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An important aspect of public health is disease prediction and health promotion through better targeting of preventive strategies. Well-targeted preventive strategies will eventually decrease burden of diseases and thus precise prediction plays a crucial role in public health. Many investigators put efforts into finding models that improve prediction using known risk factors of diseases. Recently with the overwhelming load of genetic loci discovered for complex diseases through genome-wide association studies (GWAS), much of attention has been focused on the role of these genetic loci to improve prediction models. Genetic loci in solo explain little variance of diseases. It is thus necessary to create new genetic parameters that combine the effect of as many genetic loci as possible. Such new parameters aim to better distinguish individuals who will develop a disease from those who will not. In this chapter, various polygenic methods that use multiple genetic loci to directly or indirectly improve precision of genetic prediction are discussed.

UK Medical Research Council

The global economic impact of non-communicable diseases (NCDs) on household expenditures and poverty indicators remains less well understood. To conduct a systematic review and meta-analysis of the literature evaluating the global economic impact of six NCDs [including coronary heart disease, stroke, type 2 diabetes mellitus (DM), cancer (lung, colon, cervical and breast), chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD)] on households and impoverishment. Medline, Embase and Google Scholar databases were searched from inception to November 6th 2014. To identify additional publications, reference lists of retrieved studies were searched. Randomized controlled trials, systematic reviews, cohorts, case-control, cross-sectional, modeling and ecological studies carried out in adults and assessing the economic consequences of NCDs on households and impoverishment. No language restrictions. All abstract and full text selection was done by two independent reviewers. Data were extracted by two independent reviewers and checked by a third independent reviewer. Studies were included evaluating the impact of at least one of the selected NCDs and on at least one of the following measures: expenditure on medication, transport, co-morbidities, out-of-pocket (OOP) payments or other indirect costs; impoverishment, poverty line and catastrophic spending; household or individual financial cost. From 3,241 references, 64 studies met the inclusion criteria, 75 % of which originated from the Americas and Western Pacific WHO region. Breast cancer and DM were the most studied NCDs (42 in total); CKD and COPD were the least represented (five and three studies respectively). OOP payments and financial catastrophe, mostly defined as OOP exceeding a certain proportion of household income, were the most studied outcomes. OOP expenditure as a proportion of family income, ranged between 2 and 158 % across the different NCDs and countries. Financial catastrophe due to the selected NCDs was seen in all countries and at all income levels, and occurred in 6-84 % of the households depending on the chosen catastrophe threshold. In 16 low- and middle-income countries (LMIC), 6-11 % of the total population would be impoverished at a 1.25 US dollar/day poverty line if they would have to purchase lowest price generic diabetes medication. NCDs impose a large and growing global impact on households and impoverishment, in all continents and levels of income. The true extent, however, remains difficult to determine due to the heterogeneity across existing studies in terms of populations studied, outcomes reported and measures employed. The impact that NCDs exert on households and impoverishment is likely to be underestimated since important economic domains, such as coping strategies and the inclusion of marginalized and vulnerable people who do not seek health care due to financial reasons, are overlooked in literature. Given the scarcity of information on specific regions, further research to estimate impact of NCDs on households and impoverishment in LMIC, especially the Middle Eastern, African and Latin American regions is required.

High blood pressure is the foremost heritable global risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits to date (systolic, diastolic, pulse pressure) in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared loci influencing lifestyle exposures. Our findings offer the potential for a precision medicine strategy for future cardiovascular disease prevention.

General cognitive function is a prominent human trait associated with many important life outcomes1,2, including longevity3. The substantial heritability of general cognitive function is known to be polygenic, but it has had little explication in terms of the contributing genetic variants4,5,6. Here, we combined cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N=280,360; age range = 16 to 102). We found 9,714 genome-wide significant SNPs (P−8) in 99 independent loci. Most showed clear evidence of functional importance. Among many novel genes associated with general cognitive function wereSGCZ,ATXN1,MAPT,AUTS2, andP2RY6. Within the novel genetic loci were variants associated with neurodegenerative disorders, neurodevelopmental disorders, physical and psychiatric illnesses, brain structure, and BMI. Gene-based analyses found 536 genes significantly associated with general cognitive function; many were highly expressed in the brain, and associated with neurogenesis and dendrite gene sets. Genetic association results predicted up to 4% of general cognitive function variance in independent samples. There was significant genetic overlap between general cognitive function and information processing speed, as well as many health variables including longevity.

To examine evidence for a role of gluten sensitivity (GS) or celiac disease (CD) in ALS etiology, we included participants from a population-based case–control study in The Netherlands between January 2006 and December 2015. We compared levels and seroprevalence of IgA antibodies to tissue transglutaminase 6 (TG6) in 359 ALS patients and 359 controls, and to transglutaminase 2 (TG2) and endomysium (EMA) in 199 ALS patients and 199 controls. Questionnaire data on 1829 ALS patients and 3920 controls were examined for CD or gluten-free diets (GFD). Genetic correlation and HLA allele frequencies were analyzed using two genome-wide association studies: one on ALS (12,577 cases, 23,475 controls), and one on CD (4533 cases, 10,750 controls). We found one patient with TG6, TG2 and EMA antibodies who had typical ALS and no symptoms of GS. TG6 antibody concentrations and positivity, CD prevalence and adherence to a GFD were similar in patients and controls (p > 0.66) and in these patients disease progression was compatible with typical ALS. CD and ALS were not found to be genetically correlated (p > 0.37). CD-associated HLA allele frequencies were similar in patients and controls (p > 0.28). In conclusion, we found no serological evidence for involvement of gluten-related antibodies in ALS etiology nor did we observe an association between CD and ALS in medical history or genetic data, indicating that there is no evidence in our data for an association between the two diseases. Hence, a role for a GFD in the ALS treatment seems unlikely. Electronic supplementary material The online version of this article (doi:10.1007/s00415-017-8400-8) contains supplementary material, which is available to authorized users.

High levels of serum uric acid are associated with hypertension in observational studies. The aim of this study was to investigate the association of uric acid gene variants with blood pressure. We studied 5791 participants aged ≥55 years from the Rotterdam Study. Thirty gene variants identified for serum uric acid level were used to compile genetic risk score (GRS). We used linear regression models to investigate the association of the uric acid GRS with systolic and diastolic blood pressure in the whole study population and separately in participants with and without comorbidities and medication use. In the age- and sex-adjusted model, each SD increase in uric acid GRS was associated with 0.75 mm Hg lower systolic blood pressure (95% confidence interval, −1.31 to −0.19) and 0.42 mm Hg lower diastolic blood pressure (95% confidence interval, −0.72 to −0.13). The association did not attenuate after further adjustment for antihypertensive medication use and conventional cardiovascular risk factors. In subgroup analysis, the association of uric acid GRS with systolic blood pressure was significantly stronger in participants (n=885) on diuretic treatment ( P for interaction, 0.007). In conclusion, we found that higher uric acid GRS is associated with lower systolic and diastolic blood pressure. Diuretics treatment may modify the association of uric acid genetic risk score and systolic blood pressure. Our study suggests that genome wide association study’s findings can be associated with an intermediate factor or have a pleiotropic role and, therefore, should be applied for Mendelian Randomization with caution.

Objective:Urinary sodium and potassium excretion are associated with blood pressure (BP) and cardiovascular disease (CVD). The exact biological link between these traits is not well understood.Design and method:We performed large scale genome-wide association study (GWAS) on urinary sodium and potas

In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

Sudden cardiac death (SCD) is a leading cause of total and cardiovascular mortality, and ventricular fibrillation is the underlying arrhythmia in the majority of cases. In the young, where the incidence of SCD is low, a great proportion of SCDs occur in the context of inherited disorders such as cardiomyopathy or primary electrical disease, where a monogenic hereditary component is a strong determinant of risk. Marked advancement has been made over the past 15 years in the understanding of the genetic basis of the primary electrical disorders, and this has had an enormous impact on the management of these patients. At older ages, the great majority of SCDs occur in the context of acute myocardial ischemia and infarction. Although epidemiologic studies have shown that heritable factors also determine risk in these cases, inheritance is likely complex and multifactorial, and progress in understanding the genetic and molecular mechanisms that determine susceptibility to these arrhythmias, affecting a greater proportion of the population, has been very limited. We review the most recent insights gained into the genetic basis of both the monogenic and the more complex ventricular arrhythmias.

Objective:Hypertension is the leading cause of cardiovascular morbidity. High blood pressure is highly heritable (∼30–50%), however all genetic variants identified so far only explain ∼3–4% of the trait variance. Hence much of the genetic architecture of blood pressure remains unexplained.Design and

The impact of non-communicable diseases (NCDs) in populations extends beyond ill-health and mortality with large financial consequences. To systematically review and meta-analyze studies evaluating the impact of NCDs (including coronary heart disease, stroke, type 2 diabetes mellitus, cancer (lung, colon, cervical and breast), chronic obstructive pulmonary disease and chronic kidney disease) at the macro-economic level: healthcare spending and national income. Medical databases (Medline, Embase and Google Scholar) up to November 6th 2014. For further identification of suitable studies, we searched reference lists of included studies and contacted experts in the field. We included randomized controlled trials, systematic reviews, cohorts, case-control, cross-sectional, modeling and ecological studies carried out in adults assessing the economic consequences of NCDs on healthcare spending and national income without language restrictions. All abstracts and full text selection was done by two independent reviewers. Any disagreements were resolved through consensus or consultation of a third reviewer. Data were extracted by two independent reviewers using a pre-designed data collection form. Studies evaluating the impact of at least one of the selected NCDs on at least one of the following outcome measures: healthcare expenditure, national income, hospital spending, gross domestic product (GDP), gross national product, net national income, adjusted national income, total costs, direct costs, indirect costs, inpatient costs, outpatient costs, per capita healthcare spending, aggregate economic outcome, capital loss in production levels in a country, economic growth, GDP per capita (per capita income), percentage change in GDP, intensive growth, extensive growth, employment, direct governmental expenditure and non-governmental expenditure. From 4,364 references, 153 studies met our inclusion criteria. Most of the studies were focused on healthcare related costs of NCDs. 30 studies reported the economic impact of NCDs on healthcare budgets and 13 on national income. Healthcare expenditure for cardiovascular disease (12-16.5 %) was the highest; other NCDs ranged between 0.7 and 7.4 %. NCD-related health costs vary across the countries, regions, and according to type of NCD. Additionally, there is an increase in costs with increased severity and years lived with the disease. Low- and middle-income (LMI) countries were the focus of just 16 papers, which suggests an information shortage concerning the true economic burden of NCDs in these countries. NCDs pose a significant financial burden on healthcare budgets and nations' welfare, which is likely to increase over time. However further work is required to standardize more consistently the methods available to assess the economic impact of NCDs and to involve (hitherto under-addressed) LMI populations across the globe.

Non-communicable diseases (NCDs) have large economic impact at multiple levels. To systematically review the literature investigating the economic impact of NCDs [including coronary heart disease (CHD), stroke, type 2 diabetes mellitus (DM), cancer (lung, colon, cervical and breast), chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD)] on macro-economic productivity. Systematic search, up to November 6th 2014, of medical databases (Medline, Embase and Google Scholar) without language restrictions. To identify additional publications, we searched the reference lists of retrieved studies and contacted authors in the field. Randomized controlled trials, cohort, case–control, cross-sectional, ecological studies and modelling studies carried out in adults (>18 years old) were included. Two independent reviewers performed all abstract and full text selection. Disagreements were resolved through consensus or consulting a third reviewer. Two independent reviewers extracted data using a predesigned data collection form. Main outcome measure was the impact of the selected NCDs on productivity, measured in DALYs, productivity costs, and labor market participation, including unemployment, return to work and sick leave. From 4542 references, 126 studies met the inclusion criteria, many of which focused on the impact of more than one NCD on productivity. Breast cancer was the most common (n = 45), followed by stroke (n = 31), COPD (n = 24), colon cancer (n = 24), DM (n = 22), lung cancer (n = 16), CVD (n = 15), cervical cancer (n = 7) and CKD (n = 2). Four studies were from the WHO African Region, 52 from the European Region, 53 from the Region of the Americas and 16 from the Western Pacific Region, one from the Eastern Mediterranean Region and none from South East Asia. We found large regional differences in DALYs attributable to NCDs but especially for cervical and lung cancer. Productivity losses in the USA ranged from 88 million US dollars (USD) for COPD to 20.9 billion USD for colon cancer. CHD costs the Australian economy 13.2 billion USD per year. People with DM, COPD and survivors of breast and especially lung cancer are at a higher risk of reduced labor market participation. Overall NCDs generate a large impact on macro-economic productivity in most WHO regions irrespective of continent and income. The absolute global impact in terms of dollars and DALYs remains an elusive challenge due to the wide heterogeneity in the included studies as well as limited information from low- and middle-income countries. Electronic supplementary material The online version of this article (doi:10.1007/s10654-015-0026-5) contains supplementary material, which is available to authorized users.

Sudden cardiac death (SCD) from ventricular fibrillation during myocardial infarction is a leading cause of total and cardiovascular mortality. It has a multifactorial, complex nature and aggregates in families, implicating the involvement of heritable factors in the determination of risk. During the last few years, genome-wide association studies have uncovered common genetic variants modulating risk of SCD. We here review the current insight on genetic determinants of SCD in the community and describe the genome-wide association approaches undertaken thus far in uncovering genetic determinants of SCD risk.

BackgroundEpidemiological studies on genital human papilloma viruses infection (HPVs) in general population are crucial for the implementation of health policy guidelines for developing the strategies to prevent the primary and secondary cervical cancer. In different parts of Iran, there is a lack of population-based studies to determine the prevalence of HPV in the general population. The aim of this population-based study is to compare the prevalence rate of genital HPV infection among reproductive women with our previous clinic-based data, which showed a prevalence rate of 5% in women in southern Iran.ResultsUsing general primers for all genotypes of HPV, of 799 randomly selected women, five (0.63%, 95% CI 0.23-1.55%) tested positive for HPV DNA. Overall, seven different HPV genotypes were detected: six types (16, 18, 31, 33, 51 and 56) were carcinogenic, or “high risk genotypes” and one genotype (HPV-66) was “probably carcinogenic.”ConclusionsIn a population-based study, the prevalence of HPV infection among southern Iranian women was lower than that observed worldwide. However, our gynaecological clinic-based study on the prevalence of HPV infection showed results comparable with other studies in the Middle East and Persian Gulf countries. Since gynaecological clinic-based data may generally overestimate HPV prevalence, estimates of prevalence according to clinic-based data should be adjusted downward by the population-based survey estimates.

Sudden cardiac death from ventricular fibrillation during acute myocardial infarction is a leading cause of total and cardiovascular mortality. To our knowledge, we here report the first genome-wide association study for this trait, conducted in a set of 972 individuals with a first acute myocardial infarction, 515 of whom had ventricular fibrillation and 457 of whom did not, from the Arrhythmia Genetics in The Netherlands (AGNES) study. The most significant association to ventricular fibrillation was found at 21q21 (rs2824292, odds ratio = 1.78, 95% CI 1.47-2.13, P = 3.3 × 10 -10). The association of rs2824292 with ventricular fibrillation was replicated in an independent case-control set consisting of 146 out-of-hospital cardiac arrest individuals with myocardial infarction complicated by ventricular fibrillation and 391 individuals who survived a myocardial infarction (controls) (odds ratio = 1.49, 95% CI 1.14-1.95, P = 0.004). The closest gene to this SNP is CXADR, which encodes a viral receptor previously implicated in myocarditis and dilated cardiomyopathy and which has recently been identified as a modulator of cardiac conduction. This locus has not previously been implicated in arrhythmia susceptibility.

Objective: To assess the association among serum insulinlike growth factor I (IGF-I) concentrations, bone mineral density (BMD), and biochemical markers of bone turnover in a large group of postmenopausal women from the general population. Design: As an extension of a larger epidemiological study, the Iranian Multicentral Osteoporosis Study, a total of 406 healthy postmenopausal women (age, 59.0 T 7.6 years) were randomly selected from 13 clusters in Bushehr Port. IGF-I, serum CrossLaps, degradation products of C-terminal telopeptides of type I collagen, and osteocalcin were measured by highly specific enzyme-linked immunosorbent assay. BMD was determined for the lumbar spine (L2Y4) and proximal femur using dual-energy x-ray absorptiometry. Results: The mean (T SD) serum IGF-I concentration for all postmenopausal women was 183.35 T 65.60 ng/mL. In age-adjusted analyses, there was no correlation between IGF-I and BMD at the lumbar spine and femoral neck. Compared with women in the lowest quartile of IGF-I, women in the highest quartile had a significantly greater means of osteocalcin (P = 0.04) and alkaline phosphatase (P = 0.01). Analysis by quartiles of IGF-I did not reveal an association with serum CrossLaps. Conclusions: Circulating IGF-I is associated with biochemical markers of bone formation, but there is no relationship among IGF-I, degradation products of C-terminal telopeptides of type I collagen, and BMD in postmenopausal women. Clearly more work will be needed before serum IGF-I can be used in clinical practice as a risk predictor for postmenopause-associated loss of bone mass.

Background Both Chlamydia pneumoniae infection and hyperhomocysteinaemia have been assumed to increase the atherosclerotic risk independently of each other and independently of the classic risk factors. The correlation between hyperhomocysteinaemia, C. pneumoniae infection and coronary artery disease (CAD) have not been investigated in the general population. Methods In an ancillary study to the Persian Gulf Healthy Heart Study, a cohort study of men and women aged ≥25 years, a random sample of 1699 (48.9% males, 51.1% females) subjects were evaluated. Total homocysteine, high sensitivity C-reactive protein (CRP) and IgG antibodies to C. pneumoniae were determined by ELISA. Minnesota coding criteria of a 12-lead resting electrocardiogram was used for evaluation of CAD. Results A total of 12.4% of the subjects had electrocardiogram-defined (Minnesota-coding criteria) coronary artery disease. Hyperhomocysteinaemia (>14μmol/l) and IgG seropositivity were found in 50.8% and 37.7%, respectively. Neither of hyperhomocysteinaemia nor C. pneumoniae IgG seropositivity showed a significant association with CAD after adjusting of sex and age. Concurrent elevated CRP level (>8.2mg/l) and C. pneumoniae seropositivity (chronic C. pneumoniae infection) had a significant association with CAD [OR=1.73, CI (1.09–2.75); p =0.01] after adjusting for age, sex, systolic and diastolic blood pressures, BMI, and serum levels of LDL-cholesterol, fasting blood sugar and triglyceride as covariates in a logistic regression model. This odds ratio increased to 2.11, CI (1.18–4.12; p =0.02) when concurrent hyperhomocysteinaemia and chronic C. pneumoniae infection, as a single covariate entity; was adjusted for multiple risk factors in another logistic regression model. Conclusion Concurrent hyperhomocysteinaemia and chronic C. pneumoniae infection, as a single entity, was independently associated with coronary artery disease in the general population. This synergism may have important implications for risk-stratification and intervention trials.

Cardiovascular health promotion in children has the potential to reduce the risk of atherosclerosis in both the individual child and the population at large. It thus seems eminently reasonable to initiate healthful lifestyle training in childhood to promote improved cardiovascular health in adult life.To test the hypothesis that a year long, classroom-based education for the third and fourth graders could change their knowledge scores about healthy heart.A randomized, controlled trial in elementary schools of Bushehr/Iran.A total of 14 elementary schools, categorized by socioeconomic types and male and female setting were selected and randomized into control or intervention groups. Subjects were 1128 third and fourth graders, aged 9 to 10 years (49.1% boys and 50.9% girls). Over a course of 8 weeks, health educators and sport teachers of the elementary schools presented two hours sessions per week on heart function, nutrition, and exercise for healthy heart and living tobacco free for the intervention group. The education program was based on HeartPower! Program, an American Heart Association program.Mann-Whitney U test and Wilcoxon matched-pairs signed rank test and Bonferroni correction for the two pair wise comparisons were used.Total heart knowledge at posttest was 25% correct higher in the intervention than in the control group (p0.001). Difference in means of total healthy heart knowledge scores between control and intervention group increased from 1.43 points in baseline to 4.02 points in posttest (p0.001).It can be concluded that the classroom-based cardiovascular health promotion had a significant effect on the heart healthy knowledge. Therefore, schools provide an excellent setting for introducing comprehensive healthy heart education and promotion of cardiovascular health to the general population.

BackgroundVentricular fibrillation (VF) in the setting of acute ST elevation myocardial infarction (STEMI) is a leading cause of mortality. Although the risk of VF has a genetic component, the underlying genetic factors are largely unknown. Since heart rate and ECG intervals of conduction and repolarization during acute STEMI differ between patients who do and patients who do not develop VF, we investigated whether SNPs known to modulate these ECG indices in the general population also impact on the respective ECG indices during STEMI and on the risk of VF.Methods and resultsThe study population consisted of participants of the Arrhythmia Genetics in the NEtherlandS (AGNES) study, which enrols patients with a first STEMI that develop VF (cases) and patients that do not develop VF (controls). SNPs known to impact on RR interval, PR interval, QRS duration or QTc interval in the general population were tested for effects on the respective STEMI ECG indices (stage 1). Only those showing a (suggestive) significant association were tested for association with VF (stage 2). On average, VF cases had a shorter RR and a longer QTc interval compared to non-VF controls. Eight SNPs showed a trend for association with the respective STEMI ECG indices. Of these, three were also suggestively associated with VF.ConclusionsRR interval and ECG indices of conduction and repolarization during acute STEMI differ between patients who develop VF and patients who do not. Although the effects of the SNPs on ECG indices during an acute STEMI seem to be similar in magnitude and direction as those found in the general population, the effects, at least in isolation, are too small to explain the differences in ECGs between cases and controls and to determine risk of VF.

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000–300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10−10). The risk allele, while ancestral, has a frequency of ∼1.4%, suggesting strong negative selection and increases risk for SCD by 1.92–fold per allele (95% CI 1.57–2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006)., Author Summary Family studies have clearly demonstrated a role for genes in modifying risk for sudden cardiac death (SCD), however genetic studies have been limited by available samples. Here we have assembled over 4,400 SCD cases with >30,000 controls, all of European ancestry, and utilize a two-stage study design. In the first stage, we conducted an unbiased genome-wide scan in 1,283 SCD cases and >20,000 controls, and then performed follow-up genotyping in the remainder of the samples. We demonstrate strong association to a region of the genome not previously implicated in SCD, the BAZ2B locus, which contains 3 genes not previously known to play a role in cardiac biology. In addition, we used the genome-wide scan data to test a focused hypothesis that genetic variants that modulate ECG traits associated with SCD (QT, QRS, and RR intervals) also modify risk for SCD, and we demonstrate that QT- and QRS-prolonging alleles are, as a group, associated with increased risk of SCD. Taken together, these findings begin to elucidate the genetic contribution to SCD susceptibility and provide important targets for functional studies to investigate the etiology and pathogenesis of SCD.

Background Cardiovascular disease remains the leading killer of women in most developed areas of the world. Rates of physical inactivity and poor nutrition, which are two of the most important modifiable risk factors for cardiovascular disease in women, are substantial. This study sought to examine the effectiveness of a community-based lifestyle-modification program on increasing women's physical activity in a randomized trial guided by community-based participatory research (CBPR) methods. Methods A total of 335 healthy, 25–64 years old women who had been selected by a multiple-stage stratified cluster random sampling method in Bushehr Port/I.R. Iran, were randomized into control and intervention groups. The intervention group completed an 8-week lifestyle modification program for increasing their physical activity, based on a revised form of Choose to Move program; an American Heart Association Physical Activity Program for Women. Audio-taped activity instructions with music and practical usage of the educational package were given to the intervention group in weekly home-visits by 53 volunteers from local non-governmental and community-based organizations. Results Among the participants, the percentage who reported being active (at lease 30 minutes of moderate intensity physical activity for at least 5 days a week, or at least 20 minutes of vigorous physical activity for at least three days a week) increased from 3% and 2.7% at baseline to 13.4% and 3% (p < 0.0001) at the ending of the program in the intervention and control groups, respectively. The participants in the intervention group reported more minutes of physical activity per week (mean = 139.81, SE = 23.35) than women in the control group (mean = 40.14, SE = 12.65) at week 8 (p < 0.0001). The intervention group subjects exhibited a significantly greater decrease in systolic blood pressure (-10.0 mmHg) than the control group women (+2.0. mmHg). The mean ranks for posttest healthy heart knowledge in the intervention and control groups were 198.91 and 135.77, respectively (P < 0.0001). Conclusion An intervention based on CBPR methods can be effective for the short-term adoption of physical activity behavior among women. The development of participatory process to support the adequate delivery of lifestyle-modification programs is feasible and an effective healthcare delivery strategy for cardiovascular community health promotion. Trial Registration ACTRNO12606000521527

BACKGROUND: An elevated serum level of C-reactive protein (CRP) is an independent predictor of coronary artery disease (CAD). Chronic infections have also been implicated in the pathogenesis of CAD. AIMS: To investigate how concomitant chronic infection and CRP related to electrocardiogram-defined CAD in a general population. SETTING AND DESIGN : A population-based cross-sectional study, which was conducted in three Iranian ports in the northern Persian Gulf. MATERIALS and METHODS : For evaluation of CAD, we used Minnesota coding criteria of a 12-lead resting electrocardiogram in 1,754 subjects, aged 25 years and over, selected by cluster random sampling. Sera were analyzed for IgG antibodies to Chlamydia pneumoniae (C. pneumoniae), Herpes simplex virus type 1 (HSV-1), Helicobacter pylori (H. pylori) and cytomegalovirus (CMV) using ELISA. Measurement of CRP by a high-sensitivity CRP assay was done. STATISTICAL ANALYSIS: Multiple logistic regression analysis was used. RESULTS: None of the infectious agents (CMV, H. pylori, C. pneumoniae and HSV-1) showed a significant association with electrocardiogram-defined CAD after adjusting for sex and age. Elevated CRP levels did not show significant association with electrocardiogram-defined CAD independent of seropositivity to one of the four infectious agents, but concurrent elevated CRP levels (>10.0 mg/L) and anti-C. pneumoniae [OR = 1.68 (CI, 1.24-2.59; P=0.04)], H. pylori [OR = 1.98 (CI, 1.26-3.13; P=0.003)], CMV [OR = 1.66 (CI, 1.10-2.49; P=0.01)] or HSV-1 [OR=1.79 (CI, 1.18-2.72; P=0.006)] IgG antibodies were associated with prevalence of electrocardiogram-defined CAD in the general population, after adjustment for multiple risk factors, including age, sex and the components of the metabolic syndrome. CONCLUSIONS: Beyond traditional cardiovascular risk factors, concomitant chronic infection and elevated CRP are significantly correlated with electrocardiogram-defined CAD.

Markers of biological aging have potential utility in primary care and public health. We developed a model of age based on untargeted metabolic profiling across multiple platforms, including nuclear magnetic resonance spectroscopy and liquid chromatography–mass spectrometry in urine and serum, within a large sample (N = 2,239) from the UK Airwave cohort. We validated a subset of model predictors in a Finnish cohort including repeat measurements from 2,144 individuals. We investigated the determinants of accelerated aging, including lifestyle and psychological risk factors for premature mortality. The metabolomic age model was well correlated with chronological age (mean r = .86 across independent test sets). Increased metabolomic age acceleration (mAA) was associated after false discovery rate (FDR) correction with overweight/obesity, diabetes, heavy alcohol use and depression. DNA methylation age acceleration measures were uncorrelated with mAA. Increased DNA methylation phenotypic age acceleration (N = 1,110) was associated after FDR correction with heavy alcohol use, hypertension and low income. In conclusion, metabolomics is a promising approach for the assessment of biological age and appears complementary to established epigenetic clocks., We have developed a novel assessment of biological age using broad metabolomic profiling of small molecules circulating in blood and urine, collected from over 2,000 working age adults. We compare this metabolomic age assessment with an established epigenetic ‘clocks’ and show that ‘age acceleration’ is associated with risk factors of premature mortality, including depression.