Association of clonal hematopoiesis and mosaic chromosomal alterations with solid malignancy incidence and mortality.

BACKGROUND: Understanding the impact of clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) on solid tumor risk and mortality can shed light on novel cancer pathways. METHODS: The authors analyzed whole genome sequencing data from the Trans-Omics for Precision Medicine Women's Health Initiative study (n = 10,866). They investigated the presence of CHIP and mCA and their association with the development and mortality of breast, lung, and colorectal cancers. RESULTS: CHIP was associated with higher risk of breast (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.03-1.64; p = .02) but not colorectal (p = .77) or lung cancer (p = .32). CHIP carriers who developed colorectal cancer also had a greater risk for advanced-stage (p = .01), but this was not seen in breast or lung cancer. CHIP was associated with increased colorectal cancer mortality both with (HR, 3.99; 95% CI, 2.41-6.62; p < .001) and without adjustment (HR, 2.50; 95% CI, 1.32-4.72; p = .004) for advanced-stage and a borderline higher breast cancer mortality (HR, 1.53; 95% CI, 0.98-2.41; p = .06). Conversely, mCA (cell fraction [CF] >3%) did not correlate with cancer risk. With higher CFs (mCA >5%), autosomal mCA was associated with increased breast cancer risk (HR, 1.39; 95% CI, 1.06-1.83; p = .01). There was no association of mCA (>3%) with breast, colorectal, or lung mortality except higher colon cancer mortality (HR, 2.19; 95% CI, 1.11-4.3; p = .02) with mCA >5%. CONCLUSIONS: CHIP and mCA (CF >5%) were associated with higher breast cancer risk and colorectal cancer mortality individually. These data could inform on novel pathways that impact cancer risk and lead to better risk stratification.

Association of Gaseous Ambient Air Pollution and Dementia-Related Neuroimaging Markers in the ARIC Cohort, Comparing Exposure Estimation Methods and Confounding by Study Site.

BACKGROUND: Evidence linking gaseous air pollution to late-life brain health is mixed. OBJECTIVE: We explored associations between exposure to gaseous pollutants and brain magnetic resonance imaging (MRI) markers among Atherosclerosis Risk in Communities (ARIC) Study participants, with attention to the influence of exposure estimation method and confounding by site. METHODS: We considered data from 1,665 eligible ARIC participants recruited from four US sites in the period 1987-1989 with valid brain MRI data from Visit 5 (2011-2013). We estimated 10-y (2001-2010) mean carbon monoxide (CO), nitrogen dioxide (NO2), nitrogen oxides (NOx), and 8- and 24-h ozone (O3) concentrations at participant addresses, using multiple exposure estimation methods. We estimated site-specific associations between pollutant exposures and brain MRI outcomes (total and regional volumes; presence of microhemorrhages, infarcts, lacunes, and severe white matter hyperintensities), using adjusted linear and logistic regression models. We compared meta-analytically combined site-specific associations to analyses that did not account for site. RESULTS: Within-site exposure distributions varied across exposure estimation methods. Meta-analytic associations were generally not statistically significant regardless of exposure, outcome, or exposure estimation method; point estimates often suggested associations between higher NO2 and NOx and smaller temporal lobe, deep gray, hippocampal, frontal lobe, and Alzheimer disease signature region of interest volumes and between higher CO and smaller temporal and frontal lobe volumes. Analyses that did not account for study site more often yielded significant associations and sometimes different direction of associations. DISCUSSION: Patterns of local variation in estimated air pollution concentrations differ by estimation method. Although we did not find strong evidence supporting impact of gaseous pollutants on brain changes detectable by MRI, point estimates suggested associations between higher exposure to CO, NOx, and NO2 and smaller regional brain volumes. Analyses of air pollution and dementia-related outcomes that do not adjust for location likely underestimate uncertainty and may be susceptible to confounding bias. https://doi.org/10.1289/EHP13906.

Associations of Epigenetic Age Estimators With Cognitive Function Trajectories in the Women's Health Initiative Memory Study.

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 (ß = -0.118, 95% CI -0.202 to -0.034; p = 0.0006) and fully adjusted (ß = -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 (ß = -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.

Association of midlife air pollution exposures and residential road proximity with incident dementia: The Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Increasing evidence links higher air pollution exposures to increased risk of cognitive impairment. While midlife risk factors are often most strongly linked to dementia risk, few studies have considered associations between midlife roadway proximity or ambient air pollution exposure and incident dementia decades later, in late life. OBJECTIVES: Our objective was to determine if midlife exposures to ambient air pollution or roadway proximity are associated with increased risk of dementia in the Atherosclerosis Risk in Communities (ARIC) study over up to 29 years of follow-up. METHODS: Our eligible sample included Black and White ARIC participants without dementia at Visit 2 (1990-1992). Participants were followed through Visit 7 (2018-2019), with dementia status and onset date defined based on formal dementia ascertainment at study visits, informant interviews, and surveillance efforts. We used adjusted Weibull survival models to assess the associations of midlife ambient air pollution and road proximity with incident dementia. RESULTS: The median age at baseline (1990-1992, Visit 2) of the 12,700 eligible ARIC participants was 57.0 years; 56.0% were female, 24.2% were Black, and 78.9% had at least a high school education. Over up to 29 years of follow-up, 2511 (19.8%) persons developed dementia. No associations were found between ambient air pollutants and proximity to major roadways with risk of incident dementia. In exploratory analyses, living closer to roadways in midlife increased dementia risk in individuals younger at baseline and those without midlife hypertension, and there was evidence of increased risk of dementia with increased midlife exposure to NOx, several PM2.5 components, and trace metals among those with diabetes in midlife. CONCLUSIONS: Midlife exposure to ambient air pollution and midlife roadway proximity was not associated with dementia risk over decades of follow-up. Further investigation to explore potential for greater susceptibility among specific subgroups identified here is needed.

Identifying the relation between food groups and biological ageing: a data-driven approach.

BACKGROUND: Heterogeneity in ageing rates drives the need for research into lifestyle secrets of successful agers. Biological age, predicted by epigenetic clocks, has been shown to be a more reliable measure of ageing than chronological age. Dietary habits are known to affect the ageing process. However, much remains to be learnt about specific dietary habits that may directly affect the biological process of ageing. OBJECTIVE: To identify food groups that are directly related to biological ageing, using Copula Graphical Models. METHODS: We performed a preregistered analysis of 3,990 postmenopausal women from the Women's Health Initiative, based in North America. Biological age acceleration was calculated by the epigenetic clock PhenoAge using whole-blood DNA methylation. Copula Graphical Modelling, a powerful data-driven exploratory tool, was used to examine relations between food groups and biological ageing whilst adjusting for an extensive amount of confounders. Two food group-age acceleration networks were established: one based on the MyPyramid food grouping system and another based on item-level food group data. RESULTS: Intake of eggs, organ meat, sausages, cheese, legumes, starchy vegetables, added sugar and lunch meat was associated with biological age acceleration, whereas intake of peaches/nectarines/plums, poultry, nuts, discretionary oil and solid fat was associated with decelerated ageing. CONCLUSION: We identified several associations between specific food groups and biological ageing. These findings pave the way for subsequent studies to ascertain causality and magnitude of these relationships, thereby improving the understanding of biological mechanisms underlying the interplay between food groups and biological ageing.

A comparison of PM2.5 exposure estimates from different estimation methods and their associations with cognitive testing and brain MRI outcomes.

BACKGROUND: Reported associations between particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5) and cognitive outcomes remain mixed. Differences in exposure estimation method may contribute to this heterogeneity. OBJECTIVES: To assess agreement between PM2.5 exposure concentrations across 11 exposure estimation methods and to compare resulting associations between PM2.5 and cognitive or MRI outcomes. METHODS: We used Visit 5 (2011-2013) cognitive testing and brain MRI data from the Atherosclerosis Risk in Communities (ARIC) Study. We derived address-linked average 2000-2007 PM2.5 exposure concentrations in areas immediately surrounding the four ARIC recruitment sites (Forsyth County, NC; Jackson, MS; suburbs of Minneapolis, MN; Washington County, MD) using 11 estimation methods. We assessed agreement between method-specific PM2.5 concentrations using descriptive statistics and plots, overall and by site. We used adjusted linear regression to estimate associations of method-specific PM2.5 exposure estimates with cognitive scores (n = 4678) and MRI outcomes (n = 1518) stratified by study site and combined site-specific estimates using meta-analyses to derive overall estimates. We explored the potential impact of unmeasured confounding by spatially patterned factors. RESULTS: Exposure estimates from most methods had high agreement across sites, but low agreement within sites. Within-site exposure variation was limited for some methods. Consistently null findings for the PM2.5-cognitive outcome associations regardless of method precluded empirical conclusions about the potential impact of method on study findings in contexts where positive associations are observed. Not accounting for study site led to consistent, adverse associations, regardless of exposure estimation method, suggesting the potential for substantial bias due to residual confounding by spatially patterned factors. DISCUSSION: PM2.5 estimation methods agreed across sites but not within sites. Choice of estimation method may impact findings when participants are concentrated in small geographic areas. Understanding unmeasured confounding by factors that are spatially patterned may be particularly important in studies of air pollution and cognitive or brain health.

Aircraft noise exposure and body mass index among female participants in two Nurses' Health Study prospective cohorts living around 90 airports in the United States.

OBJECTIVE: Aircraft noise exposure is linked to cardiovascular disease risk. One understudied candidate pathway is obesity. This study investigates the association between aircraft noise and obesity among female participants in two prospective Nurses' Health Study (NHS and NHSII) cohorts. METHODS: Aircraft day-night average sound levels (DNL) were estimated at participant residential addresses from modeled 1 dB (dB) noise contours above 44 dB for 90 United States (U.S.) airports in 5-year intervals 1995-2010. Biennial surveys (1994-2017) provided information on body mass index (BMI; dichotomized, categorical) and other individual characteristics. Change in BMI from age 18 (BMI18; tertiles) was also calculated. Aircraft noise exposures were dichotomized (45, 55 dB), categorized (<45, 45-54, ≥55 dB) or continuous for exposure ≥45 dB. Multivariable multinomial logistic regression using generalized estimating equations were adjusted for individual characteristics and neighborhood socioeconomic status, greenness, population density, and environmental noise. Effect modification was assessed by U.S. Census region, climate boundary, airline hub type, hearing loss, and smoking status. RESULTS: At baseline, the 74,848 female participants averaged 50.1 years old, with 83.0%, 14.8%, and 2.2% exposed to <45, 45-54, and ≥55 dB of aircraft noise, respectively. In fully adjusted models, exposure ≥55 dB was associated with 11% higher odds (95% confidence interval [95%CI]: -1%, 24%) of BMIs ≥30.0, and 15% higher odds (95%CI: 3%, 29%) of membership in the highest tertile of BMI18 (ΔBMI 6.7 to 71.6). Less-pronounced associations were observed for the 2nd tertile of BMI18 (ΔBMI 2.9 to 6.6) and BMI 25.0-29.9 as well as exposures ≥45 versus <45 dB. There was evidence of DNL-BMI trends (ptrends ≤ 0.02). Stronger associations were observed among participants living in the West, arid climate areas, and among former smokers. DISCUSSION: In two nationwide cohorts of female nurses, higher aircraft noise exposure was associated with higher BMI, adding evidence to an aircraft noise-obesity-disease pathway.

Radon Exposure and Incident Stroke Risk in the Women's Health Initiative.

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.

Racial disparities in stroke incidence in the Women's Health Initiative: Exploring biological, behavioral, psychosocial, and social risk factors.

Background: - Disparities in incident stroke risk among women by race and ethnicity persist. Few studies report the distribution and association of stroke risk factors by age group among a diverse sample of women. Methods: - Data from the Women's Health Initiative (WHI) Observational Study collected between 1993 and 2010 were used to calculate cumulative stroke incidence and incidence rates among non-Hispanic African American (NHAA), non-Hispanic white (NHW), and Hispanic white or African American (HWAA) women by age group in participants aged ≥50 years at baseline (N = 77,247). Hazard ratios (HRs) and 95% CIs for biological, behavioral, psychosocial, and socioeconomic factors overall and by race or ethnicity were estimated using sequential Cox proportional hazard regression models. Results: - Average follow-up time was 11.52 (SD, 3.48) years. The incident stroke rate was higher among NHAA (306 per 100,000 person-years) compared to NHW (279/100,000py) and HWAA women (147/100,000py) overall and in each age group. The disparity was largest at ages >75 years. The association between stroke risk factors (e.g., smoking, BMI, physical activity) and incident stroke varied across race and ethnicity groups. Higher social support was significantly associated with decreased stroke risk overall (HR:0.84, 95% CI, 0.76, 0.93); the degree of protection varied across race and ethnicity groups. Socioeconomic factors did not contribute additional stroke risk beyond risk conferred by traditional and psychosocial factors. Conclusions: - The distribution and association of stroke risk factors differed between NHAA and NHW women. There is a clear need for stroke prevention strategies that address factors driving racial disparities in stroke risk.

Diet Quality and Epigenetic Aging in the Women's Health Initiative.

BACKGROUND: Higher diet quality scores are associated with a lower risk for many chronic diseases and all-cause mortality; however, it is unclear if diet quality is associated with aging biology. OBJECTIVE: This study aimed to examine the association between diet quality and a measure of biological aging known as epigenetic aging. DESIGN: A cross-sectional data analysis was used to examine the association between three diet quality scores based on self-reported food frequency questionnaire data and five measures of epigenetic aging based on DNA methylation (DNAm) data from peripheral blood. PARTICIPANTS/SETTING: This study included 4,500 postmenopausal women recruited from multiple sites across the United States (1993-98), aged 50 to 79 years, with food frequency questionnaire and DNAm data available from the Women's Health Initiative baseline visit. MAIN OUTCOME MEASURES: Five established epigenetic aging measures were generated from HumanMethylation450 Beadchip DNAm data, including AgeAccelHannum, AgeAccelHorvath, AgeAccelPheno, AgeAccelGrim, and DunedinPACE. STATISTICAL ANALYSES PERFORMED: Linear mixed models were used to test for associations between three diet quality scores (Healthy Eating Index, Dietary Approaches to Stop Hypertension, and alternate Mediterranean diet scores) and epigenetic aging measures, adjusted for age, race and ethnicity, education, tobacco smoking, physical activity, Women's Health Initiative substudy from which DNAm data were obtained, and DNAm-based estimates of leukocyte proportions. RESULTS: Healthy Eating Index, Dietary Approaches to Stop Hypertension, and alternate Mediterranean diet scores were all inversely associated with AgeAccelPheno, AgeAccelGrim, and DunedinPACE (P < 0.05), with the largest effects with DunedinPACE. A one standard deviation increment in diet quality scores was associated with a decrement (ß ± SE) in DunedinPACE z score of -0.097 ± 0.014 (P = 9.70 x 10-13) for Healthy Eating Index, -0.107 ± 0.014 (P = 1.53 x 10-14) for Dietary Approaches to Stop Hypertension, and -0.068 ± 0.013 (P = 2.31 x 10-07) for the alternate Mediterranean diet. CONCLUSIONS: In postmenopausal women, diet quality scores were inversely associated with DNAm-based measures of biological aging, particularly DunedinPACE.

Radon Exposure, Clonal Hematopoiesis, and Stroke Susceptibility in the Women's Health Initiative.

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 (ptrend = 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 (pinteraction = 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 (pinteraction = 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.

Clonal Hematopoiesis and Incident Heart Failure With Preserved Ejection Fraction.

Importance: Clonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion of hematopoietic stem cells with leukemogenic acquired genetic variants, is associated with incident heart failure (HF). Objective: To evaluate the associations of CHIP and key gene-specific CHIP subtypes with incident HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). Design, Setting, and Participants: This population-based cohort study included participants from 2 racially diverse prospective cohort studies with uniform HF subtype adjudication: the Jackson Heart Study (JHS) and Women's Health Initiative (WHI). JHS participants were enrolled during 2000 to 2004 and followed up through 2016. WHI participants were enrolled during 1993 to 1998 and followed up through 2022. Participants who underwent whole-genome sequencing, lacked prevalent HF at baseline, and were followed up for HF adjudication were included. Follow-up occurred over a median (IQR) of 12.0 (11.0-12.0) years in the JHS and 15.3 (9.0-22.0) years in the WHI. Statistical analysis was performed from June to December 2023. Exposures: Any CHIP and the most common gene-specific CHIP subtypes (DNMT3A and TET2 CHIP). Main Outcomes and Measures: First incident hospitalized HF events were adjudicated from hospital records and classified as HFpEF (left ventricular ejection fraction ≥50%) or HFrEF (ejection fraction <50%). Results: A total of 8090 participants were included; 2927 from the JHS (median [IQR] age, 56 [46-65] years; 1846 [63.1%] female; 2927 [100.0%] Black or African American) and 5163 from the WHI (median [IQR] age, 67 [62-72] years; 5163 [100.0%] female; 29 [0.6%] American Indian or Alaska Native, 37 [0.7%] Asian or Pacific Islander, 1383 [26.8%] Black or African American, 293 [5.7%] Hispanic or Latinx, 3407 [66.0%] non-Hispanic White, and 14 [0.3%] with other race and ethnicity). The multivariable-adjusted hazard ratio (HR) for composite CHIP and HFpEF was 1.28 (95% CI, 0.93-1.76; P = .13), and for CHIP and HFrEF it was 0.79 (95% CI, 0.49-1.25; P = .31). TET2 CHIP was associated with HFpEF in both cohorts (meta-analyzed HR, 2.35 [95% CI, 1.34 to 4.11]; P = .003) independent of cardiovascular risk factors and coronary artery disease. Analyses stratified by C-reactive protein (CRP) in the WHI found an increased risk of incident HFpEF in individuals with CHIP and CRP greater than or equal to 2 mg/L (HR, 1.94 [95% CI, 1.20-3.15]; P = .007), but not in those with CHIP and CRP less than 2 mg/L or those with CRP greater than or equal to 2 mg/L without CHIP, when compared with participants without CHIP and CRP less than 2 mg/L. Conclusions and Relevance: In this cohort study, TET2 CHIP was an independent risk factor associated with incident HFpEF. This finding may have implications for the prevention and management of HFpEF, including development of targeted therapies.

Individual and Neighborhood-level Socioeconomic Status and Somatic Mutations Associated With Increased Risk of Cardiovascular Disease and Mortality: A Cross-Sectional Analysis in the Women's Health Initiative.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), the expansion of leukemogenic mutations in white blood cells, has been associated with increased risk of atherosclerotic cardiovascular diseases, cancer, and mortality. OBJECTIVE: We examined the relationship between individual- and neighborhood-level socioeconomic status (SES) and CHIP and evaluated effect modification by interpersonal and intrapersonal resources. METHODS: The study population included 10,799 postmenopausal women from the Women's Health Initiative without hematologic malignancy or antineoplastic medication use. Individual- and neighborhood (Census tract)-level SES were assessed across several domains including education, income, and occupation, and a neighborhood-level SES summary z-score, which captures multiple dimensions of SES, was generated. Interpersonal and intrapersonal resources were self-reports. CHIP was ascertained based on a prespecified list of leukemogenic driver mutations. Weighted logistic regression models adjusted for covariates were used to estimate risk of CHIP as an odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: The interval-scale neighborhood-level SES summary z-score was associated with a 3% increased risk of CHIP: OR (95% CI) = 1.03 (1.00-1.05), p = .038. Optimism significantly modified that estimate, such that among women with low/medium and high levels of optimism, the corresponding ORs (95% CIs) were 1.03 (1.02-1.04) and 0.95 (0.94-0.96), pInteraction < .001. CONCLUSIONS: Our findings suggest that reduced risk of somatic mutation may represent a biological pathway by which optimism protects contextually advantaged but at-risk women against age-related chronic disease and highlight potential benefits of long-term, positive psychological interventions.

Stressful life events, social support, and epigenetic aging in the Women's Health Initiative.

BACKGROUND: Elevated psychosocial stress has been linked with accelerated biological aging, including composite DNA methylation (DNAm) markers that predict aging-related outcomes ("epigenetic age"). However, no study has examined whether stressful life events (SLEs) are associated with epigenetic age acceleration in postmenopausal women, an aging population characterized by increased stress burden and disease risk. METHODS: We leveraged the Women's Health Initiative, a large muti-ancestry cohort of postmenopausal women with available psychosocial stress measures over the past year and epigenomic data. SLEs and social support were ascertained via self-report questionnaires. Whole blood DNAm array (450 K) data were used to calculate five DNAm-based predictors of chronological age, health span and life span, and telomere length (HorvathAge, HannumAge, PhenoAge, GrimAge, DNAmTL). RESULTS: After controlling for potential confounders, higher SLE burden was significantly associated with accelerated epigenetic aging, as measured by GrimAge (ß: 0.34, 95% CI: 0.08, 0.59) and DNAmTL (ß: -0.016, 95% CI: -0.028, -0.004). Exploratory analyses showed that SLEs-GrimAge associations were stronger in Black women as compared to other races/ethnicities and in those with lower social support levels. In women with lower social support, SLEs-DNAmTL associations showed opposite association in Hispanic women as compared to other race/ethnicity groups. CONCLUSIONS: Our findings suggest that elevated stress burden is associated with accelerated epigenetic aging in postmenopausal women. Lower social support and/or self-reported race/ethnicity may modify the association of stress with epigenetic age acceleration. These findings advance understanding of how stress may contribute to aging-related outcomes and have important implications for disease prevention and treatment in aging women.

Heart rate variability and risk of agitation in Alzheimer's disease: the Atherosclerosis Risk in Communities Study.

Agitation in Alzheimer's disease is common and may be related to impaired emotion regulation capacity. Heart rate variability, a proposed index of autonomic and emotion regulation neural network integrity, could be associated with agitation propensity in Alzheimer's disease. We used the Atherosclerosis Risk in Communities Study cohort data, collected over seven visits spanning over two decades, to investigate whether heart rate variability (change) was associated with agitation risk in individuals clinically diagnosed with dementia due to Alzheimer's disease. Agitation (absence/presence) at Visit 5, the primary outcome, was based on the Neuropsychiatric Inventory agitation/aggression subscale, or a composite score comprising the total number of agitation/aggression, irritability, disinhibition and aberrant motor behaviour subscales present. Visit 1-5 heart rate variability measures were the log-transformed root mean square of successive differences in R-R intervals and standard deviation of normal-to-normal R-R intervals obtained from resting, supine, standard 12-lead ECGs. To aid interpretability, heart rate variability data were scaled such that model outputs were expressed for each 0.05 log-unit change in heart rate variability (which approximated to the observed difference in heart rate variability with every 5 years of age). Among 456 participants who had dementia, 120 were clinically classified to have dementia solely attributable to Alzheimer's disease. This group showed a positive relationship between heart rate variability and agitation risk in regression models, which was strongest for measures of (potentially vagally mediated) heart rate variability change over the preceding two decades. Here, a 0.05 log-unit of heart rate variability change was associated with an up to 10-fold increase in the odds of agitation and around a half-unit increase in the composite agitation score. Associations persisted after controlling for participants' cognitive status, heart rate (change), sociodemographic factors, co-morbidities and medications with autonomic effects. Further confirmatory studies, incorporating measures of emotion regulation, are needed to support heart rate variability indices as potential agitation propensity markers in Alzheimer's disease and to explore underlying mechanisms as targets for treatment development.

Characterizing temporal trends in populations exposed to aircraft noise around U.S. airports: 1995-2015.

BACKGROUND: Aircraft noise is a key concern for communities surrounding airports, with increasing evidence for health effects and inequitable distributions of exposure. However, there have been limited national-scale assessments of aircraft noise exposure over time and across noise metrics, limiting evaluation of population exposure patterns. OBJECTIVE: We evaluated national-scale temporal trends in aviation noise exposure by airport characteristics and across racial/ethnic populations in the U.S. METHODS: Noise contours were modeled for 90 U.S. airports in 5-year intervals between 1995 and 2015 using the Federal Aviation Administration's Aviation Environmental Design Tool. We utilized linear fixed effects models to estimate changes in noise exposure areas for day-night average sound levels (DNL) of 45, 65, and a nighttime equivalent sound level (Lnight) of 45 A-weighted decibels (dB[A]). We used group-based trajectory modeling to identify distinct groups of airports sharing underlying characteristics. We overlaid noise contours and Census tract data from the U.S. Census Bureau and American Community Surveys for 2000 to 2015 to estimate exposure changes overall and by race/ethnicity. RESULTS: National-scale analyses showed non-monotonic trends in mean exposed areas that peaked in 2000, followed by a 37% decrease from 2005 to 2010 and a subsequent increase in 2015. We identified four distinct trajectory groups of airports sharing latent characteristics related to size and activity patterns. Those populations identifying as minority (e.g., Hispanic/Latino, Black/African American, Asian) experienced higher proportions of exposure relative to their subgroup populations compared to non-Hispanic or White populations across all years, indicating ethnic and racial disparities in airport noise exposure that persist over time. SIGNIFICANCE: Overall, these data identified differential exposure trends across airports and subpopulations, helping to identify vulnerable communities for aviation noise in the U.S. IMPACT STATEMENT: We conducted a descriptive analysis of temporal trends in aviation noise exposure in the U.S. at a national level. Using data from 90 U.S. airports over a span of two decades, we characterized the noise exposure trends overall and by airport characteristics, while estimating the numbers of exposed by population demographics to help identify the impact on vulnerable communities who may bear the burden of aircraft noise exposure.

The association of long-term exposure to criteria air pollutants, fine particulate matter components, and airborne trace metals with late-life brain amyloid burden in the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Studies suggest associations between long-term ambient air pollution exposure and outcomes related to Alzheimer's disease (AD). Whether a link exists between pollutants and brain amyloid accumulation, a biomarker of AD, is unclear. We assessed whether long-term air pollutant exposures are associated with late-life brain amyloid deposition in Atherosclerosis Risk in Communities (ARIC) study participants. METHODS: We used a chemical transport model with data fusion to estimate ambient concentrations of PM2.5 and its components, NO2, NOx, O3 (24-hour and 8-hour), CO, and airborne trace metals. We linked concentrations to geocoded participant addresses and calculated 10-year mean exposures (2002 to 2011). Brain amyloid deposition was measured using florbetapir amyloid positron emission tomography (PET) scans in 346 participants without dementia in 2012-2014, and we defined amyloid positivity as a global cortical standardized uptake value ratio ≥ the sample median of 1.2. We used logistic regression models to quantify the association between amyloid positivity and each air pollutant, adjusting for putative confounders. In sensitivity analyses, we considered whether use of alternate air pollution estimation approaches impacted findings for PM2.5, NO2, NOx, and 24-hour O3. RESULTS: At PET imaging, eligible participants (N = 318) had a mean age of 78 years, 56% were female, 43% were Black, and 27% had mild cognitive impairment. We did not find evidence of associations between long-term exposure to any pollutant and brain amyloid positivity in adjusted models. Findings were materially unchanged in sensitivity analyses using alternate air pollution estimation approaches for PM2.5, NO2, NOx, and 24-hour O3. CONCLUSIONS: Air pollution may impact cognition and dementia independent of amyloid accumulation, though whether air pollution influences AD pathogenesis later in the disease course or at higher exposure levels deserves further consideration.

Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Incident Type 2 Diabetes Risk.

OBJECTIVE: Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D. RESEARCH DESIGN AND METHODS: CHIP was derived from whole-genome sequencing of blood DNA in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) prospective cohorts. We performed analysis for 17,637 participants from six cohorts, without prior T2D, cardiovascular disease, or cancer. We evaluated baseline CHIP versus no CHIP prevalence with incident T2D, including associations with DNMT3A, TET2, ASXL1, JAK2, and TP53 variants. We estimated multivariable-adjusted hazard ratios (HRs) and 95% CIs with adjustment for age, sex, BMI, smoking, alcohol, education, self-reported race/ethnicity, and combined cohorts' estimates via fixed-effects meta-analysis. RESULTS: Mean (SD) age was 63.4 (11.5) years, 76% were female, and CHIP prevalence was 6.0% (n = 1,055) at baseline. T2D was diagnosed in n = 2,467 over mean follow-up of 9.8 years. Participants with CHIP had 23% (CI 1.04, 1.45) higher risk of T2D than those with no CHIP. Specifically, higher risk was for TET2 (HR 1.48; CI 1.05, 2.08) and ASXL1 (HR 1.76; CI 1.03, 2.99) mutations; DNMT3A was nonsignificant (HR 1.15; CI 0.93, 1.43). Statistical power was limited for JAK2 and TP53 analyses. CONCLUSIONS: CHIP was associated with higher incidence of T2D. CHIP mutations located on genes implicated in CHD and mortality were also related to T2D, suggesting shared aging-related pathology.

Cumulative Use of Proton Pump Inhibitors and Risk of Dementia: The Atherosclerosis Risk in Communities Study.

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.

Associations between Ambient Air Pollutants and Clonal Hematopoiesis of Indeterminate Potential.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related somatic mutation associated with incident hematologic cancer. Environmental stressors which, like air pollution, generate oxidative stress at the cellular level, may induce somatic mutations and some mutations may provide a selection advantage for persistence and expansion of specific clones. METHODS: We used data from the Multi-Ethnic Study of Atherosclerosis (MESA) N = 4,379 and the Women's Health Initiative (WHI) N = 7,701 to estimate cross-sectional associations between annual average air pollution concentrations at participant address the year before blood draw using validated spatiotemporal models. We used covariate-adjusted logistic regression to estimate risk of CHIP per interquartile range increases in particulate matter (PM2.5; 4 µg/m3) and nitrogen dioxide (NO2; 10 ppb) as ORs (95% confidence intervals). RESULTS: Prevalence of CHIP at blood draw (variant allele fraction > 2%) was 4.4% and 8.7% in MESA and WHI, respectively. The most common CHIP driver mutation was in DNMT3A. Neither pollutant was associated with CHIP: ORMESA PM2.5 = 1.00 (0.68-1.45), ORMESA NO2 = 1.05 (0.69-1.61), ORWHI PM2.5 = 0.97 (0.86-1.09), ORWHI NO2 = 0.98 (0.88-1.10); or with DNMT3A-driven CHIP. CONCLUSIONS: We did not find evidence that air pollution contributes to CHIP prevalence in two large observational cohorts. IMPACT: This is the first study to estimate associations between air pollution and CHIP.