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Association of genetic variation on chromosome 9p21.3 and arterial stiffness
Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.ORCID iD: 0000-0002-9095-403X
Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
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2009 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 265, no 3, 373-381 p.Article in journal (Refereed) Published
Abstract [en]

Genome wide association studies have consistently reported associations between a region on chromosome 9p21.3 and a broad range of vascular diseases, such as coronary artery disease (CAD), aortic and intracranial aneurysms and type-2 diabetes (T2D). However, clear associations with intermediate phenotypes have not been described so far. To shed light on a possible influence of this chromosomal region on arterial wall integrity, we analysed associations between single nucleotide polymorphisms (SNPs) and degree of stiffness of the abdominal aorta in elderly individuals.

A total of 400 subjects, 212 men and 188 women, aged 70-88 years were included. Arterial stiffness was examined at the midpoint between the renal arteries and the aortic bifurcation. Two CAD- and aneurysm-associated SNPs (rs10757274 and rs2891168) and one T2D-associated SNP (rs1081161) within the 9p21.3 region were genotyped. Aortic compliance and distensibility coefficients were higher in carriers of the rs10757274G and rs2891168G alleles in men reflecting a decrease in aortic stiffness. Adjustment for age and mean arterial pressure had no effect on these associations. The two SNPs were not associated with intima-media thickness or lumen diameter of the abdominal aorta. There were no associations between the rs10811661 SNP and any measure of aortic stiffness.

Impaired mechanical properties of the arterial wall may explain the association between chromosome 9p21.3 polymorphisms and vascular disease.

Place, publisher, year, edition, pages
2009. Vol. 265, no 3, 373-381 p.
Keyword [en]
arterial stiffness, polymorphism, vascular disease
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-16963DOI: 10.1111/j.1365-2796.2008.02020.xOAI: oai:DiVA.org:liu-16963DiVA: diva2:200850
Note

This is the authors’ version of the following article: Hanna Björck, Toste Länne, Urban Alehagen, Karin Persson, Louise Rundkvist, A Hamsten, Ulf Dahlström and P Eriksson, Association of genetic variation on chromosome 9p21.3 and arterial stiffness, 2009, Journal of Internal Medicine, (265), 3, 373-381. which has been published in final form at: http://dx.doi.org/10.1111/j.1365-2796.2008.02020.x Copyright: Blackwell Publishing Ltd http://eu.wiley.com/WileyCDA/Brand/id-35.html

Available from: 2009-02-28 Created: 2009-02-27 Last updated: 2017-03-27Bibliographically approved
In thesis
1. Vessel wall integrity: influence of genetics and flow
Open this publication in new window or tab >>Vessel wall integrity: influence of genetics and flow
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cardiovascular disease (CVD) is the major cause of death worldwide. Underlying causes, such as atherosclerosis and hypertension, are associated with remodeling of the vessel wall ultimately leading to loss of structural integrity. There are a number of factors that can influence vascular remodeling and hence structural integrity. The overall aim of this thesis was to investigate aortic wall integrity in relation to genetics and blood flow.

The influence of SNPs within the currently most robust susceptibility locus identified for CVD (chromosome 9p21.3) on abdominal aortic integrity was studied in elderly individuals. In men, risk-variants were associated with a decreased abdominal aortic stiffness, independent of other factors related to arterial stiffness. Impaired mechanical properties of the abdominal aortic wall may explain the association between chromosome 9p21.3 and vascular disease.

Plasminogen activator inhibitor 1 (PAI-1) is the key inhibitor of fibrinolysis, and involved in several processes associated with vascular remodeling. We investigated the impact of the PAI-1 4G/5G polymorphism on central aortic blood pressure as this pressure more strongly relates to cardiovascular morbidity and mortality than the peripheral pressure. Elderly women carrying the 4G/4G genotype had higher central aortic blood pressure than women carrying the 5G/5G genotype. The association was regardless of other risk factors related to hypertension, suggesting that an impaired fibrinolytic potential may play an important role in the development of hypertension in women.

Blood flow is a strong determinant of arterial growth and vascular function. We investigated flow-dependent gene expression and vessel wall morphology in the rat aorta under physiological conditions. Microarray analysis revealed a strong differential gene expression between disturbed and uniform flow pattern regions, particularly associated with transcriptional regulation. Moreover, several genes related to Ca2+ signalling were among the most highly differentially expressed. Up-regulation of Ca2+-related genes may be due to endothelial response to disturbed flow and assembly of cilia, consequently leading to functional and structural modifications of the vessel wall.

Bicuspid aortic valve (BAV) is a congenital disorder associated with disturbed ascending aortic blood flow. Using a new strategy to dissect flow-mediated gene expression we identified several novel flow-associated genes, particularly related to angiogenesis, wound healing and mechanosensing, showing differential expression in the ascending aorta between BAV and tricuspid aortic valve patients. Fifty-five percent of the identified genes were confirmed to be flowresponsive in the rat aorta. A disturbed flow, and consequently an altered gene expression, may contribute to the increased aneurysm susceptibility associated with BAV morphology.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 84 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1270
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-73958 (URN)978‐91‐7393‐033‐8 (ISBN)
Public defence
2012-01-20, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:15 (Swedish)
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Available from: 2012-01-17 Created: 2012-01-17 Last updated: 2017-03-27Bibliographically approved

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Björck, HannaLänne, TosteAlehagen, UrbanPersson, KarinRundkvist, LouiseDahlström, Ulf

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