes. The C statistic was 0.67 for the Framingham model and 0.68 for the CIMT model. The absolute 10 year risk for developing a myocardial infarction or stroke was 16% in both models. There was no net reclassification improvement with the addition of mean common CIMT (1.7%; 95% CI -1.8, 3.8). There were no differences in the results between men and women. CONCLUSIONS/INTERPRETATION: There is no improvement in risk prediction in individuals with diabetes when measurement of the mean common CIMT is added to the Framingham risk score. Therefore, this measurement is not recommended for improving individual cardiovascular risk stratification in individuals with diabetes.

Atrial fibrillation is the most common sustained arrhythmia in the elderly. Serum potassium is associated with ventricular arrhythmias and cardiac arrest. Little is known about the association of serum potassium with atrial fibrillation. The objective of this study was to investigate the association of serum potassium and the risk of atrial fibrillation in a population based setting.The study was performed within the prospective population-based Rotterdam Study. The study population consisted of 4059 participants without atrial fibrillation at baseline for whom baseline levels of serum potassium were measured. Atrial fibrillation was ascertained from centre visit ECG assessments as well as medical records.During a mean follow up of 11.8 years (SD=5.2 yr), 474 participants developed atrial fibrillation. Participants with hypokalemia (3.5 mmol/l) had a higher risk of atrial fibrillation (HR: 1.63, 95%CI: 1.03-2.56) than those with normokalemia (3.5-5.0 mmol/l). This association was independent of age, sex, serum magnesium, and other potential confounders. Especially in participants with a history of myocardial infarction, those with hypokalemia had a higher risk of atrial fibrillation than those with normokalemia (HR: 3.81, 95%-CI: 1.51-9.61).In this study low serum levels of potassium were associated with a higher risk of atrial fibrillation.

The purpose of this study was to determine the association of coronary artery calcification (CAC) with incident heart failure in the elderly and examine its independence of overt coronary heart disease (CHD).Heart failure is often observed as a first manifestation of coronary atherosclerosis rather than a sequela of overt CHD. Although numerous studies have shown that CAC, an established measure of coronary atherosclerosis, is a strong predictor of CHD, the association between CAC and future heart failure has not been studied prospectively.In the Rotterdam Study, a population-based cohort, 1,897 asymptomatic participants (mean age, 69.9 years; 58% women) underwent CAC scoring and were followed for the occurrence of heart failure and CHD.During a median follow-up of 6.8 years, there were 78 cases of heart failure and 76 cases of nonfatal CHD. After adjustment for cardiovascular risk factors, increasing CAC scores were associated with heart failure (p for trend = 0.001), with a hazard ratio of 4.1 (95% confidence interval [CI]: 1.7 to 10.1) for CAC scores400 compared with CAC scores of 0 to 10. After censoring participants for incident nonfatal CHD, increasing extent of CAC remained associated with heart failure (p for trend = 0.046), with a hazard ratio of 2.9 (95% CI: 1.1 to 7.4) for CAC scores400. Moreover, adding CAC to cardiovascular risk factors resulted in an optimism-corrected increase in the c-statistic by 0.030 (95% CI: 0.001 to 0.050) to 0.734 (95% CI: 0.698 to 0.770) and substantially improved the risk classification of subjects (continuous net reclassification index = 34.0%).CAC has a clear association with the risk of heart failure, independent of overt CHD. Because heart failure is highly prevalent in the elderly, it might be worthwhile to include heart failure as an outcome in future risk assessment programs incorporating CAC.

Background— Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. Methods and Results— To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMT mean , IMT max , and IMT mean-max ), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11 590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1 ) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P =6.75×10 −7 for IMT max ; replication P =7.24×10 −6 for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort ( P =0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77–0.90], P =6.53×10 −6 , n=13 591; and 0.95 [0.92–0.98], P =1.83×10 −4 , n=82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126–138). Conclusions— This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent.

Aims To investigate whether genetic variation in the renin-angiotensin-aldosterone system (RAAS) and kallikrein-bradykinin pathways is related to hypertension and blood pressure (BP) response to angiotensin-converting enzyme (ACE) inhibitor therapy in stable coronary artery disease (CAD) patients. Methods and results In 8907 stable CAD patients from the EUROPA trial, 52 haplotype-tagging single-nucleotide polymorphisms (SNPs) in 12 candidate genes within the RAAS and kallikrein-bradykinin pathways were investigated for association with hypertension (defined as BP >= 160/95 mmHg or use of antihypertensives) and BP response to ACE inhibitors, during a 4-week run-in period. All analyses were adjusted for age, sex, body mass index and creatinine clearance and corrected for multiple testing. Results Hypertension was present in 28.3% of the patients (n = 2526); median BP reduction after perindopril was 10/4mmHg. Four polymorphisms, located in the ACE (rs4291), angiotensinogen (rs5049) and (pro) renin receptor (rs2968915; rs5981008) genes were significantly associated with hypertension in two vascular disease populations of CAD (EUROPA) and cerebrovascular disease (PROGRESS; n = 3571). A cumulative profile demonstrated a stepwise increase in the prevalence of hypertension, mounting to a 2-3-fold increase (P for trend < 0.001). Similar associations on hypertension were observed for angiotensinogen in a healthy population (n = 2197). In addition, genetic polymorphisms were identified that significantly modified the BP reduction by ACE inhibitor therapy; however, the observed BP differences were small and did not remain significant after permutation analysis. Conclusion This large genetic association study identified genetic determinants of hypertension in three cohorts of patients with vascular disease and healthy individuals. J Hypertens 29:509-519 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Obesity is globaLy prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined aSociations betwEn body maS index and ĝ̂1/42.8 miLion SNPs in up to 123,865 individuals with targeted foLow up of 42 SNPs in up to 125,931 aDitional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci aSociated with body maS index (P < 5-10-8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly aSociated loci may provide new insights into human body weight regulation. © 2010 Nature America, Inc. All rights reserved.

White blood cells (WBCs) mediate immune systems and consist of various subtypes with distinct roles. Elucidation of the mechanism that regulates the counts of the WBC subtypes would provide useful insights into both the etiology of the immune system and disease pathogenesis. In this study, we report results of genome-wide association studies (GWAS) and a replication study for the counts of the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects enrolled in the BioBank Japan Project. We identified 12 significantly associated loci that satisfied the genome-wide significance threshold of P, Author Summary White blood cells (WBCs) are blood cells that mediate immune systems and defend the body against foreign microorganisms. It is well known that WBCs consist of various subtypes of cells with distinct roles, although the genetic background of each of the WBC subtypes has yet to be examined. In this study, we report genome-wide association studies (GWAS) for the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects. We identified 12 significantly associated genetic loci, and 9 of them were novel. Evaluation of the associations of these identified loci in cohorts of Caucasian populations demonstrated both ethnically common and divergent genetic backgrounds of the WBC subtypes. These loci also indicated a variety of patterns of pleiotropic associations within the hematological traits, including the other WBC subtypes, total WBC count, platelet count, or red blood cell-related traits, which suggests unique and common functional roles of these loci in the processes of hematopoiesis.

The purpose of the present study is to examine HFE gene mutations in relation to newly diagnosed (incident) coronary heart disease (CHD). In a population-based follow-up study of 7,983 individuals aged 55 years and older, we compared the risk of incident CHD between HFE carriers and non-carriers, overall and stratified by sex and smoking status. HFE mutations were significantly associated with an increased risk of incident CHD in women but not in men (hazard ratio [HR] for women = 1.7, 95% confidence interval [CI] 1.2-2.4 versus HR for men = 0.9, 95% CI 0.7-1.2). This increased CHD risk associated with HFE mutations in women was statistically significant in never smokers (HR = 1.8, 95% CI 1.1-2.8) and current smokers (HR = 3.1, 95% CI 1.4-7.1), but not in former smokers (HR = 1.3, 95% CI 0.7-2.4). HFE mutations are associated with increased risk of incident CHD in women.