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  • Ovid Technologies (Wolters Kluwer Health)  (3)
  • Franceschini, Nora  (3)
  • 1
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    Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Journal of the American Heart Association Vol. 6, No. 6 ( 2017-11-06)
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    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 6, No. 6 ( 2017-11-06)
    Abstract: Plasminogen activator inhibitor type 1 ( PAI ‐1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI ‐1 levels are associated with increased risk of coronary heart disease ( CHD ). However, it is unclear whether the association reflects a causal influence of PAI ‐1 on CHD risk. Methods and Results To evaluate the association between PAI ‐1 and CHD , we applied a 3‐step strategy. First, we investigated the observational association between PAI ‐1 and CHD incidence using a systematic review based on a literature search for PAI ‐1 and CHD studies. Second, we explored the causal association between PAI ‐1 and CHD using a Mendelian randomization approach using summary statistics from large genome‐wide association studies. Finally, we explored the causal effect of PAI ‐1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta‐analysis, the highest quantile of blood PAI ‐1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age‐ and sex‐adjusted model. The effect size was reduced in studies using a multivariable‐adjusted model (odds ratio=1.46; 95% CI : 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI ‐1 level on CHD risk (odds ratio=1.22 per unit increase of log‐transformed PAI ‐1; 95% CI : 1.01, 1.47). In addition, we also detected a causal effect of PAI ‐1 on elevating blood glucose and high‐density lipoprotein cholesterol. Conclusions Our study indicates a causal effect of elevated PAI ‐1 level on CHD risk, which may be mediated by glucose dysfunction.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.116.004918
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 2653953-6
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  • 2
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    Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Hypertension Vol. 79, No. 8 ( 2022-08), p. 1656-1667
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    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 79, No. 8 ( 2022-08), p. 1656-1667
    Abstract: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure. Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants. Results: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings ( P 〈 5×10 -8 ). Among them, a rare intergenic variant at novel locus, LOC100506274 , was associated with lower systolic blood pressure in stage-1 (beta [SE]=−32.6 [6.0] ; P =4.99×10 -8 ) but not stage-2 analysis ( P =0.11). Furthermore, a novel common variant at the known INSR locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=−0.36 [0.07] ; P =4.18×10 -7 ) and attained genome-wide significance in stage-2 (beta [SE]=−0.29 [0.03] ; P =7.28×10 -23 ). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings ( P 〈 1×10 -6 and P 〈 1×10 -4 , respectively). Discussion: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.122.19324
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 2094210-2
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  • 3
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    NFAT5 and SLC4A10 Loci Associate with Plasma Osmolality
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Journal of the American Society of Nephrology Vol. 28, No. 8 ( 2017-8), p. 2311-2321
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 28, No. 8 ( 2017-8), p. 2311-2321
    Abstract: Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P 〈 5.0 × 10 −6 . Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis ( P =3.1 × 10 −5 ), with combined stages 1 and 2 genome-wide significance of P =5.6 × 10 −10 . Transethnic meta-analysis further supported the association at rs9980 ( P =5.9 × 10 −12 ). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis ( P =6.7 × 10 −8 ). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2016080892
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 2029124-3
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