Genome-Wide Association Study of Peripheral Arterial Disease in a Japanese Population

Matsukura, Mitsuru; Ozaki, Kouichi; Takahashi, Atsushi; Onouchi, Yoshihiro; Morizono, Takashi; Komai, Hiroyoshi; Shigematsu, Hiroshi; Kudo, Toshifumi; Inoue, Yasuhiro; Kimura, Hideo; Hosaka, Akihiro; Shigematsu, Kunihiro; Miyata, Tomohiro; Watanabe, Toshiaki; Tsunoda, Tatsuhiko; Kubo, Michiaki; Tanaka, Toshihiro

doi:10.1371/journal.pone.0139262

Cited by 40 publications

(38 citation statements)

References 48 publications

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“…This association persisted after adjusting for diabetes mellitus, smoking, lipid levels, prior myocardial infarction, and hypertension, indicating a novel pathophysiological pathway. In another study by Matsukura et al (79), a GWAS with 785 cases and 3383 controls in a Japanese population identified 3 novel PAD susceptibility loci at importin-5 (IPO5)/RAS-related protein 2A, endothelin receptor type A, and histone deacetylase 9. Fine mapping at the IPO5/RAS-related protein 2A locus revealed that an SNP resulting in reduced expression of IPO5 conferred risk of PAD.…”

Section: Studies Of Genetic Determinants Of Human Padmentioning

confidence: 99%

Biomarkers and Genetics in Peripheral Artery Disease

Hazarika

Annex

2017

Clinical Chemistry

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BACKGROUND Peripheral artery disease (PAD) is highly prevalent and there is considerable diversity in the initial clinical manifestation and disease progression among individuals. Currently, there is no ideal biomarker to screen for PAD, to risk stratify patients with PAD, or to monitor therapeutic response to revascularization procedures. Advances in human genetics have markedly enhanced the ability to develop novel diagnostic and therapeutic approaches across a host of human diseases, but such developments in the field of PAD are lagging. CONTENT In this article, we will discuss the epidemiology, traditional risk factors for, and clinical presentations of PAD. We will discuss the possible role of genetic factors and gene–environment interactions in the development and/or progression of PAD. We will further explore future avenues through which genetic advances can be used to better our understanding of the pathophysiology of PAD and potentially find newer therapeutic targets. We will discuss the potential role of biomarkers in identifying patients at risk for PAD and for risk stratifying patients with PAD, and novel approaches to identification of reliable biomarkers in PAD. SUMMARY The exponential growth of genetic tools and newer technologies provides opportunities to investigate and identify newer pathways in the development and progression of PAD, and thereby in the identification of newer biomarkers and therapies.

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Section: Studies Of Genetic Determinants Of Human Padmentioning

confidence: 99%

Biomarkers and Genetics in Peripheral Artery Disease

Hazarika

Annex

2017

Clinical Chemistry

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“…Recent genome‐wide association studies have implicated the ET A receptor as a genetic determinant of coronary artery disease,54, 55 carotid atherosclerosis,54 large‐artery stroke,55 and peripheral artery disease,56 suggesting a role of this receptor in atherogenesis across diverse arterial systems. These findings are supported by clinical and preclinical studies that suggest a direct role of the ET A receptor on the development of atherosclerosis 57, 58, 59, 60, 61.…”

Section: Discussionmentioning

confidence: 99%

Acute Pressor Response to Psychosocial Stress Is Dependent on Endothelium‐Derived Endothelin‐1

Fox

Becker

Loria

et al. 2018

JAHA

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BackgroundAcute psychosocial stress provokes increases in circulating endothelin‐1 (ET‐1) levels in humans and animal models. However, key questions about the physiological function and cellular source of stress‐induced ET‐1 remain unanswered. We hypothesized that endothelium‐derived ET‐1 contributes to the acute pressor response to stress via activation of the endothelin A receptor.Methods and ResultsAdult male vascular endothelium‐specific ET‐1 knockout mice and control mice that were homozygous for the floxed allele were exposed to acute psychosocial stress in the form of cage switch stress (CSS), with blood pressure measured by telemetry. An acute pressor response was elicited by CSS in both genotypes; however, this response was significantly blunted in vascular endothelium‐specific ET‐1 knockout mice compared with control mice that were homozygous for the floxed allele. In mice pretreated for 3 days with the endothelin A antagonist, ABT‐627, or the dual endothelin A/B receptor antagonist, A‐182086, the pressor response to CSS was similar between genotypes. CSS significantly increased plasma ET‐1 levels in control mice that were homozygous for the floxed allele. CSS failed to elicit an increase in plasma ET‐1 in vascular endothelium‐specific ET‐1 knockout mice. Telemetry frequency domain analyses suggested similar autonomic responses to stress between genotypes, and isolated resistance arteries demonstrated similar sensitivity to α1‐adrenergic receptor‐mediated vasoconstriction.ConclusionsThese findings specify that acute stress‐induced activation of endothelium‐derived ET‐1 and subsequent endothelin A receptor activation is a novel mediator of the blood pressure response to acute psychosocial stress.

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“…This locus has previously been associated with a variety of vascular phenotypes, including coronary artery disease, carotid plaques, and peripheral arterial disease (in concordant direction with ischaemic stroke), as well as intracranial aneurysm (in concordant direction with intracerebral haemorrhage). [21-24] The locus has also been associated with migraine in candidate gene studies, [25] but this has not been validated in GWA studies. [26] EDNRA encodes the type A receptor ( ET A ) for Endothelin-1 ( ET-1 ), a potent vasoconstrictor with pro-inflammatory effects.…”

Section: Discussionmentioning

confidence: 99%

The Subtype Specificity of Genetic Loci Associated with Stroke in 16,664 cases and 32,792 controls

Traylor

Anderson

Rutten-Jacobs

et al. 2018

Preprint

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68Background: Genome-wide association studies have identified multiple loci associated with 69 stroke. However, the specific stroke subtypes affected, and whether loci influence both 70 ischaemic and haemorrhagic stroke, remains unknown. For loci associated with stroke, we 71 aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess 72 the extent to which such loci have homogeneous effects across stroke subtypes. 73Methods: We performed Bayesian multinomial regression in 16,664 stroke cases and 32,792 74 controls of European ancestry to determine the most likely combination of stroke subtypes 75 affected for loci with published genome-wide stroke associations, using model selection. 76 Cases were subtyped under two commonly used stroke classification systems, Trial of Org 77 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS). All 78 individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. 79 Results: Sixteen loci were considered for analysis. Seven loci influenced both haemorrhagic 80 and ischaemic stroke, three of which influenced ischaemic and haemorrhagic subtypes under 81 both TOAST and CCS. Under CCS, 4 loci influenced both small vessel stroke and 82 intracerebral haemorrhage. An EDNRA locus demonstrated opposing effects on ischaemic 83and haemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same 84 direction and only one locus (12q24) was predicted to influence all ischaemic stroke subtypes. 85Conclusions: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is 86 pervasive, reflecting differing causal pathways. However, overlap exists between 87 haemorrhagic and ischaemic stroke, which may reflect shared pathobiology predisposing to 88 small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored 89 analytic strategies to decipher genetic mechanisms. 90

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Genome-Wide Association Study of Peripheral Arterial Disease in a Japanese Population

Cited by 40 publications

References 48 publications

Biomarkers and Genetics in Peripheral Artery Disease

Biomarkers and Genetics in Peripheral Artery Disease

Acute Pressor Response to Psychosocial Stress Is Dependent on Endothelium‐Derived Endothelin‐1

The Subtype Specificity of Genetic Loci Associated with Stroke in 16,664 cases and 32,792 controls

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