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Adverse drug reactions are common, serious, difficult to predict, and may be influenced by genetics, prompting the increasing popularity of pharmacogenomic studies. Many pharmacogenomic studies are conducted in nonexperimental settings, yet little is known about the influence of confounding by contraindication. We, therefore, compared the two designs [the overall population (OPD) and the treated-only (TOD) design] by simulating a pharmacogenomic study of the ECG QT interval (QT).Simulations were informed by data from the Atherosclerosis Risk in Communities Study and a literature review examining QT, QT-prolonging drug use, and modification by single nucleotide polymorphisms (SNP). Drug treatment was assigned on the basis of age, sex, and QTlong, representing confounding by contraindication. QT was simulated as a function of drug treatment, one SNP, the drug-SNP interaction, and clinical covariates.Failure to adjust for confounding by contraindication produced a varying degree of bias in the OPD, whereas the TOD was biased by the SNP main effect. For example, in the OPD, the false-positive proportion for the drug-SNP interaction was 5% across the range of SNP main effects (0-10 ms), but increased to 19% without adjusting for confounding by contraindication. In the TOD, the false-positive proportion increased to 89% with SNP main effects greater than 4 ms, although bias was reduced by 39% with adjustment for covariates affected by the SNP.The potential for bias from confounding by contraindication (OPD) should be weighed against bias from SNP main effects (TOD) when selecting the study design that best suits the given context. [ABSTRACT FROM AUTHOR]

Background: Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown.Methods: We included postmenopausal women from the UK Biobank (n=11 495) aged 40 to 70 years with whole exome sequences and from the Women's Health Initiative (n=8111) aged 50 to 79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of any CHIP and CHIP with variant allele frequency >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes, and hormone therapy use. Secondary analyses considered natural versus surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease.Results: The sample included 19 606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with versus without a history of premature menopause was 8.8% versus 5.5% (P<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: odds ratio, 1.36 [95% 1.10-1.68]; P=0.004; CHIP with variant allele frequency >0.1: odds ratio, 1.40 [95% CI, 1.10-1.79]; P=0.007). Associations were larger for natural premature menopause (all CHIP: odds ratio, 1.73 [95% CI, 1.23-2.44]; P=0.001; CHIP with variant allele frequency >0.1: odds ratio, 1.91 [95% CI, 1.30-2.80]; P<0.001) but smaller and nonsignificant for surgical premature menopause. In gene-specific analyses, only DNMT3A CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (hazard ratio associated with all CHIP: 1.36 [95% CI, 1.07-1.73]; P=0.012; hazard ratio associated with CHIP with variant allele frequency >0.1: 1.48 [95% CI, 1.13-1.94]; P=0.005).Conclusions: Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background--Knowledge of trends in the incidence of and survival after myocardial infarction (MI) in a community setting is important to understanding trends in coronary heart disease (CHD) mortality rates. Methods and Results--We estimated race- and gender-specific trends in the incidence of hospitalized MI, case fatality, and CHD mortality from community-wide surveillance and validation of hospital discharges and of in- and out-of-hospital deaths among 35- to 74-year-old residents of 4 communities in the Atherosclerosis Risk in Communities (ARIC) Study. Biomarker adjustment accounted for change from reliance on cardiac enzymes to widespread use of troponin measurements over time. During 1987-2008, a total of 30 985 fatal or nonfatal hospitalized acute MI events occurred. Rates of CHD death among persons without a history of MI fell an average 4.7%/y among men and 4.3%/y among women. Rates of both in- and out-of-hospital CHD death declined significantly throughout the period. Age- and biomarker-adjusted average annual rate of incident MI decreased 4.3% among white men, 3.8% among white women, 3.4% among black women, and 1.5% among black men. Declines in CHD mortality and MI incidence were greater in the second decade (1997-2008). Failure to account for biomarker shift would have masked declines in incidence, particularly among blacks. Age-adjusted 28-day case fatality after hospitalized MI declined 3.5%/y among white men, 3.6%/y among black men, 3.0%/y among white women, and 2.6%/y among black women. Conclusions--Although these findings from 4 communities may not be directly generalizable to blacks and whites in the entire United States, we observed significant declines in MI incidence, primarily as a result of downward trends in rates between 1997 and 2008. INSET: CLINICAL PERSPECTIVE. [ABSTRACT FROM AUTHOR]

Introduction: DNA methylation age acceleration (DNAmAA) scores, which are epigenetic biomarkers of aging and physiological responses to environmental factors such as lifestyle and health behaviors, have been previously shown to be associated with cardiovascular disease (CVD) outcomes and all-cause mortality. Life's Simple 7 (LS7) is a tool promoted by the American Heart Association that summarizes individual adherence to seven key cardiovascular health and lifestyle metrics. We hypothesized that greater LS7 adherence would be associated with lower DNAmAA, consistent with slower biological aging. Methods: Associations between DNAmAA and LS7 were estimated separately in 2,312 African American (AA) and 1,036 European American (EA) adult participants in the Atherosclerosis Risk in Communities (ARIC) study. Visit 1 (mean age = 53 yrs in AA adults, 56 yrs in EA adults) LS7 was calculated for each participant, with 0, 1, or 2 points assigned by adherence to each component: smoking status, body mass index, physical activity, diet, plasma cholesterol, blood pressure, and fasting glucose. The summed score was categorized as inadequate (0-4), intermediate (5-9), or ideal (10-14) LS7 status. Three different previously published DNAmAA scores (Horvath, Hannum, and PhenoAge), were calculated using data from the Illumina HM450K BeadChip on stored frozen leukocytes available at visit 2 or 3 (approximately 3-6 years later). Linear regression models tested the association of LS7 category with DNAm scores, adjusting for sex, chronological age, education, income, study center, alcohol use , white blood cell count , imputed WBC type proportions using the Houseman method, Illumina HumanExome Beadchip principal components for genetic ancestry , and Illumina HM450K control probe principal components for technical adjustment. The Bonferonni-corrected threshold for statistical significance across the six tests was set to p<0.0083 (0.05/6). Results: Among AA adults, ideal LS7 status (compared to poor status) was associated with a 1 year lower PhenoAge acceleration (β=-1.03; 95%CI=-1.70, -0.35; p=0.003), but was not significantly associated with Horvath or Hannum DNAmAA scores. In EA adults, ideal LS7 adherence was not significantly associated with any of the three DNAmAA scores, but the direction and magnitude of the PhenoAge acceleration association in EA was similar to that in AA (β=-0.96; 95%CI=-2.66, 0.73; p=0.27). Conclusions: African American adults with ideal LS7 status had lower PhenoAge acceleration than African Americans who did not, suggesting that heart-healthy lifestyles may slow biological aging processes in this population. Future studies should examine the prospective associations of changes in healthy lifestyle and changes in epigenetic biomarkers of aging as well as modifiers of this relationship. [ABSTRACT FROM AUTHOR]

Background: Metabolic syndrome is related to increased cardiovascular disease (CVD) risk. Although continuous metabolic syndrome score (cMets) is a marker of cardiometabolic burden in adolescence, the relationship between cardiometabolic burden and DNA methylation has been rarely assessed at this stage of the life course. Hypothesis: Cardiometabolic burden is related to methylation levels in genes related to CVD risk in adolescents. Methods: A sample of 263 independent adolescents from the population-based Penn State Child Cohort follow-up exam (N=421) was used in this analysis. cMets was calculated as the sum of standardized residuals of five established cardiometabolic risk factors, namely waist circumference, mean arterial pressure, homeostatic model assessment of insulin resistance, triglycerides, and high density lipoprotein cholesterol (HDL) concentration. cMets was log-transformed to improve the distribution. Peripheral leukocyte DNA was extracted and subjected to enhanced, reduced representation bisulfite sequencing. The assay provided single nucleotide resolution of DNA methylation in cytosine-phosphate-guanine (CpG) sites and surrounding regions. Bases with < 10x coverage were excluded, resulting a total of 1,609,424 methylation sites. Linear regression was used to model the association between site-specific methylation level and cMets. All models were adjusted for age, race, and sex. A p < 10x10-8 was used to determine statistical significance. The significant sites were mapped to the hg19 assembly and subjected to Ingenuity Pathway Analysis (IPA) wherein mapped gene sets were examined for enrichment of downstream function and diseases. Permutations were further performed to confirm the robustness of our findings. Results: On average, the sample was 55% male, 79% white, and aged 16.7 (standard deviation = 2.2) years. cMetS was significantly associated with 52 sites within 43 genes. Among the genes, three were related to glucose tolerance, two to endothelial function, and two more to oxidative stress. IPA indicated that genes associated with these functions were significantly enriched for glucose tolerance (p=0.029), endothelial function (p=0.009), and oxidative stress (p=0.028). Indeed, high cMetS was associated with hypermethylation of PRKCD, which is related to diabetes risk, and PRDX5, which encodes anti-oxidant peroxiredoxin-5. Higher cMetS also was associated with hypomethylation of ID3. Conclusion: Despite validation is pending, these preliminary findings suggest that cardiometabolic burden in adolescents is related to DNA methylation in genes related to CVD risk factors in adulthood, including glucose tolerance, endothelial function, and oxidative stress. [ABSTRACT FROM AUTHOR]

Background: Obesity, especially abdominal obesity, is a risk factor for coronary artery disease (CAD) in various populations. Little is known regarding the role of epigenetics in the association between abdominal obesity and cardiovascular health in adolescents. Hypothesis: Abdominal and especially visceral obesity is associated with DNA methylation in genes related to cardiovascular health among adolescents. Methods: We used data from a sample of 263 adolescents participating in the population-based Penn State Child Cohort follow-up exam (N=421). Dual-energy X-ray absorptiometry was used to measure visceral and subcutaneous fat areas (VAT; SAT, in cm²) in each participant. We extracted DNA from peripheral leukocytes and subjected it to enhanced, reduced representation bisulfite sequencing. A high-throughput assay provided single nucleotide resolution of DNA methylation in cytosine-phosphate-guanine (CpG) sites and surrounding regions. We excluded bases with < 10x coverage or available from < 20 individuals. We analyzed a total of 1,609,424 methylation sites. We used linear regression models to assess the association between site-specific methylation level (expressed as %) and VAT and SAT. We adjusted all models for age, race, sex, and body mass index (BMI) percentile. We used Bonferroni-adjusted statistical tests to identify sites significantly related to VAT and separately, SAT. We mapped the VAT- and SAT-associated sites to the hg19 assembly and subjected them to Ingenuity Pathway Analysis (IPA) wherein mapped gene sets were examined for enrichment of downstream function and diseases. Results: On average, the sample was 55% male, 79% white and aged 16.7 (standard deviation = 2.2) years. VAT and SAT were significantly associated with methylation at 296 sites within 193 genes and 101 sites within 87 genes, respectively. Among them, seven genes related to VAT and five related to SAT were associated with CAD. IPA revealed that CAD-related genes were significantly enriched in both gene sets (for VAT: p=1.97x10-2; SAT: p=9.67x10-3). Genes related to VAT also were significantly enriched in endothelial activation (p=8.16x10-3), fibrogenesis (p=5.01x10-5), and dyslipidemia (p=7.99x10-3). Indeed, higher VAT was associated with hypomethylation of CD14 and hypermethylation of GNMT, while higher SAT was associated with hypermethylation of ADRB1 and hypomethylation of TUBB4A. Conclusion: If externally validated, our data would suggest that (1) abdominal obesity in adolescence is associated with DNA methylation of genes related to cardiovascular health, independent of BMI; and (2) visceral adiposity has a more prominent association with cardiovascular health through DNA methylation of genes with roles in atherogenesis. [ABSTRACT FROM AUTHOR]

Background: Numerous studies suggest that long-term exposure to ambient particulate matter (PM) and nitrogen oxide (NOx) air pollution may be diabetogenic, but little is known about the effects of shorter-term exposures on markers of diabetes risk. Therefore, our objective was to determine whether short- and long-term ambient PM and NOx exposures are associated with glucose, insulin, and insulin resistance measures. Methods: We studied a stratified, random minority oversample of non-diabetic Women's Health Initiative (WHI) clinical trials participants for whom estimates of fasting glucose, fasting insulin, insulin resistance, and geocoded address-specific daily mean concentrations of PM < 10 μm (PM10), PM < 2.5 μm (PM2.5), and NOx were available at screening and up to three follow-up visits between 1993-2004 (total n=4,019; mean age: 62.2 yr; 24% black; 12% Hispanic; 51% white). We measured insulin resistance using the homeostatic model assessment [HOMA], triglyceride to high-density lipoprotein cholesterol ratio, and the triglyceride-glucose index. We log-transformed the glucose, insulin, and insulin resistance measures, then used multi-level, mixed, longitudinal models weighted for sampling design / attrition and adjusted for sociodemographic, clinical, and meteorological covariates to estimate their associations with 2- and 365-day mean PM10 and NOx and 365-day mean PM2.5 concentrations. Results: Measures of glucose homeostasis decreased with short-term exposure to ambient PM10. For example, we found a -0.2% (95% confidence interval: -0.4%, 0.1%), -0.9% (-1.7%, -0.1%), and -1.1% (-2.0%, -0.3%) change in glucose, insulin, and HOMA per 10 μg/m³ increase in the 2-day mean PM10 concentration. In contrast, we found generally null results per 10 μg/m³ increase in 365-day mean PM10 concentration. Measures of glucose homeostasis similarly did not appear to be associated with short- and long-term increases in mean NOx or PM2.5 concentrations. Conclusion: The findings suggest that responses to ambient exposure to PM10 in women may be adaptive (i.e. capable of re-establishing normal glucose homeostasis and improving insulin sensitivity) over the short-term. Endoplasmic reticulum stress-response mechanisms involving decreases in protein misfolding may help explain this observed phenomena. Contrary to previous studies, results also suggest that sustained exposure to ambient PM and NOx has nominal influence on glucose homeostasis. [ABSTRACT FROM AUTHOR]

Background: Systolic blood pressure (SBP) usually decreases as heart rate (HR) increases over serial recordings, an autonomic phenomenon mediated by the baroreflex arc and attributed to recovery from stress associated with instrumentation for sphygmomanometry and initial cuff inflation. Despite clinical relevance of baroreflex pathophysiology and widespread availability of simultaneously recorded BP and HR, few epidemiologic studies have examined their relationship, its reliability or population distribution. We therefore investigated the reflex in the National Longitudinal Study of Adolescent Health (Add Health), hypothesizing that it is reliably measured and affected by major cardiovascular disease (CVD) risk factors. Methods: We examined 15,701 U.S. adults aged 24-34 yr (mean = 28.4 yr; 49% female; 34% racial/ethnic minority) at the Add Health Wave IV (2008) in-home visit, which included 3 resting, seated SBPs and HRs recorded at 30 sec intervals. We used random-effects models to estimate SBP recovery (SBPR), HR recovery (HRR), and baroreflex sensitivity (BRS) as the decrease in SBP, increase in HR, and slope of the RR interval-SBP association across recordings. In a stratified, random subset of 100 participants examined twice, 1-2 wk (mean = 8.6 d) apart, we then used random-effects models to estimate their reliability as an intra-class correlation coefficient and 95% confidence interval (ICC, 95% CI) and compare it with HR variability, i.e. the standard deviation of and root mean square of successive differences in RR (SDRR; RMSSD). In the entire sample, we used logistic regression to estimate associations of the measures with CVD risk factors as odds ratios (ORs, 95% CIs). We adjusted estimation parameters for participant clustering, sampling probabilities, and attrition to facilitate inference. Results: The means (SDs) of initial SBP, HR and RR were 127 (15) mmHg, 73 (12) b/min and 841 (141) ms. For SBPR, HRR and BRS, they were -1.2 (4.4) mmHg, 0.6 (4.3) b/min and 0.2 (1.0) ms/mm Hg. The corresponding ICCs (95%CI) were 0.78 (0.70,0.86), 0.47 (0.32,0.63) and 0.63 (0.51,0.75), but only 0.22 (0.03,0.41) and 0.15 (-0.05,0.34) for SDRR and RMSSD. Relative to those without a given CVD risk factor, the OR (95%CI) for BRS < 50th percentile was higher among female, older (> 28 yr), obese (BMI ≥ 30 kg/m2), diabetic (HbA1c ≥ 6.5%), hypertensive (SBP/DBP ≥ 140/90 mm Hg), sedentary and currently smoking participants: 1.7 (1.5,1.8), 1.1 (1.0,1.2), 2.1 (1.9,2.3), 2.3 (1.7,3.0), 1.6 (1.4,1.7), 1.6 (1.4,1.8) and 1.2 (1.1,1.4). Similar associations were observed for SBPR and HRR. Conclusion: Simple, noninvasive measures of hemodynamic recovery and baroreflex sensitivity as estimated from brief recordings of resting, seated SBP and HR are reliable and consistently related to CVD risk factors in young U.S. adults, suggesting potential utility in subclinical assessment of CVD risk. [ABSTRACT FROM AUTHOR]

Background and Objectives: Epigenetic age estimators indicating faster/slower biological aging vs chronological age independently associate with several age-related outcomes; however, longitudinal associations with cognitive function are understudied. We examined associations of epigenetic age estimators with cognitive function measured annually., Methods: This longitudinal study consisted of older women enrolled in the Women's Health Initiative Memory Study with DNA methylation (DNAm) collected at baseline (1995-1998) from 3 ancillary studies and were followed up to 13 years. Global cognitive function was measured annually by Modified Mini-Mental State Examination (3MS; baseline-2007) and by modified Telephone Interview for Cognitive Status (TICS-m, 2008-2021). We calculated 5 epigenetic age estimators: extrinsic AgeAccel, intrinsic AgeAccel, AgeAccelPheno, AgeAccelGrim2, Dunedin Pace of Aging Calculated From the Epigenome (DunedinPACE), and AgeAccelGrim2 components (DNA-based plasma protein surrogates). We estimated longitudinal epigenetic age estimator-cognitive function associations using linear mixed-effects models containing age, education, race or ethnicity, and subsequently alcohol, smoking, body mass index, and comorbidities. We examined effect modification by APOE ε4 carriage., Results: A total of 795 participants were enrolled. The mean baseline age was 70.8 ± 4 years (10.7% Black, 3.9% Hispanic or Latina, 85.4% White), A 1-SD (0.12) increment in DunedinPACE associated with faster annual declines in TICS-m scores in minimally adjusted (β = -0.118, 95% CI -0.202 to -0.034; p = 0.0006) and fully adjusted (β = -0.123, 95% CI -0.211 to -0.036; p = 0.006) models. AgeAccelPheno associated with faster annual declines in TICS-m with minimal adjustment (β = -0.091, 95% CI -0.176 to -0.006; p = 0.035) but not with full adjustment. No other epigenetic age estimators associated with changes in 3MS or TICS-m. Higher values of DNAm-based surrogates of growth differentiation factor 15, beta-2 microglobulin, Cystatin C, tissue inhibitor metalloproteinase 1, and adrenomedullin associated with faster annual declines in 3MS and TICS-m. Higher DNAm log A1c associated with faster annual declines in TICS-m only. DunedinPACE associated with faster annual declines in 3MS among APOE ε4 carriers but not among noncarriers ( p -interaction = 0.020)., Discussion: Higher DunedinPACE associated with faster declines in TICS-m and 3MS scores among APOE ε4 carriers. DunedinPACE may help identify older women at risk of future cognitive decline. Limitations include the ancillary studies that collected epigenetic data not designed to study epigenetics and cognitive function. We examined epigenetic age estimators with global cognitive function and not specific cognitive domains. Findings may not generalize to men and more diverse populations.

Background and Objectives: Little is known about the role of radon in the epidemiology of stroke among women. We therefore examined the association between home radon exposure and risk of stroke among middle-aged and older women in the United States., Methods: We conducted a prospective cohort study of postmenopausal women aged 50-79 years at baseline (1993-1998) in the Women's Health Initiative. We measured exposures as 2-day, indoor, lowest living-level average radon concentrations in picocuries per liter (pCi/L) as estimated in 1993 by the US Geological Survey and reviewed by the Association of American State Geologists under the Indoor Radon Abatement Act. We used Cox proportional hazards models to estimate risk of incident, neurologist-adjudicated stroke during follow-up through 2020 as a hazard ratio and 95% CI, adjusting for study design and participant demographic, social, behavioral, and clinical characteristics., Results: Among 158,910 women without stroke at baseline (mean age 63.2 years; 83% white), 6,979 incident strokes were identified over follow-up (mean 13.4 years). Incidence rates were 333, 343, and 349 strokes per 100,000 woman-years at radon concentrations of <2, 2-4, and >4 pCi/L, respectively. Compared with women living at concentrations <2 pCi/L, those at 2-4 and >4 pCi/L had higher covariate-adjusted risks of incident stroke: hazard ratio (95% CI) 1.06 (0.99-1.13) and 1.14 (1.05-1.22). Using nonlinear spline functions to model radon, stroke risk was significantly elevated at concentrations ranging from 2 to 4 pCi/L ( p = 0.0004), that is, below the United States Environmental Protection Agency Radon Action Level for mitigation (4 pCi/L). Associations were slightly stronger for ischemic (especially cardioembolic, small vessel occlusive, and large artery atherosclerotic) than hemorrhagic stroke, but otherwise robust in sensitivity analyses., Discussion: Radon exposure is associated with moderately increased stroke risk among middle-aged and older women in the United States, suggesting that promulgation of a lower Radon Action Level may help reduce the domestic impact of cerebrovascular disease on public health.

Background and Objectives: Studies suggest that clonal hematopoiesis of indeterminate potential (CHIP) may increase risk of hematologic malignancy and cardiovascular disease, including stroke. However, few studies have investigated plausible environmental risk factors for CHIP such as radon, despite the climate-related increases in and documented infrequency of testing for this common indoor air pollutant.The purpose of this study was to estimate the risk of CHIP related to radon, an established environmental mutagen., Methods: We linked geocoded addresses of 10,799 Women's Health Initiative Trans-Omics for Precision Medicine (WHI TOPMed) participants to US Environmental Protection Agency-predicted, county-level, indoor average screening radon concentrations, categorized as follows: Zone 1 (>4 pCi/L), Zone 2 (2-4 pCi/L), and Zone 3 (<2 pCi/L). We defined CHIP as the presence of one or more leukemogenic driver mutations with variant allele frequency >0.02. We identified prevalent and incident ischemic and hemorrhagic strokes; subtyped ischemic stroke using Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria; and then estimated radon-related risk of CHIP as an odds ratio (OR) and 95% CI using multivariable-adjusted, design-weighted logistic regression stratified by age, race/ethnicity, smoking status, and stroke type/subtype., Results: The percentages of participants with CHIP in Zones 1, 2, and 3 were 9.0%, 8.4%, and 7.7%, respectively ( p trend = 0.06). Among participants with ischemic stroke, Zones 2 and 1 were associated with higher estimated risks of CHIP relative to Zone 3: 1.39 (1.15-1.68) and 1.46 (1.15-1.87), but not among participants with hemorrhagic stroke: 0.98 (0.68-1.40) and 1.03 (0.70-1.52), or without stroke: 1.04 (0.74-1.46) and 0.95 (0.63-1.42), respectively ( p interaction = 0.03). Corresponding estimates were particularly high among TOAST-subtyped cardioembolism: 1.78 (1.30-2.47) and 1.88 (1.31-2.72), or other ischemic etiologies: 1.37 (1.06-1.78) and 1.50 (1.11-2.04), but not small vessel occlusion: 1.05 (0.74-1.49) and 1.00 (0.68-1.47), respectively ( p interaction = 0.10). Observed patterns of association among strata were insensitive to attrition weighting, ancestry adjustment, prevalent stroke exclusion, separate analysis of DNMT3A driver mutations, and substitution with 3 alternative estimates of radon exposure., Discussion: The robust elevation of radon-related risk of CHIP among postmenopausal women who develop incident cardioembolic stroke is consistent with a potential role of somatic genomic mutation in this societally burdensome form of cerebrovascular disease, although the mechanism has yet to be confirmed.

Background and Objectives: Studies on the association between proton pump inhibitor (PPI) use and dementia report mixed results and do not examine the impact of cumulative PPI use. We evaluated the associations between current and cumulative PPI use and risk of incident dementia in the Atherosclerosis Risk in Communities (ARIC) Study., Methods: These analyses used participants from a community-based cohort (ARIC) from the time of enrollment (1987-1989) through 2017. PPI use was assessed through visual medication inventory at clinic visits 1 (1987-1989) to 5 (2011-2013) and reported annually in study phone calls (2006-2011). This study uses ARIC visit 5 as baseline because this was the first visit in which PPI use was common. PPI use was examined 2 ways: current use at visit 5 and duration of use before visit 5 (from visit 1 to 2011, exposure categories: 0 day, 1 day-2.8 years, 2.8-4.4 years, >4.4 years). The outcome was incident dementia after visit 5. Cox proportional hazard models were used, adjusted for demographics, comorbid conditions, and other medication use., Results: A total of 5,712 dementia-free participants at visit 5 (mean age 75.4 ± 5.1 years; 22% Black race; 58% female) were included in our analysis. The median follow-up was 5.5 years. The minimum cumulative PPI use was 112 days, and the maximum use was 20.3 years. There were 585 cases of incident dementia identified during follow-up. Participants using PPIs at visit 5 were not at a significantly higher risk of developing dementia during subsequent follow-up than those not using PPIs (hazard ratio (HR): 1.1 [95% confidence interval (CI) 0.9-1.3]). Those who used PPIs for >4.4 cumulative years before visit 5 were at 33% higher risk of developing dementia during follow-up (HR: 1.3 [95% CI 1.0-1.8]) than those reporting no use. Associations were not significant for lesser durations of PPI use., Discussion: Future studies are needed to understand possible pathways between cumulative PPI use and the development of dementia., Classification of Evidence: This study provides Class III evidence that the use of prescribed PPIs for >4.4 years by individuals aged 45 years and older is associated with a higher incidence of newly diagnosed dementia., (Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Background: Evidence of associations between daily variation in air pollution and blood pressure (BP) is varied and few prior longitudinal studies adjusted for calendar time., Methods: We studied 143,658 postmenopausal women 50 to 79 years of age from the Women's Health Initiative (1993-2005). We estimated daily atmospheric particulate matter (PM) (in three size fractions: PM2.5, PM2.5-10, and PM10) and nitrogen dioxide (NO2) concentrations at participants' residential addresses using validated lognormal kriging models. We used linear mixed-effects models to estimate the association between air pollution concentrations and repeated measures of systolic and diastolic BP (SBP, DBP) adjusting for confounders and calendar time., Results: Short-term PM2.5 and NO2 were each positively associated with DBP {0.10 mmHg [95% confidence interval (CI): 0.04, 0.15]; 0.13 mmHg (95% CI: 0.09, 0.18), respectively} for interquartile range changes in lag 3-5 day PM2.5 and NO2. Short-term NO2 was negatively associated with SBP [-0.21 mmHg (95%CI: -0.30, -0.13)]. In two-pollutant models, the NO2-DBP association was slightly stronger, but for PM2.5 was attenuated to null, compared with single-pollutant models. Associations between short-term NO2 and DBP were more pronounced among those with higher body mass index, lower neighborhood socioeconomic position, and diabetes. When long-term (annual) and lag 3-5 day PM2.5 were in the same model, associations with long-term PM2.5 were stronger than for lag 3-5 day., Conclusions: We observed that short-term PM2.5 and NO2 levels were associated with increased DBP, although two-pollutant model results suggest NO2 was more likely responsible for observed associations. Long-term PM2.5 effects were larger than short-term., Competing Interests: Dr. Wellenius serves as a paid consultant for the Health Effects Institute (Boston, MA) and Google, LLC (Mountain View, CA). The other authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Higher optimism is associated with reduced mortality and a lower risk of age-related chronic diseases. DNA methylation (DNAm) may provide insight into mechanisms underlying these relationships. We hypothesized that DNAm would differ among older individuals who are more versus less optimistic., Methods: Using cross-sectional data from two population-based cohorts of women with diverse races/ethnicities ( n = 3816) and men (only White, n = 667), we investigated the associations of optimism with epigenome-wide leukocyte DNAm. Random-effects meta-analyses were subsequently used to pool the individual results. Significantly differentially methylated cytosine-phosphate-guanines (CpGs) were identified by the "number of independent degrees of freedom" approach: effective degrees of freedom correction using the number of principal components (PCs), explaining >95% of the variation of the DNAm data (PC-correction). We performed regional analyses using comb-p and pathway analyses using the Ingenuity Pathway Analysis software., Results: We found that essentially all CpGs (total probe N = 359,862) were homogeneous across sex and race/ethnicity in the DNAm-optimism association. In the single CpG site analyses based on homogeneous CpGs, we identified 13 significantly differentially methylated probes using PC-correction. We found four significantly differentially methylated regions and two significantly differentially methylated pathways. The annotated genes from the single CpG site and regional analyses are involved in psychiatric disorders, cardiovascular disease, cognitive impairment, and cancer. Identified pathways were related to cancer, and neurodevelopmental and neurodegenerative disorders., Conclusion: Our findings provide new insights into possible mechanisms underlying optimism and health., (Copyright © 2022 by the American Psychosomatic Society.)

Background and Purpose: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke., Methods: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes ( DNMT3A , TET2 , and ASXL1 ) with any stroke, ischemic stroke, and hemorrhagic stroke., Results: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; P =0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; P =0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke., Conclusions: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.

Background: Exposure to fine particulate matter (PM2.5) is an established risk factor for human mortality. However, previous US studies have been limited to select cities or regions or to population subsets (e.g., older adults)., Methods: Here, we demonstrate how to use the novel geostatistical method Bayesian maximum entropy to obtain estimates of PM2.5 concentrations in all contiguous US counties, 2000-2016. We then demonstrate how one could use these estimates in a traditional epidemiologic analysis examining the association between PM2.5 and rates of all-cause, cardiovascular, respiratory, and (as a negative control outcome) accidental mortality., Results: We estimated that, for a 1 log(μg/m3) increase in PM2.5 concentration, the conditional all-cause mortality incidence rate ratio (IRR) was 1.029 (95% confidence interval [CI]: 1.006, 1.053). This implies that the rate of all-cause mortality at 10 µg/m3 would be 1.020 times the rate at 5 µg/m3. IRRs were larger for cardiovascular mortality than for all-cause mortality in all gender and race-ethnicity groups. We observed larger IRRs for all-cause, nonaccidental, and respiratory mortality in Black non-Hispanic Americans than White non-Hispanic Americans. However, our negative control analysis indicated the possibility for unmeasured confounding., Conclusion: We used a novel method that allowed us to estimate PM2.5 concentrations in all contiguous US counties and obtained estimates of the association between PM2.5 and mortality comparable to previous studies. Our analysis provides one example of how Bayesian maximum entropy could be used in epidemiologic analyses; future work could explore other ways to use this approach to inform important public health questions., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood., Methods: Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval)., Results: We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes ( KCNQ1 , KCNH2 , and SCN5A ), a controversial monogenic SCD gene ( KCNE1 ), and novel genes ( PAM and MFGE8 ) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block ( P =8.4×10 -5 ). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation ( P =4×10 -25 ), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals., Conclusions: Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.

Objective: To examine whether long-chain omega-3 polyunsaturated fatty acid (LCn3PUFA) levels modify the potential neurotoxic effects of particle matter with diameters <2.5 µm (PM 2.5 ) exposure on normal-appearing brain volumes among dementia-free elderly women., Methods: A total of 1,315 women (age 65-80 years) free of dementia were enrolled in an observational study between 1996 and 1999 and underwent structural brain MRI in 2005 to 2006. According to prospectively collected and geocoded participant addresses, we used a spatiotemporal model to estimate the 3-year average PM 2.5 exposure before the MRI. We examined the joint associations of baseline LCn3PUFAs in red blood cells (RBCs) and PM 2.5 exposure with brain volumes in generalized linear models., Results: After adjustment for potential confounders, participants with higher levels of RBC LCn3PUFA had significantly greater volumes of white matter and hippocampus. For each interquartile increment (2.02%) in omega-3 index, the average volume was 5.03 cm 3 ( p < 0.01) greater in the white matter and 0.08 cm 3 ( p = 0.03) greater in the hippocampus. The associations with RBC docosahexaenoic acid and eicosapentaenoic acid levels were similar. Higher LCn3PUFA attenuated the inverse associations between PM 2.5 exposure and white matter volumes in the total brain and multimodal association areas (frontal, parietal, and temporal; all p for interaction <0.05), while the associations with other brain regions were not modified. Consistent results were found for dietary intakes of LCn3PUFAs and nonfried fish., Conclusions: Findings from this prospective cohort study among elderly women suggest that the benefits of LCn3PUFAs on brain aging may include the protection against potential adverse effects of air pollution on white matter volumes., (© 2020 American Academy of Neurology.)

Background: We examined how expanding electrocardiographic trait genome-wide association studies to include ancestrally diverse populations, prioritize more precise phenotypic measures, and evaluate evidence for shared genetic effects enabled the detection and characterization of loci., Methods: We decomposed 10 seconds, 12-lead electrocardiograms from 34 668 multi-ethnic participants (15% Black; 30% Hispanic/Latino) into 6 contiguous, physiologically distinct (P wave, PR segment, QRS interval, ST segment, T wave, and TP segment) and 2 composite, conventional (PR interval and QT interval) interval scale traits and conducted multivariable-adjusted, trait-specific univariate genome-wide association studies using 1000-G imputed single-nucleotide polymorphisms. Evidence of shared genetic effects was evaluated by aggregating meta-analyzed univariate results across the 6 continuous electrocardiographic traits using the combined phenotype adaptive sum of powered scores test., Results: We identified 6 novels ( CD36, PITX2, EMB, ZNF592, YPEL2 , and BC043580 ) and 87 known loci (adaptive sum of powered score test P <5×10 -9 ). Lead single-nucleotide polymorphism rs3211938 at CD36 was common in Blacks (minor allele frequency=10%), near monomorphic in European Americans, and had effects on the QT interval and TP segment that ranked among the largest reported to date for common variants. The other 5 novel loci were observed when evaluating the contiguous but not the composite electrocardiographic traits. Combined phenotype testing did not identify novel electrocardiographic loci unapparent using traditional univariate approaches, although this approach did assist with the characterization of known loci., Conclusions: Despite including one-third as many participants as published electrocardiographic trait genome-wide association studies, our study identified 6 novel loci, emphasizing the importance of ancestral diversity and phenotype resolution in this era of ever-growing genome-wide association studies.

Background: DNA methylation patterns associated with habitual diet have not been well studied., Methods: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality., Results: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected P <1.6×10 -3 ). Hypermethylation of cg18181703 ( SOCS3 ) was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality ( P =5.7×10 -15 ). Ten additional diet-associated CpGs were nominally associated with all-cause mortality ( P <0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MR P <4.5×10 -4 ). For example, hypermethylation of cg11250194 ( FADS2 ) was associated with lower triglyceride concentrations (MR, P =1.5×10 -14 ).and hypermethylation of cg02079413 ( SNORA54 ; NAP1L4 ) was associated with body mass index (corrected MR, P =1×10 -6 )., Conclusions: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.

Background: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts., Methods: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts., Results: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts., Conclusion: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

Background: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies., Methods and Results: We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant ( P <5×10 - ) novel loci and replicated a prior association with S 8 ) novel loci and replicated a prior association with S CN10A. We identified 3 loci at SCN5A , TBX5 , and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction., Conclusions: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias., (© 2017 American Heart Association, Inc.)

Background: PCSK9 loss-of-function (LOF) variants allow for the examination of the effects of lifetime reduced low-density lipoprotein cholesterol (LDL-C) on cardiovascular events. We examined the association of PCSK9 LOF variants with LDL-C and incident coronary heart disease and stroke through a meta-analysis of data from 8 observational cohorts and 1 randomized trial of statin therapy., Methods and Results: These 9 studies together included 17 459 blacks with 403 (2.3%) having at least 1 Y142X or C679X variant and 31 306 whites with 955 (3.1%) having at least 1 R46L variant. Unadjusted odds ratios for associations between PCSK9 LOF variants and incident coronary heart disease (851 events in blacks and 2662 events in whites) and stroke (523 events in blacks and 1660 events in whites) were calculated using pooled Mantel-Haenszel estimates with continuity correction factors. Pooling results across studies using fixed-effects inverse-variance-weighted models, PCSK9 LOF variants were associated with 35 mg/dL (95% confidence interval [CI], 32-39) lower LDL-C in blacks and 13 mg/dL (95% CI, 11-16) lower LDL-C in whites. PCSK9 LOF variants were associated with a pooled odds ratio for coronary heart disease of 0.51 (95% CI, 0.28-0.92) in blacks and 0.82 (95% CI, 0.63-1.06) in whites. PCSK9 LOF variants were not associated with incident stroke (odds ratio, 0.84; 95% CI, 0.48-1.47 in blacks and odds ratio, 1.06; 95% CI, 0.80-1.41 in whites)., Conclusions: PCSK9 LOF variants were associated with lower LDL-C and coronary heart disease incidence. PCSK9 LOF variants were not associated with stroke risk., (© 2017 American Heart Association, Inc.)

Background and Purpose: Low heart rate variability (HRV), a marker of cardiac autonomic dysfunction, has been associated with increased all-cause and cardiovascular mortality. We examined the association between reduced HRV and incident stroke in a community-based cohort., Methods: The Atherosclerosis Risk in Communities (ARIC) study measured HRV using 2-minute ECG readings in 12 550 middle-aged adults at baseline (1987-1989). HRV indices were calculated using the SD of RR intervals (SDNN), the mean of all normal RR intervals (meanNN), the root mean square of successive differences of successive RR intervals (RMSSD), low (LF) and high (HF) frequency power, and the LF/HF ratio. All HRV measures were categorized into quintiles. Incident stroke was adjudicated through 2011. Cox regression was used to estimate hazard ratios (HRs) with the lowest HRV quintile as the reference, with and without stratification by prevalent diabetes mellitus., Results: Over a median follow-up of 22 years, 816 (6.5%) participants experienced incident stroke. After covariate adjustment, there was no strong evidence of association between HRV and stroke risk. In stratified analyses, the lowest HRV quintile was associated with higher stroke risk compared with the highest quintile for SDNN (HR, 2.0, 95% confidence interval, 1.1-4.0), RMSSD (HR, 1.7; 95% confidence interval, 0.9-3.2), LF (HR, 1.5; 95% confidence interval, 0.8-3.0), and HF (HR, 1.7; 95% confidence interval, 0.9-3.0) only among people with diabetes mellitus., Conclusions: Lower HRV was associated with higher risk of incident stroke among middle-aged adults with prevalent diabetes mellitus but not among people without diabetes mellitus., (© 2016 American Heart Association, Inc.)

Background: QT interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations., Methods: Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n = 16,398), African (n = 5,437), American Indian (n = 5,032), Hispanic (n = 1,143), and Asian (n = 932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test., Results: Of 21 SNPs, 7 showed consistent direction of effect across all 5 populations, and an additional 9 had estimated effects that were consistent across 4 populations. Despite consistent direction of effect, 9 of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity., Conclusions: These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.

Background: Although ambient concentrations of particulate matter ≤10 μm (PM10) are often used as proxies for total personal exposure, correlation (r) between ambient and personal PM10 concentrations varies. Factors underlying this variation and its effect on health outcome-PM exposure relationships remain poorly understood., Methods: We conducted a random-effects meta-analysis to estimate effects of study, participant, and environmental factors on r; used the estimates to impute personal exposure from ambient PM10 concentrations among 4,012 nonsmoking, participants with diabetes in the Women's Health Initiative clinical trial; and then estimated the associations of ambient and imputed personal PM10 concentrations with electrocardiographic measures, such as heart rate variability., Results: We identified 15 studies (in years 1990-2009) of 342 participants in five countries. The median r was 0.46 (range = 0.13 to 0.72). There was little evidence of funnel plot asymmetry but substantial heterogeneity of r, which increased 0.05 (95% confidence interval = 0.01 to 0.09) per 10 µg/m increase in mean ambient PM10 concentration. Substituting imputed personal exposure for ambient PM10 concentrations shifted mean percent changes in electrocardiographic measures per 10 µg/m increase in exposure away from the null and decreased their precision, for example, -2.0% (-4.6% to 0.7%) versus -7.9% (-15.9% to 0.9%), for the standard deviation of normal-to-normal RR interval duration., Conclusions: Analogous distributions and heterogeneity of r in extant meta-analyses of ambient and personal PM2.5 concentrations suggest that observed shifts in mean percent change and decreases in precision may be generalizable across particle size.

Background: Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval., Methods and Results: First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN., Conclusions: We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.

Background: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans., Methods and Results: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8))., Conclusions: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.

Background: In the United States, where coronary heart disease (CHD) is the leading cause of mortality, CHD risk assessment is a priority and accurate blood pressure (BP) measurement is essential., Methods: Hypertension estimates in the National Longitudinal Study of Adolescent Health (Add Health), Wave IV (2008)-a nationally representative field study of 15,701 participants aged 24-32-was referenced against NHANES (2007-2008) participants of the same age. We examined discordances in hypertension, and estimated the accuracy and reliability of blood pressure in the Add Health study., Results: Hypertension rates (BP: ≥ 140/90 mm Hg) were higher in Add Health compared with NHANES (19% vs. 4%), but self-reported history was similar (11% vs. 9%) among adults aged 24-32. Survey weights and adjustments for differences in participant characteristics, examination time, use of antihypertensive medications, and consumption of food/caffeine/cigarettes before blood pressure measurement had little effect on between-study differences in hypertension estimates. Among Add Health participants interviewed and examined twice (full and abbreviated interviews), blood pressure was similar, as was blood pressure at the in-home and in-clinic examinations conducted by NHANES III (1988-1994). In Add Health, there was minimal digit preference in blood pressure measurements; mean bias never exceeded 2 mm Hg; and reliability (estimated as intraclass correlation coefficients) was 0.81 and 0.68 for systolic and diastolic BPs, respectively., Conclusions: The proportion of young adults in NHANES reporting a history of hypertension was twice that with measured hypertension, whereas the reverse was found in Add Health. Between-survey differences were not explained by digit preference, low validity, or reliability of Add Health blood pressure data, or by salient differences in participant selection, measurement context, or interview content. The prevalence of hypertension among Add Health Wave IV participants suggests an unexpectedly high risk of cardiovascular disease among US young adults and warrants further scrutiny.

Background: Several methods have been used to account for measurement error inherent in using ambient concentration of particulate matter < 2.5 microm/m(3) (PM(2.5)) as a proxy for personal exposure. Such methods commonly rely on the estimated correlation between ambient and personal PM(2.5) concentrations (r). However, studies of r have not been systematically and quantitatively assessed for publication bias or heterogeneity., Methods: We searched 7 electronic reference databases for studies of the within-participant correlation between ambient and personal PM(2.5)., Results: We identified 567 candidate studies, 18 (3%) of which met inclusion criteria and were abstracted. The studies were published between 1999 and 2008, representing 619 nonsmoking participants aged 6-93 years in 17 European and North American cities. Correlation coefficients (median 0.54; range 0.09-0.83) were based on a median of 8 ambient-personal PM(2.5) pairs per participant (range 5-20) collected over 27-547 days. Overall, there was little evidence for publication bias (funnel plot symmetry tests: Begg's log-rank test, P 0.9; Egger's regression asymmetry test, P 0.2). However, strong evidence for heterogeneity was noted (Cochran's Q test for heterogeneity, P = 0.001). European locales, eastern longitudes in North America, higher ambient PM(2.5) concentrations, higher relative humidity, and lower between-participant variation in r were associated with increased r., Conclusions: Characteristics of participants, studies, and the environments in which they are conducted may affect the accuracy of ambient PM2.5 as a proxy for personal exposure.

Previous studies have established that leukotriene B4 (LTB4) sensitizes cutaneous nociceptors. In this study the effects of LTB4 on spontaneous and stimulus-evoked nerve activity from primary afferents innervating the dentin of canines in adult cats were examined. LTB4 treatment (25 micrograms/ml) significantly enhanced stimulus-evoked intradental nerve activity (INA) for at least 20 min after the removal of the compound from the recording preparation. Teeth treated with LTB4 demonstrated enhanced spontaneous nerve activity following the removal of hypertonic saline used to evoked INA. These findings provide additional evidence that LTB4 is able to sensitize nociceptors and may be a long-lasting hyperalgesic factor which may contribute to pain of pulpal origin.