Increased risk of venous thromboembolism (VTE) is a life-threatening side effect for users of oral contraceptives (OCs) or hormone therapy (HT).
To investigate the potential for genetic ...predisposition to VTE in OC or HT users, we conducted a gene-by-environment case-only meta-analysis of genome-wide association studies (GWAS).
Use or nonuse of OCs (7 studies) or HT (8 studies) at the time of the VTE event was determined by pharmacy records or self-report. A synergy index (SI) was modeled for each variant in each study and submultiplicative/supramultiplicative gene-by-environment interactions were estimated. The SI parameters were first meta-analyzed across OC and HT studies and subsequently meta-analyzed to obtain an overall estimate. The primary analysis was agnostic GWAS and interrogated all imputed genotypes using a P value threshold of <5.0 × 10−8; secondary analyses were candidate-based.
The VTE case-only OC meta-analysis included 2895 OC users and 6607 nonusers; the case-only HT meta-analysis included 2434 HT users and 12 793 nonusers. In primary GWAS meta-analyses, no variant reached genome-wide significance, but the smallest P value approached statistical significance: rs9386463 (P = 5.03 × 10−8). We tested associations for 138 candidate variants and identified 2 that exceeded statistical significance (0.05/138 = 3.62 × 10−4): F5 rs6025 (P = 1.87 × 10−5; SI, 1.29; previously observed) and F11 rs2036914 (P = 2.0 × 10−4; SI, 0.91; new observation).
The candidate variant approach to identify submultiplictive/supramultiplicative associations between genetic variation and OC and HT use identified a new association with common genetic variation in F11, while the agnostic interrogations did not yield new discoveries.
Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed ...GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR)=1.62, P=3.9×10(-8)) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR=1.15, P=3.9×10(-4); discovery and replication combined OR=1.21, P=4.7×10(-8)). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Regulatory organizations recommend assessing hospital-acquired (HA) venous thromboembolism (VTE) risk for medical inpatients.
To develop and validate a risk assessment model (RAM) for HA-VTE in ...medical inpatients using objective and assessable risk factors knowable at admission.
The development cohort included people admitted to medical services at the University of Vermont Medical Center (Burlington, Vermont) between 2010 and 2019, and the validation cohorts included people admitted to Hennepin County Medical Center (Minneapolis, Minnesota), University of Michigan Medical Center (Ann Arbor, Michigan), and Harris Health Systems (Houston, Texas). Individuals with VTE at admission, aged <18 years, and admitted for <1 midnight were excluded. We used a Bayesian penalized regression technique to select candidate HA-VTE risk factors for final inclusion in the RAM.
The development cohort included 60 633 admissions and 227 HA-VTE, and the validation cohorts included 111 269 admissions and 651 HA-VTE. Seven HA-VTE risk factors with t statistics ≥1.5 were included in the RAM: history of VTE, low hemoglobin level, elevated creatinine level, active cancer, hyponatremia, increased red cell distribution width, and malnutrition. The areas under the receiver operating characteristic curve and calibration slope were 0.72 and 1.10, respectively. The areas under the receiver operating characteristic curve and calibration slope were 0.70 and 0.93 at Hennepin County Medical Center, 0.70 and 0.87 at the University of Michigan Medical Center, and 0.71 and 1.00 at Harris Health Systems, respectively. The RAM performed well stratified by age, sex, and race.
We developed and validated a RAM for HA-VTE in medical inpatients. By quantifying risk, clinicians can determine the potential benefits of measures to reduce HA-VTE.
Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify ...new loci associated with plasma levels.
The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (<5.0x10(-324)), 12p13 (1.7x10(-32)), 12q23 (7.3x10(-10)), 12q24.3 (3.8x10(-11)), 14q32 (2.3x10(-10)), and 19p13.2 (1.3x10(-9)). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated.
New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.
Genetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate information ...at the ABO blood group locus, which is one of the major susceptibility loci. However, there is no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when properly assessing association between ABO locus and VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in 5425 cases and 8445 controls from 6 studies, we demonstrate that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal, because 5% of rs8176719-delG carriers do not have an increased risk of developing VT. Instead, we recommend the use of 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B), and rs41302905 (O2), when assessing the impact of ABO locus on VT risk to avoid any risk misestimation. Compared with the O1 haplotype, the A2 haplotype is associated with a modest increase in VT risk (odds ratio, ∼1.2), the A1 and B haplotypes are associated with an ∼1.8-fold increased risk, whereas the O2 haplotype tends to be slightly protective (odds ratio, ∼0.80). In addition, although the A1 and B blood groups are associated with increased von Willebrand factor and factor VIII plasma levels, only the A1 blood group is associated with ICAM levels, but in an opposite direction, leaving additional avenues to be explored to fully understand the spectrum of biological effects mediated by ABO locus on cardiovascular traits.
•Four ABO SNPs (rs2519093, rs1053878, rs8176743, rs41302905) must be studied in any work assessing the risk of ABO locus on VT.•Molecularly defined ABO blood groups are more accurate than serologically determined (A/B/O) groups for estimating risk of VT.
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Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among ...predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid).
Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis.
In the single variant association analysis in TOPMed, we identified one novel locus
for large artery at whole-genome-wide significance (
<5.00×10
) and 4 novel loci at genome-wide significance (
<5.00×10
), all of which need confirmation in independent studies. Lead variants in all 5 loci are low-frequency but are more common in non-European populations. An aggregation of synonymous rare variants within the gene
demonstrated suggestive evidence of association for hemorrhagic stroke (
<3.11×10
). By meta-analyzing European ancestry samples in TOPMed and UK BioBank, we replicated several previously reported stroke loci including
,
,
, and
.
We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes.
Objective
To determine whether greater pericardial fat volume would be associated with increased risk of incident atrial fibrillation (AF).
Methods
In the Multi‐Ethnic Study of Atherosclerosis and ...Jackson Heart Study, pericardial fat volume was quantified by computed tomography. Incident AF was identified from discharge diagnosis codes, study electrocardiograms, and Medicare claims.
Results
Among 7,991 participants, 40% were African American, 32% white, 18% Hispanic, and 10% Chinese American; mean age was 62 years; 55% were women. During an average of 10.0 years of follow‐up in the Multi‐Ethnic Study of Atherosclerosis and 4.5 years in the Jackson Heart Study, 756 incident AF cases were identified. After adjustment for age, sex, study, race/ethnicity, height, glucose status, systolic blood pressure, treated hypertension, and BMI, greater pericardial fat volume was associated with higher AF risk in Hispanics (hazard ratio 1.24 per SD, 95% confidence interval 1.05‐1.46) but not overall (hazard ratio 1.06, 95% confidence interval 0.97‐1.15). In mediation analysis, pericardial fat volume partially mediated the association of BMI with incident AF in Hispanics.
Conclusions
After adjustment for BMI, greater pericardial fat volume was associated with incident AF in Hispanics but not overall. Additional research is needed on the mechanisms by which pericardial fat volume is related to increased AF risk and possible differences by race/ethnicity.
Background
Left ventricular (LV) hypertrophy affects up to 43% of African Americans (AAs). Antihypertensive treatment reduces LV mass (LVM). However, interindividual variation in LV traits in ...response to antihypertensive treatments exists. We hypothesized that genetic variants may modify the association of antihypertensive treatment class with LV traits measured by echocardiography.
Methods
We evaluated the main effects of the three most common antihypertensive treatments for AAs as well as the single nucleotide polymorphism (SNP)‐by‐drug interaction on LVM and relative wall thickness (RWT) in 2,068 participants across five community‐based cohorts. Treatments included thiazide diuretics (TDs), angiotensin converting enzyme inhibitors (ACE‐Is), and dihydropyridine calcium channel blockers (dCCBs) and were compared in a pairwise manner. We performed fixed effects inverse variance weighted meta‐analyses of main effects of drugs and 2.5 million SNP‐by‐drug interaction estimates.
Results
We observed that dCCBs versus TDs were associated with higher LVM after adjusting for covariates (p = 0.001). We report three SNPs at a single locus on chromosome 20 that modified the association between RWT and treatment when comparing dCCBs to ACE‐Is with consistent effects across cohorts (smallest p = 4.7 × 10−8, minor allele frequency range 0.09–0.12). This locus has been linked to LV hypertrophy in a previous study. A marginally significant locus in BICD1 (rs326641) was validated in an external population.
Conclusions
Our study identified one locus having genome‐wide significant SNP‐by‐drug interaction effect on RWT among dCCB users in comparison to ACE‐I users. Upon additional validation in future studies, our findings can enhance the precision of medical approaches in hypertension treatment.
This study highlights the potential impact of antihypertensive treatments as well as their pharmacogenetic effect of on left ventricular (LV) traits in African Americans among 2,068 participants across five community‐based cohorts. Dihydropyridine calcium channel blocker (dCCB) use was observed to be associated with greater LV mass than thiazide diuretic use. A single locus on chromosome 20 was also identified to modify the association between relative wall thickness and treatment when comparing dCCBs to angiotensin converting enzyme inhibitors with consistent effects across cohorts.
We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and ...LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs developed from multiple independent GWAS, perform best across all race/ethnic backgrounds. Stratified analysis in All of Us shows that PRSs are better predictive of BP in females compared to males, individuals without obesity, and middle-aged (40-60 years) compared to older and younger individuals.
Purpose
Opioids, gabapentinoids, and nonsteroidal anti‐inflammatory drugs (NSAIDs) may have adverse cardiovascular effects. We evaluated whether these medications were associated with incident ...clinically detected atrial fibrillation (AF) or monitor‐detected supraventricular ectopy (SVE), including premature atrial contractions (PACs) and supraventricular tachycardia (SVT).
Methods
We used data from the Multi‐Ethnic Study of Atherosclerosis (MESA), a cohort study that enrolled 6814 Americans without clinically detected cardiovascular disease in 2000 to 2002. At the 2016 to 2018 examination, 1557 individuals received ambulatory electrocardiographic (ECG) monitoring. Longitudinal analyses investigated time‐varying medication exposures at the first five exams (through 2011) in relation to incident clinically detected AF through 2015 using Cox proportional hazards regression models. Cross‐sectional analyses investigated medication exposures at 2016 to 2018 examination and the risk of monitor‐detected SVE using linear regression models.
Results
The longitudinal cohort included 6652 participants. During 12.4 years of mean follow‐up, 982 participants (14.7%) experienced incident clinically detected AF. Use of opioids, gabapentinoids, and NSAIDs were not associated with incident AF. The cross‐sectional analysis included 1435 participants with ECG monitoring. Gabapentinoid use was associated with an 84% greater average frequency of PACs/hour (95% CI, 25%‐171%) and a 44% greater average number of runs of SVT/day (95% CI, 3%‐100%). No associations were found with use of opioids or NSAIDs in cross‐sectional analyses.
Conclusions
In this study, gabapentinoid use was associated with SVE. Given the rapid increase in gabapentinoid use, additional studies are needed to clarify whether these medications cause cardiovascular complications.
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