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  • Ovid Technologies (Wolters Kluwer Health)  (3)
  • Horikoshi, Momoko  (3)
  • 1
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 138, No. 17 ( 2018-10-23), p. 1839-1849
    Abstract: Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with statins decreases circulating levels of low-density lipoprotein cholesterol and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown. Methods: We performed a 2-stage genome-wide association study of CHD events during statin therapy. We first identified 3099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7681 controls without CHD events during comparable intensity and duration of statin therapy from 4 sites in the Electronic Medical Records and Genomics Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth Electronic Medical Records and Genomics site, which joined the network after the initial genome-wide association study. Finally, we performed a phenome-wide association study for other traits linked to the most significant locus. Results: The meta-analysis identified 7 single nucleotide polymorphisms at a genome-wide level of significance within the LPA/PLG locus associated with CHD events on statin treatment. The most significant association was for an intronic single nucleotide polymorphism within LPA/PLG (rs10455872; minor allele frequency, 0.069; odds ratio, 1.58; 95% confidence interval, 1.35–1.86; P =2.6×10 − 10 ). In the replication cohort, rs10455872 was also associated with CHD events (odds ratio, 1.71; 95% confidence interval, 1.14–2.57; P =0.009). The association of this single nucleotide polymorphism with CHD events was independent of statin-induced change in low-density lipoprotein cholesterol (odds ratio, 1.62; 95% confidence interval, 1.17–2.24; P =0.004) and persisted in individuals with low-density lipoprotein cholesterol ≤70 mg/dL (odds ratio, 2.43; 95% confidence interval, 1.18–4.75; P =0.015). A phenome-wide association study supported the effect of this region on coronary heart disease and did not identify noncardiovascular phenotypes. Conclusions: Genetic variations at the LPA locus are associated with CHD events during statin therapy independently of the extent of low-density lipoprotein cholesterol lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 1466401-X
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  • 2
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 116, No. suppl_16 ( 2007-10-16)
    Abstract: Mrf-2/Arid5b, a member of AT-rich interaction domain family of transcription factors, is highly expressed in the cardiovascular system and is believed to play essential roles in the phenotypic change through its regulation of smooth muscle cell differentiation. In addition, recent studies on gene-engineered mice suggested that this transcriptional factor is involved in obesity and adipogenesis, which are critical aspects of metabolic syndrome and diabetes mellitus. Thus, we hypothesized that genetic variations of the Mrf-2 gene may be associated with susceptibility to coronary artery disease (CAD) and diabetes mellitus (DM). To examine the association between Mrf-2 polymorphisms and CAD, we investigated 17 common SNPs of Mrf-2 in 475 CAD subjects and 310 control subjects. Four nearby SNPs (rs2893880, rs10740055, rs7087507 and rs10761600) showed almost complete linkage disequilibrium, and disease associations were revealed not only for individual SNPs ( P =0.0002, rs2893880; P =0.0067, rs7087507, respectively) but also for their haplotype combination ( P =0.04, G-C-G-A (rs2893880-rs10740055-rs7087507-rs10761600)). Furthermore, these positive disease associations still existed after logistic regression analysis was performed to eliminate confounding conventional coronary risk factors. Subsequent analysis revealed that the aforementioned SNPs also statistically conferred risk of DM. To confirm these findings, we recruited another 500 DM subjects and 500 control subjects, and assessed the same haplotype block for their disease associations. Consistent significant associations were observed ( P =0.0238, rs2893880; P =0.0014, rs10740055; P =0.0067, rs7087507; P =0.0022, rs10761600; P =0.0031 and P =0.04, C-A-A-T and G-C-G-A (rs2893880-rs10740055-rs7087507- rs10761600), respectively). Moreover, the disease-associated genotypes were also revealed to be correlated with the level of serum adiponectin, which is known as an anti-diabetic adipocytokine. . In conclusion, our study implicates genetic variations of Mrf-2 as previously unknown genetic risk factors for CAD and DM. We believe that the associations of Mrf-2 with CAD may be mediated at least partly via its associations with DM.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2007
    detail.hit.zdb_id: 1466401-X
    Location Call Number Limitation Availability
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  • 3
    In: Obstetrical & Gynecological Survey, Ovid Technologies (Wolters Kluwer Health), Vol. 71, No. 7 ( 2016-07), p. 389-391
    Type of Medium: Online Resource
    ISSN: 0029-7828
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 2043471-6
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