ABSTRACT
Ectonucleoside triphosphate diphosphohydrolase 1 (NTPDase1) degrades the purines ATP and ADP that are key regulators of inflammation and clotting. We hypothesized that NTPDase1 polymorphisms ...exist and that they regulate this pathway. We sequenced the ENTPD1 gene (encoding NTPDase1) in 216 subjects then assessed genotypes in 2 cohorts comprising 2213 humans to identify ENTPD1 polymorphisms associated with venous thromboembolism (VTE). The G allele of the intron 1 polymorphism rs3176891 was more common in VTE vs. controls (odds ratio 1.26–1.9); it did not affect RNA splicing, but it was in strong linkage disequilibrium with the G allele of the promoter polymorphism rs3814159, which increased transcriptional activity by 8‐fold. Oligonucleotides containing the G allele of this promoter region bound nuclear extracts more avidly. Carriers of rs3176891 G had endothelial cells with increased NTPDase1 activity and protein expression, and had platelets with enhanced aggregation. Thus, the G allele of rs3176891 marks a haplotype associated with increased clotting and platelet aggregation attributable to a promoter variant associated with increased transcription, expression, and activity of NTPDase1. We term this gain‐of‐function phenotype observed with rs3814159 G “CD39 Denver.”—Maloney, J. P., Branchford, B. R., Brodsky, G. L., Cosmic, M. S., Calabrese, D. W., Aquilante, C. L., Maloney, K. W., Gonzalez, J. R., Zhang, W., Moreau, K. L., Wiggins, K. L., Smith, N. L., Broeckel, U., Di Paola, J. The ENTPD1 promoter polymorphism −860 A > G (rs3814159) is associated with increased gene transcription, protein expression, CD39/NTPDase1 enzymatic activity, and thromboembolism risk. FASEB J. 31, 2771–2784 (2017). www.fasebj.org
BACKGROUND AND PURPOSE—Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample ...sizes. We assessed evidence for a shared genetic basis among the 3 major subtypeslarge artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses.
METHODS—Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA–SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles.
RESULTS—High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10) and profile scores (rg=0.72; 95% confidence interval, 0.52–0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10) for single nucleotide polymorphisms near the opioid receptor μ1 (OPRM1) gene.
CONCLUSIONS—Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.
Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole-blood mtDNA copy number (CN) with several cardiometabolic disease traits in ...408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: each additional 10 years of age was associated with a 0.03 SD higher level of mtDNA CN (p = 0.0014) among younger participants (younger than 65 years) versus a 0.14 SD lower level of mtDNA CN (p = 1.82 × 10−13) among older participants (65 years and older). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity (p = 5.6 × 10−238), hypertension (p = 2.8 × 10−50), diabetes (p = 3.6 × 10−7), and hyperlipidemia (p = 6.3 × 10−56). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.
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mtDNA copy number in peripheral blood measured in large multi-ancestry cohortsmtDNA copy number in blood cells declined with age after age 65Lower mtDNA copy number was associated with cardiometabolic disease traits
Liu et al. examined the association of mitochondrial DNA (mtDNA) copy number (CN) with cardiometabolic traits in 408,361 individuals from TOPMed and UK Biobank, representing the most comprehensive cross-ancestry analyses for these traits. They identify a decline in mtDNA CN in participants older than 65 years and, at lower mtDNA CN levels, age-independent associations with obesity, diabetes, hypertension, and hyperlipidemia.
Abstract Objectives Eicosanoids are lipid mediators that may play a role in atherosclerosis. We investigated the association of common genetic variation in prostaglandin H synthase 1 ( PTGS1 ), ...prostaglandin H synthase 2 ( PTGS2 ), thromboxane A2 synthase ( TBXAS1 ), prostacyclin synthase ( PTGIS ), prostaglandin E synthase ( PTGES ), 5-lipoxygenase activating protein ( ALOX5AP ), 12-lipoxygenase ( ALOX12 ) and 15-lipoxygenase ( ALOX15 ) with the risks of myocardial infarction (MI) and ischemic stroke. A secondary aim was to replicate the interaction of PTGS2 rs20417 (-765G to C) with aspirin use on coronary heart disease risk observed in the Atherosclerosis Risk in Communities Study (ARIC). Methods We conducted a case-control study in a large Health Maintenance Organization. Cases were men and women, aged 30–79 years with incident non-fatal myocardial infarction ( n = 1063) or ischemic stroke ( n = 469) between January 1995 and December 2004. Controls ( n = 3462) were randomly selected and frequency matched to cases on age, sex, hypertension and calendar year. Results Common variation in TBXAS1 and PTGIS was associated with MI risk ( p -value for global Chi-square test, 0.01 and 0.03, respectively). Common variation in ALOX5AP , ALOX12 , ALOX15 , PTGS1 , PTGS2 and PTGES was not associated with risks of MI and ischemic stroke. We replicated the observation of the Atherosclerosis Risk in Communities Study and observed an interaction of rs20417 with aspirin use on myocardial infarction risk ( p for interaction = 0.03). Conclusions Study results suggest that variation in TBXAS1 and PTGIS may influence MI risk, and carriers of rs20417C allele might derive greater benefits from aspirin use in primary prevention.
Recently, a novel locus at 17q25 was associated with white matter hyperintensities (WMH) on MRI in stroke-free individuals. We aimed to replicate the association with WMH volume (WMHV) in patients ...with ischemic stroke. If the association acts by promoting a small vessel arteriopathy, it might be expected to also associate with lacunar stroke.
We quantified WMH on MRI in the stroke-free hemisphere of 2588 ischemic stroke cases. Association between WMHV and 6 single-nucleotide polymorphisms at chromosome 17q25 was assessed by linear regression. These single-nucleotide polymorphisms were also investigated for association with lacunar stroke in 1854 cases and 51 939 stroke-free controls from METASTROKE. Meta-analyses with previous reports and a genetic risk score approach were applied to identify other novel WMHV risk variants and uncover shared genetic contributions to WMHV in community participants without stroke and ischemic stroke.
Single-nucleotide polymorphisms at 17q25 were associated with WMHV in ischemic stroke, the most significant being rs9894383 (P=0.0006). In contrast, there was no association between any single-nucleotide polymorphism and lacunar stroke. A genetic risk score analysis revealed further genetic components to WMHV shared between community participants without stroke and ischemic stroke.
This study provides support for an association between the 17q25 locus and WMH. In contrast, it is not associated with lacunar stroke, suggesting that the association does not act by promoting small-vessel arteriopathy or the same arteriopathy responsible for lacunar infarction.
Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA ADMA) and l-arginine uptake into the cell (ADMA and symmetrical DMA SDMA). In ...prospective clinical studies, ADMA has been characterized as a cardiovascular risk marker, whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterize the environmental and genetic contributions to interindividual variability of these biomarkers.
This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (Framingham Heart Study FHS; n=2992, Gutenberg Health Study GHS; n=4354, and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study MONICA/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany KORA F3 n=581) and identified replicated loci (DDAH1, MED23, Arg1, and AGXT2) associated with the interindividual variability in ADMA, l-arginine, and SDMA. Experimental in silico and in vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants, and various cardiometabolic risk factors. AGXT2 variants were not associated with poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
These genome-wide association study support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and l-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.
•Genetic regulation of MDD and VTE was correlated.•Genetic predisposition to MDD was associated with an increased risk of VTE.
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Major depressive disorder (MDD), bipolar disorder (BD), ...and schizophrenia (SCZ) are associated with an increased risk of cardiovascular diseases, including venous thromboembolism (VTE). The reasons for this are complex and include obesity, smoking, and use of hormones and psychotropic medications. Genetic studies have increasingly provided evidence of the shared genetic risk of psychiatric and cardiometabolic illnesses. This study aimed to determine whether a genetic predisposition to MDD, BD, or SCZ is associated with an increased risk of VTE. Genetic correlations using the largest genome-wide genetic meta-analyses summary statistics for MDD, BD, and SCZ (Psychiatric Genetics Consortium) and a recent genome-wide genetic meta-analysis of VTE (INVENT Consortium) demonstrated a positive association between VTE and MDD but not BD or SCZ. The same summary statistics were used to construct polygenic risk scores for MDD, BD, and SCZ in UK Biobank participants of self-reported White British ancestry. These were assessed for impact on self-reported VTE risk (10 786 cases, 285 124 controls), using logistic regression, in sex-specific and sex-combined analyses. We identified significant positive associations between polygenic risk for MDD and the risk of VTE in men, women, and sex-combined analyses, independent of the known risk factors. Secondary analyses demonstrated that this association was not driven by those with lifetime experience of mental illness. Meta-analyses of individual data from 6 additional independent cohorts replicated the sex-combined association. This report provides evidence for shared biological mechanisms leading to MDD and VTE and suggests that, in the absence of genetic data, a family history of MDD might be considered when assessing the risk of VTE.
We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) ...and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10
) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10
; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.
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