Epidemiologic Features of Recovery From SARS-CoV-2 Infection.

Importance: Persistent symptoms and disability following SARS-CoV-2 infection, known as post-COVID-19 condition or "long COVID," are frequently reported and pose a substantial personal and societal burden. Objective: To determine time to recovery following SARS-CoV-2 infection and identify factors associated with recovery by 90 days. Design, Setting, and Participants: For this prospective cohort study, standardized ascertainment of SARS-CoV-2 infection was conducted starting in April 1, 2020, across 14 ongoing National Institutes of Health-funded cohorts that have enrolled and followed participants since 1971. This report includes data collected through February 28, 2023, on adults aged 18 years or older with self-reported SARS-CoV-2 infection. Exposure: Preinfection health conditions and lifestyle factors assessed before and during the pandemic via prepandemic examinations and pandemic-era questionnaires. Main Outcomes and Measures: Probability of nonrecovery by 90 days and restricted mean recovery times were estimated using Kaplan-Meier curves, and Cox proportional hazards regression was performed to assess multivariable-adjusted associations with recovery by 90 days. Results: Of 4708 participants with self-reported SARS-CoV-2 infection (mean [SD] age, 61.3 [13.8] years; 2952 women [62.7%]), an estimated 22.5% (95% CI, 21.2%-23.7%) did not recover by 90 days post infection. Median (IQR) time to recovery was 20 (8-75) days. By 90 days post infection, there were significant differences in restricted mean recovery time according to sociodemographic, clinical, and lifestyle characteristics, particularly by acute infection severity (outpatient vs critical hospitalization, 32.9 days [95% CI, 31.9-33.9 days] vs 57.6 days [95% CI, 51.9-63.3 days]; log-rank P < .001). Recovery by 90 days post infection was associated with vaccination prior to infection (hazard ratio [HR], 1.30; 95% CI, 1.11-1.51) and infection during the sixth (Omicron variant) vs first wave (HR, 1.25; 95% CI, 1.06-1.49). These associations were mediated by reduced severity of acute infection (33.4% and 17.6%, respectively). Recovery was unfavorably associated with female sex (HR, 0.85; 95% CI, 0.79-0.92) and prepandemic clinical cardiovascular disease (HR, 0.84; 95% CI, 0.71-0.99). No significant multivariable-adjusted associations were observed for age, educational attainment, smoking history, obesity, diabetes, chronic kidney disease, asthma, chronic obstructive pulmonary disease, or elevated depressive symptoms. Results were similar for reinfections. Conclusions and Relevance: In this cohort study, more than 1 in 5 adults did not recover within 3 months of SARS-CoV-2 infection. Recovery within 3 months was less likely in women and those with preexisting cardiovascular disease and more likely in those with COVID-19 vaccination or infection during the Omicron variant wave.

Epigenetic and proteomic signatures associate with clonal hematopoiesis expansion rate.

Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels. Clonal expansion rate was significantly associated with both genetically predicted and measured epigenetic clocks. No associations were identified with inflammation-related lab values or diseases and CHIP expansion rate overall. A proteome-wide search identified predicted circulating levels of myeloid zinc finger 1 and anti-Müllerian hormone as associated with an increased CHIP clonal expansion rate and tissue inhibitor of metalloproteinase 1 and glycine N-methyltransferase as associated with decreased CHIP clonal expansion rate. Together, our findings identify epigenetic and proteomic patterns associated with the rate of hematopoietic clonal expansion.

Determinants of mosaic chromosomal alteration fitness.

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood.

Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer's disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole genome sequencing of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. This approach enabled us to identify differences in mLOY frequencies across populations defined by genetic similarity, revealing a higher frequency of mLOY in the European American (EA) ancestry group compared to those of Hispanic American (HA), African American (AA), and East Asian (EAS) ancestry. Further, we identified two genes ( CFHR1 and LRP6 ) that harbor multiple rare, putatively deleterious variants associated with mLOY susceptibility, show that subsets of human hematopoietic stem cells are enriched for activity of mLOY susceptibility variants, and that certain alleles on chromosome Y are more likely to be lost than others.

Plasma proteomic signature of human longevity.

The identification of protein targets that exhibit anti-aging clinical potential could inform interventions to lengthen the human health span. Most previous proteomics research has been focused on chronological age instead of longevity. We leveraged two large population-based prospective cohorts with long follow-ups to evaluate the proteomic signature of longevity defined by survival to 90 years of age. Plasma proteomics was measured using a SOMAscan assay in 3067 participants from the Cardiovascular Health Study (discovery cohort) and 4690 participants from the Age Gene/Environment Susceptibility-Reykjavik Study (replication cohort). Logistic regression identified 211 significant proteins in the CHS cohort using a Bonferroni-adjusted threshold, of which 168 were available in the replication cohort and 105 were replicated (corrected p value <0.05). The most significant proteins were GDF-15 and N-terminal pro-BNP in both cohorts. A parsimonious protein-based prediction model was built using 33 proteins selected by LASSO with 10-fold cross-validation and validated using 27 available proteins in the validation cohort. This protein model outperformed a basic model using traditional factors (demographics, height, weight, and smoking) by improving the AUC from 0.658 to 0.748 in the discovery cohort and from 0.755 to 0.802 in the validation cohort. We also found that the associations of 169 out of 211 proteins were partially mediated by physical and/or cognitive function. These findings could contribute to the identification of biomarkers and pathways of aging and potential therapeutic targets to delay aging and age-related diseases.

Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol.

Importance: Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified. Objective: To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults. Design, Setting, and Participants: A total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023. Exposures: LDL-C, cumulative past LDL-C, FH variant status. Main Outcomes and Measures: Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults. Results: Of the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant. Conclusions and Relevance: In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.

Determinants of mosaic chromosomal alteration fitness.

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well-understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our estimates of mCA fitness were correlated (R 2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using a theoretical probability distribution. Individuals with lymphoid-associated mCAs had a significantly higher white blood cell count and faster clonal expansion rate. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified TCL1A , NRIP1 , and TERT locus variants as modulators of mCA clonal expansion rate.

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.

Investigating Associations of Omega-3 Fatty Acids, Lung Function Decline, and Airway Obstruction.

Rationale: Inflammation contributes to lung function decline and the development of chronic obstructive pulmonary disease. Omega-3 fatty acids have antiinflammatory properties and may benefit lung health. Objectives: To investigate associations of omega-3 fatty acids with lung function decline and incident airway obstruction in a diverse sample of adults from general-population cohorts. Methods: Complementary study designs: 1) longitudinal study of plasma phospholipid omega-3 fatty acids and repeated FEV1 and FVC measures in the NHLBI Pooled Cohorts Study and 2) two-sample Mendelian randomization (MR) study of genetically predicted omega-3 fatty acids and lung function parameters. Measurements and Main Results: The longitudinal study found that higher omega-3 fatty acid levels were associated with attenuated lung function decline in 15,063 participants, with the largest effect sizes for the most metabolically downstream omega-3 fatty acid, docosahexaenoic acid (DHA). An increase in DHA of 1% of total fatty acids was associated with attenuations of 1.4 ml/yr for FEV1 (95% confidence interval [CI], 1.1-1.8) and 2.0 ml/yr for FVC (95% CI, 1.6-2.4) and a 7% lower incidence of spirometry-defined airway obstruction (95% CI, 0.89-0.97). DHA associations persisted across sexes and smoking histories and in Black, White, and Hispanic participants, with associations of the largest magnitude in former smokers and Hispanic participants. The MR study showed similar trends toward positive associations of genetically predicted downstream omega-3 fatty acids with FEV1 and FVC. Conclusions: The longitudinal and MR studies provide evidence supporting beneficial effects of higher levels of downstream omega-3 fatty acids, especially DHA, on lung health.

Clonal hematopoiesis is associated with protection from Alzheimer's disease.

Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer's disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P = 3.8 × 10-5), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD.

The association of myocardial infarction with cancer incidence.

In this commentary, the authors discuss the potential mechanisms for the finding of an association between myocardial infarction and cancer incidence.

Clonal Hematopoiesis of Indeterminate Potential is Associated with Acute Kidney Injury.

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown and to date no genetic mechanisms for AKI have been established. Clonal hematopoiesis of indeterminate potential (CHIP) is a recently recognized biological mechanism conferring risk of several chronic aging diseases including cardiovascular disease, pulmonary disease and liver disease. In CHIP, blood stem cells acquire mutations in myeloid cancer driver genes such as DNMT3A, TET2, ASXL1 and JAK2 and the myeloid progeny of these mutated cells contribute to end-organ damage through inflammatory dysregulation. We sought to establish whether CHIP causes acute kidney injury (AKI). To address this question, we first evaluated associations with incident AKI events in three population-based epidemiology cohorts (N = 442,153). We found that CHIP was associated with a greater risk of AKI (adjusted HR 1.26, 95% CI: 1.19-1.34, p<0.0001), which was more pronounced in patients with AKI requiring dialysis (adjusted HR 1.65, 95% CI: 1.24-2.20, p=0.001). The risk was particularly high in the subset of individuals where CHIP was driven by mutations in genes other than DNMT3A (HR: 1.49, 95% CI: 1.37-1.61, p<0.0001). We then examined the association between CHIP and recovery from AKI in the ASSESS-AKI cohort and identified that non-DNMT3A CHIP was more common among those with a non-resolving pattern of injury (HR 2.3, 95% CI: 1.14-4.64, p = 0.03). To gain mechanistic insight, we evaluated the role of Tet2-CHIP to AKI in ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) mouse models. In both models, we observed more severe AKI and greater post-AKI kidney fibrosis in Tet2-CHIP mice. Kidney macrophage infiltration was markedly increased in Tet2-CHIP mice and Tet2-CHIP mutant renal macrophages displayed greater proinflammatory responses. In summary, this work establishes CHIP as a genetic mechanism conferring risk of AKI and impaired kidney function recovery following AKI via an aberrant inflammatory response in CHIP derived renal macrophages.

Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

Trimethylamine N-oxide is associated with long-term mortality risk: the multi-ethnic study of atherosclerosis.

AIMS: Little is known about associations of trimethylamine N-oxide (TMAO), a novel gut microbiota-generated metabolite of dietary phosphatidylcholine and carnitine, and its changes over time with all-cause and cause-specific mortality in the general population or in different race/ethnicity groups. The study aimed to investigate associations of serially measured plasma TMAO levels and changes in TMAO over time with all-cause and cause-specific mortality in a multi-ethnic community-based cohort. METHODS AND RESULTS: The study included 6,785 adults from the Multi-Ethnic Study of Atherosclerosis. TMAO was measured at baseline and year 5 using mass spectrometry. Primary outcomes were adjudicated all-cause mortality and cardiovascular disease (CVD) mortality. Secondary outcomes were deaths due to kidney failure, cancer, or dementia obtained from death certificates. Cox proportional hazards models with time-varying TMAO and covariates assessed the associations with adjustment for sociodemographics, lifestyles, diet, metabolic factors, and comorbidities. During a median follow-up of 16.9 years, 1704 participants died and 411 from CVD. Higher TMAO levels associated with higher risk of all-cause mortality [hazard ratio (HR): 1.12, 95% confidence interval (CI): 1.08-1.17], CVD mortality (HR: 1.09, 95% CI: 1.00-1.09), and death due to kidney failure (HR: 1.44, 95% CI: 1.25-1.66) per inter-quintile range, but not deaths due to cancer or dementia. Annualized changes in TMAO levels associated with higher risk of all-cause mortality (HR: 1.10, 95% CI: 1.05-1.14) and death due to kidney failure (HR: 1.54, 95% CI: 1.26-1.89) but not other deaths. CONCLUSION: Plasma TMAO levels were positively associated with mortality, especially deaths due to cardiovascular and renal disease, in a multi-ethnic US cohort.

Investigating associations of omega-3 fatty acids, lung function decline, and airway obstruction.

Rationale: Inflammation contributes to lung function decline and the development of chronic obstructive pulmonary disease. Omega-3 fatty acids have anti-inflammatory properties and may benefit lung health. Objectives: Investigate associations of omega-3 fatty acids with lung function decline and incident airway obstruction in adults of diverse races/ethnicities from general population cohorts. Methods: Complementary study designs: (1) longitudinal study of plasma phospholipid omega-3 fatty acids and repeated FEV 1 and FVC measures in the National Heart, Lung, and Blood Institute Pooled Cohorts Study, and (2) two-sample Mendelian Randomization (MR) study of genetically predicted omega-3 fatty acids and lung function parameters. Measurements and Main Results: The longitudinal study found that higher omega-3 fatty acid concentrations were associated with attenuated lung function decline in 15,063 participants, with the largest effect sizes for docosahexaenoic acid (DHA). One standard deviation higher DHA was associated with an attenuation of 1.8 mL/year for FEV 1 (95% confidence interval [CI] 1.3-2.2) and 2.4 mL/year for FVC (95% CI 1.9-3.0). One standard deviation higher DHA was also associated with a 9% lower incidence of spirometry-defined airway obstruction (95% CI 0.86-0.97). DHA associations persisted across sexes, smoking histories, and Black, white and Hispanic participants, with the largest magnitude associations in former smokers and Hispanics. The MR study showed positive associations of genetically predicted omega-3 fatty acids with FEV 1 and FVC, with statistically significant findings across multiple MR methods. Conclusions: The longitudinal and MR studies provide evidence supporting beneficial effects of higher circulating omega-3 fatty acids, especially DHA, on lung health.

Lifestyle habits associated with cardiac conduction disease.

AIMS: Cardiac conduction disease can lead to syncope, heart failure, and death. The only available therapy is pacemaker implantation, with no established prevention strategies. Research to identify modifiable risk factors has been scant. METHODS AND RESULTS: Data from the Cardiovascular Health Study, a population-based cohort study of adults ≥ 65 years with annual 12-lead electrocardiograms obtained over 10 years, were utilized to examine relationships between baseline characteristics, including lifestyle habits, and conduction disease. Of 5050 participants (mean age 73 ± 6 years; 52% women), prevalent conduction disease included 257 with first-degree atrioventricular block, 99 with left anterior fascicular block, 9 with left posterior fascicular block, 193 with right bundle branch block (BBB), 76 with left BBB, and 102 with intraventricular block at baseline. After multivariable adjustment, older age, male sex, a larger body mass index, hypertension, and coronary heart disease were associated with a higher prevalence of conduction disease, whereas White race and more physical activity were associated with a lower prevalence. Over a median follow-up on 7 (interquartile range 1-9) years, 1036 developed incident conduction disease. Older age, male sex, a larger BMI, and diabetes were each associated with incident conduction disease. Of lifestyle habits, more physical activity (hazard ratio 0.91, 95% confidence interval 0.84-0.98, P = 0.017) was associated with a reduced risk, while smoking and alcohol did not exhibit a significant association. CONCLUSION: While some difficult to control comorbidities were associated with conduction disease as expected, a readily modifiable lifestyle factor, physical activity, was associated with a lower risk.

Clonal Hematopoiesis of Indeterminate Potential and Kidney Function Decline in the General Population.

RATIONALE & OBJECTIVE: Clonal hematopoiesis of indeterminate potential (CHIP), defined by the age-related ontogenesis of expanded leukemogenic variants indicative of a genetically distinct clonal leukocyte population, is associated with risk of hematologic malignancy and cardiovascular disease. In experimental models, recapitulation of CHIP promotes kidney interstitial fibrosis with direct tissue infiltration of donor macrophages. We tested the hypothesis that CHIP is associated with kidney function decline in the general population. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 12,004 individuals from 3 community-based cohorts in the TOPMed Consortium. EXPOSURE: CHIP status from whole-genome sequences obtained from DNA extracted from peripheral blood. OUTCOME: Risk of 30% decline in estimated glomerular filtration rate (eGFR) and percent eGFR decline per year during the follow-up period. ANALYTICAL APPROACH: Cox proportional hazards models for 30% eGFR decline end point and generalized estimating equations for annualized relative change in eGFR with meta-analysis. Study-specific estimates were combined using fixed-effect meta-analysis. RESULTS: The median baseline eGFR was 84mL/min/1.73m2. The prevalence of CHIP was 6.6%, 9.0%, and 12.2% in persons aged 50-60, 60-70, and>70 years, respectively. Over a median follow-up period of 8 years, for the 30% eGFR outcome 205 events occurred among 1,002 CHIP carriers (2.1 events per 100 person-years) and 2,041 events in persons without CHIP (1.7 events per 100 person-years). In meta-analysis, CHIP was associated with greater risk of a 30% eGFR decline (17% [95% CI, 1%-36%] higher; P=0.04). Differences were not observed between those with baseline eGFR above or below 60mL/min/1.73m2, of age above or below 60 years, or with or without diabetes. LIMITATIONS: Small number of participants with moderate-to-advanced kidney disease and restricted set of CHIP driver variants. CONCLUSIONS: We report an association between CHIP and eGFR decline in 3 general population cohorts without known kidney disease. Further studies are needed to investigate this novel condition and its potential impact among individuals with overt kidney disease.

The Associations of Aortic Valve Sclerosis, Aortic Annular Increased Reflectivity, and Mitral Annular Calcification with Subsequent Aortic Stenosis in Older Individuals: Findings from the Cardiovascular Health Study.

BACKGROUND: Although aortic valve sclerosis (AVS) is well described as preceding aortic stenosis (AS), the associations of AS with antecedent mitral annular calcification (MAC) and aortic annular increased reflectivity (AAIR) have not been characterized. In a population-based prospective study, the authors evaluated whether MAC, AAIR, and AVS are associated with the risk for incident AS. METHODS: Among participants of the Cardiovascular Health Study free of AS at the 1994-1995 visit, the presence of MAC, AAIR, AVS, and the combination of all three was evaluated in 3,041 participants. Cox proportional-hazards regression was used to assess the association between the presence of calcification and the incidence of moderate or severe AS in three nested models adjusting for factors associated with atherosclerosis and inflammation both relevant to the pathogenesis of AS. RESULTS: Over a median follow-up period of 11.5 years (interquartile range, 6.7-17.0 years), 110 cases of incident moderate or severe AS were ascertained. Strong positive associations with incident moderate or severe AS were found for all calcification sites after adjustment for the main model covariates: AAIR (hazard ratio [HR], 2.90; 95% CI, 1.95-4.32; P < .0005), AVS (HR, 2.20; 95% CI, 1.44-3.37; P < .0005), MAC (HR, 1.67; 95% CI, 1.14-2.45; P = .008), and the combination of all three (HR, 2.50; 95% CI, 1.65-3.78; P < .0005). In a secondary analysis, the risk for AS increased with the number of sites at which calcification was present. CONCLUSIONS: In a large cohort of community-dwelling elderly individuals, there were strong associations between each of AAIR, AVS, MAC, and the combination of the three and incident moderate or severe AS. The novel finding that AAIR had a particularly strong association with incident AS, even after adjusting for other calcification sites, suggests its value in identifying individuals at risk for AS and potential inclusion in routine assessment by transthoracic echocardiography.

Circulating differentiated and senescent lymphocyte subsets and incident diabetes risk in older adults: The Cardiovascular Health Study.

INTRODUCTION: Cellular senescence is a feature of aging implicated in the pathophysiology of diabetes mellitus (DM). Whether senescent lymphocytes are associated with the future occurrence of DM is uncertain. METHODS: We used cryopreserved peripheral blood mononuclear cells collected from 1860 Cardiovascular Health Study participants (average age 80.2 years) and flow cytometry immunophenotyping to evaluate the longitudinal relationships of naive (CD45RA+ ), memory (CD45RO+ ), senescent (CD28- ), and T effector memory RA+ (TEMRA) (CD28- CD57+ CD45RA+ ) CD4+ and CD8+ T cells, and memory B cells (CD19+ CD27+ ), with the risk of incident DM. In exploratory analyses we evaluated the relationships of 13 additional innate lymphocyte and CD4+ and CD8+ subsets with incident DM risk. RESULTS: Over a median follow-up time of 8.9 years, 155 cases of incident DM occurred. In Cox models adjusted for demographic variables (age, sex, race, study site and flow cytometry analytical batch) or diabetes risk factors (demographic variables plus education, body mass index, smoking status, alcohol use, systolic blood pressure, hypertension medication use and physical activity), no significant associations were observed for any CD4+ , CD8+ or CD19+ cell phenotypes with incident DM. CONCLUSIONS: These results suggest the frequencies of naive, memory and senescent T cells and memory B cells are not strongly associated with incident DM risk in older adults.