IMPORTANCE: A genetic variant in the TTR gene (rs76992529; Val122Ile), present more commonly in individuals with African ancestry (population frequency: 3%-4%), causes misfolding of the tetrameric ...transthyretin protein complex that accumulates as extracellular amyloid fibrils and results in hereditary transthyretin amyloidosis. OBJECTIVE: To estimate the association of the amyloidogenic Val122Ile TTR variant with the risk of heart failure and mortality in a large, geographically diverse cohort of Black individuals. DESIGN, SETTING, AND PARTICIPANTS: Retrospective population-based cohort study of 7514 self-identified Black individuals living in the US participating in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study with genetic data available and without heart failure at baseline. The participants were enrolled at the baseline visit (2003-2007). The end of follow-up for the majority of outcomes was on December 31, 2018. All-cause mortality data were available through December 31, 2020. EXPOSURES: TTR Val122Ile (rs76992529) genotype. MAIN OUTCOME AND MEASURES: The primary outcome was incident heart failure (first hospitalization for heart failure or death due to heart failure). The secondary outcomes were heart failure mortality, cardiovascular mortality, and all-cause mortality. The multivariable Cox proportional hazards regression analyses were adjusted for genetic ancestry and demographic, clinical, and social factors. RESULTS: Among 7514 Black participants (median age, 64 years IQR, 57-70 years; 61% women), the population frequency of the TTR Val122Ile variant was 3.1% (232 variant carriers and 7282 noncarriers). During a median follow-up of 11.1 years (IQR, 5.9-13.5 years), incident heart failure occurred in 535 individuals (34 variant carriers and 501 noncarriers) and the incidence of heart failure was 15.64 per 1000 person-years among variant carriers vs 7.16 per 1000 person-years among noncarriers (adjusted hazard ratio HR, 2.43 95% CI, 1.71-3.46; P < .001). Deaths due to heart failure occurred in 141 individuals (13 variant carriers and 128 noncarriers) and the incidence of heart failure mortality was 6.11 per 1000 person-years among variant carriers vs 1.85 per 1000 person-years among noncarriers (adjusted HR, 4.19 95% CI, 2.33-7.54; P < .001). Deaths due to cardiovascular causes occurred in 793 individuals (34 variant carriers and 759 noncarriers) and the incidence of cardiovascular death was 15.18 per 1000 person-years among variant carriers vs 10.61 per 1000 person-years among noncarriers (adjusted HR, 1.69 95% CI, 1.19-2.39; P = .003). Deaths due to any cause occurred in 2715 individuals (100 variant carriers and 2615 noncarriers) and the incidence of all-cause mortality was 41.46 per 1000 person-years among variant carriers vs 33.94 per 1000 person-years among noncarriers (adjusted HR, 1.46 95% CI, 1.19-1.78; P < .001). There was no significant interaction between TTR variant carrier status and sex on incident heart failure and the secondary outcomes. CONCLUSIONS AND RELEVANCE: Among a cohort of Black individuals living in the US, being a carrier of the TTR Val122Ile variant was significantly associated with an increased risk of heart failure.
Obesity is an important component of the pathophysiology of chronic diseases. Identifying epigenetic modifications associated with elevated adiposity, including DNA methylation variation, may point ...to genomic pathways that are dysregulated in numerous conditions. The Illumina 450K Bead Chip array was used to assay DNA methylation in leukocyte DNA obtained from 2097 African American adults in the Atherosclerosis Risk in Communities (ARIC) study. Mixed-effects regression models were used to test the association of methylation beta value with concurrent body mass index (BMI) and waist circumference (WC), and BMI change, adjusting for batch effects and potential confounders. Replication using whole-blood DNA from 2377 White adults in the Framingham Heart Study and CD4+ T cell DNA from 991 Whites in the Genetics of Lipid Lowering Drugs and Diet Network Study was followed by testing using adipose tissue DNA from 648 women in the Multiple Tissue Human Expression Resource cohort. Seventy-six BMI-related probes, 164 WC-related probes and 8 BMI change-related probes passed the threshold for significance in ARIC (P < 1 × 10(-7); Bonferroni), including probes in the recently reported HIF3A, CPT1A and ABCG1 regions. Replication using blood DNA was achieved for 37 BMI probes and 1 additional WC probe. Sixteen of these also replicated in adipose tissue, including 15 novel methylation findings near genes involved in lipid metabolism, immune response/cytokine signaling and other diverse pathways, including LGALS3BP, KDM2B, PBX1 and BBS2, among others. Adiposity traits are associated with DNA methylation at numerous CpG sites that replicate across studies despite variation in tissue type, ethnicity and analytic approaches.
The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain.
We conducted an association study of body mass index (BMI) and differential ...methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 SREBF1), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination.
We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND—Genetic research regarding blood lipids has largely focused on DNA sequence variation; few studies have explored epigenetic effects. Genome-wide surveys of DNA methylation may uncover ...epigenetic factors influencing lipid metabolism.
METHODS AND RESULTS—To identify whether differential methylation of cytosine-(phosphate)-guanine dinucleotides (CpGs) correlated with lipid phenotypes, we isolated DNA from CD4+ T cells and quantified the proportion of sample methylation at >450 000 CpGs by using the Illumina Infinium HumanMethylation450 Beadchip in 991 participants of the Genetics of Lipid Lowering Drugs and Diet Network. We modeled the percentage of methylation at individual CpGs as a function of fasting very-low-density lipoprotein cholesterol and triglycerides (TGs) by using mixed linear regression adjusted for age, sex, study site, cell purity, and family structure. Four CpGs (cg00574958, cg17058475, cg01082498, and cg09737197) in intron 1 of carnitine palmitoyltransferase 1A (CPT1A) were strongly associated with very-low low-density lipoprotein cholesterol (P=1.8×10 to 1.6×10) and TG (P=1.6×10 to 1.5×10). Array findings were validated by bisulfite sequencing. We performed quantitative polymerase chain reaction experiments demonstrating that methylation of the top CpG (cg00574958) was correlated with CPT1A expression. The association of cg00574958 with TG and CPT1A expression were replicated in the Framingham Heart Study (P=4.1×10 and 3.1×10, respectively). DNA methylation at CPT1A cg00574958 explained 11.6% and 5.5% of the variation in TG in the discovery and replication cohorts, respectively.
CONCLUSIONS—This genome-wide epigenomic study identified CPT1A methylation as strongly and robustly associated with fasting very-low low-density lipoprotein cholesterol and TG. Identifying novel epigenetic contributions to lipid traits may inform future efforts to identify new treatment targets and biomarkers of disease risk.
Large-scale untargeted lipidomics experiments involve the measurement of hundreds to thousands of samples. Such data sets are usually acquired on one instrument over days or weeks of analysis time. ...Such extensive data acquisition processes introduce a variety of systematic errors, including batch differences, longitudinal drifts, or even instrument-to-instrument variation. Technical data variance can obscure the true biological signal and hinder biological discoveries. To combat this issue, we present a novel normalization approach based on using quality control pool samples (QC). This method is called systematic error removal using random forest (SERRF) for eliminating the unwanted systematic variations in large sample sets. We compared SERRF with 15 other commonly used normalization methods using six lipidomics data sets from three large cohort studies (832, 1162, and 2696 samples). SERRF reduced the average technical errors for these data sets to 5% relative standard deviation. We conclude that SERRF outperforms other existing methods and can significantly reduce the unwanted systematic variation, revealing biological variance of interest.
Chronic kidney disease (CKD) is a common complex condition associated with high morbidity and mortality. Polygenic prediction could enhance CKD screening and prevention; however, this approach has ...not been optimized for ancestrally diverse populations. By combining APOL1 risk genotypes with genome-wide association studies (GWAS) of kidney function, we designed, optimized and validated a genome-wide polygenic score (GPS) for CKD. The new GPS was tested in 15 independent cohorts, including 3 cohorts of European ancestry (n = 97,050), 6 cohorts of African ancestry (n = 14,544), 4 cohorts of Asian ancestry (n = 8,625) and 2 admixed Latinx cohorts (n = 3,625). We demonstrated score transferability with reproducible performance across all tested cohorts. The top 2% of the GPS was associated with nearly threefold increased risk of CKD across ancestries. In African ancestry cohorts, the APOL1 risk genotype and polygenic component of the GPS had additive effects on the risk of CKD.
An innovative methodology using naturalistic driving data was used to examine the association between visual sensory and visual-cognitive function and rates of future crash or near-crash involvement ...among older drivers.
The Strategic Highway Research Program (SHRP2) Naturalistic Driving Study was used for this prospective analysis. The sample consisted of N = 659 drivers aged ≥70 years and study participation lasted 1 or 2 years for most participants. Distance and near visual acuity, contrast sensitivity, peripheral vision, visual processing speed, and visuospatial skills were assessed at baseline. Crash and near-crash involvement were based on video recordings and vehicle sensors. Poisson regression models were used to generate crude and adjusted rate ratios (RRs) and 95% confidence intervals, while accounting for person-miles of travel.
After adjustment, severe impairment of the useful field of view (RR = 1.33) was associated with an increased rate of near-crash involvement. Crash, severe crash, and at-fault crash involvement were associated with impaired contrast sensitivity in the worse eye (RRs = 1.38, 1.54, and 1.44, respectively) and far peripheral field loss in both eyes (RRs = 1.74, 2.32, and 1.73, respectively).
Naturalistic driving data suggest that contrast sensitivity in the worse eye and far peripheral field loss in both eyes elevate the rates of crash involvement, and impaired visual processing speed elevates rates of near-crash involvement among older drivers. Naturalistic driving data may ultimately be critical for understanding the relationship between vision and driving safety.
Developing an understanding of the biochemistry of aging in both sexes is critical for managing disease throughout the lifespan. Lipidomic associations with age and sex have been reported, but prior ...studies are limited by measurements in serum rather than plasma or by participants taking lipid-lowering medications.
Our study included lipidomic data from 980 participants aged 18-87 years old from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN). Participants were off lipid-lowering medications for at least 4 weeks, and signal intensities of 413 known lipid species were measured in plasma. We examined linear age and sex associations with signal intensity of (a) 413 lipid species; (b) 6 lipid classes (glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, fatty acids, and acylcarnitines); and (c) 15 lipid subclasses; as well as with the particle sizes of three lipoproteins.
Significant age associations were identified in 4 classes, 11 subclasses, 147 species, and particle size of one lipoprotein while significant sex differences were identified in 5 classes, 12 subclasses, 248 species, and particle sizes of two lipoproteins. For many lipid species (n = 97), age-related associations were significantly different between males and females. Age*sex interaction effects were most prevalent among phosphatidylcholines, sphingomyelins, and triglycerides.
We identified several lipid species, subclasses, and classes that differ by age and sex; these lipid phenotypes may serve as useful biomarkers for lipid changes and associated cardiovascular risk with aging in the future. Future studies of age-related changes throughout the adult lifespan of both sexes are warranted.
ClinicalTrials.gov NCT00083369 ; May 21, 2004.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this study, we conducted an epigenome-wide association study of metabolic syndrome (MetS) among 846 participants of European descent in the Genetics of Lipid Lowering Drugs and Diet Network ...(GOLDN). DNA was isolated from CD4+ T cells and methylation at ~470,000 cytosine-phosphate-guanine dinucleotide (CpG) pairs was assayed using the Illumina Infinium HumanMethylation450 BeadChip. We modeled the percentage methylation at individual CpGs as a function of MetS using linear mixed models. A Bonferroni-corrected P-value of 1.1 x 10(-7) was considered significant. Methylation at two CpG sites in CPT1A on chromosome 11 was significantly associated with MetS (P for cg00574958 = 2.6x10(-14) and P for cg17058475 = 1.2x10(-9)). Significant associations were replicated in both European and African ancestry participants of the Bogalusa Heart Study. Our findings suggest that methylation in CPT1A is a promising epigenetic marker for MetS risk which could become useful as a treatment target in the future.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
The purpose of this study was to examine the association between secondary task involvement and risk of crash and near-crash involvement among older drivers using naturalistic ...driving data.
Methods
Data from drivers aged ≥70 years in the Strategic Highway Research Program (SHRP2) Naturalistic Driving Study database was utilized. The personal vehicle of study participants was equipped with four video cameras enabling recording of the driver and the road environment. Secondary task involvement during a crash or near-crash event was compared to periods of noncrash involvement in a case-crossover study design. Conditional logistic regression was used to generate odds ratios (ORs) and 95% confidence intervals (CI).
Results
Overall, engaging in any secondary task was not associated with crash (OR = 0.94, 95% CI 0.68–1.29) or near-crash (OR = 1.08, 95% CI 0.79–1.50) risk. The risk of a major crash event with cell phone use was 3.79 times higher than the risk with no cell phone use (95% CI 1.00–14.37). Other glances into the interior of the vehicle were associated with an increased risk of near-crash involvement (OR = 2.55, 95% CI 1.24–5.26). Other distractions external to the vehicle were associated with a decreased risk of crash involvement (OR = 0.53, 95% CI 0.30–0.94). Interacting with a passenger and talking/singing were not associated with crash or near-crash risk.
Conclusions
Older drivers should avoid any cell phone use and minimize nondriving-related eye glances towards the interior of the vehicle while driving. Certain types of events external to the vehicle are associated with a reduced crash risk among older drivers.
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