Premature Menopause, Clonal Hematopoiesis, and Coronary Artery Disease in Postmenopausal Women

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% (P0.1: 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]; P0.1: 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

Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure

Background: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF). Objectives: This study sought to evaluate whether CHIP is associated with incident HF. Methods: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses. Results: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction. Conclusions: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF

Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease

Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD

Genome-wide association study of heart rate and its variability in Hispanic/Latino cohorts

Background Although time–domain measures of heart rate variability (HRV) are used to estimate cardiac autonomic tone and disease risk in multiethnic populations, the genetic epidemiology of HRV in Hispanics/Latinos has not been characterized. Objective The purpose of this study was to conduct a genome-wide association study of heart rate (HR) and its variability in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Women's Health Initiative Hispanic SNP-Health Association Resource project (n = 13,767). Methods We estimated HR (bpm), standard deviation of normal-to-normal interbeat intervals (SDNN, ms), and root mean squared difference in successive, normal-to-normal interbeat intervals (RMSSD, ms) from resting, standard 12-lead ECGs. We estimated associations between each phenotype and 17 million genotyped or imputed single nucleotide polymorphisms (SNPs), accounting for relatedness and adjusting for age, sex, study site, and ancestry. Cohort-specific estimates were combined using fixed-effects, inverse-variance meta-analysis. We investigated replication for select SNPs exceeding genome-wide (P <5 × 10–8) or suggestive (P <10–6) significance thresholds. Results Two genome-wide significant SNPs replicated in a European ancestry cohort, 1 one for RMSSD (rs4963772; chromosome 12) and another for SDNN (rs12982903; chromosome 19). A suggestive SNP for HR (rs236352; chromosome 6) replicated in an African-American cohort. Functional annotation of replicated SNPs in cardiac and neuronal tissues identified potentially causal variants and mechanisms. Conclusion This first genome-wide association study of HRV and HR in Hispanics/Latinos underscores the potential for even modestly sized samples of non-European ancestry to inform the genetic epidemiology of complex traits

Clonal Hematopoiesis Is Associated with Higher Risk of Stroke

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

Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD

Human vibrotactile frequency discriminative capacity after adaptation to 25 Hz or 200 Hz stimulation

A two-interval forced-choice (2-IFC) tracking procedure was used to evaluate the effects of a 15-s pre-exposure to either 25 Hz or 200 Hz stimulation (“25 Hz or 200 Hz adaptation”) on human vibrotactile frequency discrimination threshold (frequency DL/Weber fraction). Three subjects were studied. All stimuli (standard and comparison) were delivered to a central location on the thenar eminence of the hand. The frequency DL/Weber fraction was determined for each subject under the following conditions: (1) no recent prior exposure to vibrotactile stimulation (“unadapted”); (2) after 15 s adaptation to 25 Hz stimulation; and (3) after 15 s adaptation to 200 Hz stimulation. The results demonstrate that the effects of frequency of adaptation on frequency discriminative capacity when the standard stimulus is 25 Hz are not the same as when the standard stimulus is 200 Hz. The differential changes in the capacity of subjects to discriminate frequency of cutaneous flutter (10–50 Hz) or vibratory (>200 Hz) stimulation that occur subsequent to a 15-s exposure of the thenar to 25 Hz or 200 Hz stimulation are proposed to reflect frequency-specific, adaptation-induced modification of the response of contralateral primary somatosensory cortex (SI and SII) to skin mechanoreceptor afferent drive

Decreased Spinothalamic and Dorsal Column Medial Lemniscus-Mediated Function Is Associated with Neuropathic Pain after Spinal Cord Injury

Neuropathic pain (NP) after spinal cord injury (SCI) can significantly and negatively affect quality of life and is often refractory to currently available treatments. In order to find more effective therapeutic avenues, it would be helpful to identify the primary underlying pathophysiological mechanisms in each individual. The aim of the present study was to assess the relationship between the presence and severity of NP after SCI and measures of somatosensory function mediated via the dorsal column medial lemniscal (DCML) pathway and the spinothalamic tract (STT). Vibratory, mechanical, thermal, and pain thresholds measured in areas at and below the neurological level of injury (LOI) in persons with SCI and NP (SCI-NP, n=47) and in persons with SCI without NP (SCI-noNP, n=18) were normalized to data obtained from able-bodied pain-free control subjects (A-B, n=30). STT-mediated function at and below the LOI was significantly impaired in both SCI groups compared with A-B controls (p<0.001), but not significantly different between the two SCI groups (NP vs. no-NP). In contrast, the SCI-NP group had significantly greater impairment of DCML-mediated function at the LOI, as reflected by greater vibratory detection deficits (z=−3.89±0.5), compared with the SCI-noNP group (z=−1.95±0.7, p=0.034). Within the SCI-NP group, NP severity was significantly associated with increased thermal sensitivity below the LOI (r=0.50, p=0.038). Our results suggest that both impaired STT and DCML-mediated function are necessary for the development of NP after SCI. However, within the SCI-NP group, greater NP severity was associated with greater sensitivity to thermal stimuli below the LOI. This finding concurs with other studies suggesting that STT damage with some sparing is associated with NP