Genetic analysis of ischemic stroke and predisposing carotid artery stenosis : a stroke carol
Author: Kostulas, Konstantinos
Date: 2007-12-07
Location: Föreläsningssal B64, Barngatan 4, plan 6, Karolinska Universitetssjukhuset, Huddinge
Time: 09.00
Department: Institutionen för klinisk neurovetenskap / Department of Clinical Neuroscience
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Thesis (1.212Mb)
Abstract
Ischemic cerebrovascular disease (ICVD), consisting of ischemic stroke
and transient ischemic attacks (TIA), is a complex disease where
contribution from both the environment and genes promote pathogenesis of
the disease-complex. Carotid stenosis is sometimes a predisposing factor
or cause for ICVD and a complex disease in itself. Studies of adoptees
and twins support the idea that genes are of importance in ICVD and
family studies in CS. Two different strategies have been applied to
search the genome for ICVD genes, a candidate genome approach and a
genome-wide search in familial disease. During the last two decades
different candidate genes coding for coagulation-proteins, lipoproteins,
renin-angiotensin-aldosterone system and different inflammatory genes
have been investigated with different results. Successful examples of the
genome-wide search are the phosphodiesterase 4D (PDE4D) gene and the 5-
lipoxygenase activating protein (ALOX5AP) gene found in an Icelandic
population. These genes have later been studied as a candidate gene in
different populations.
The South Stockholm Ischemic Stroke Study (SSISS) was started in 1996 to study genetic associations of ICVD and predisposing carotid stenosis (CS), the hypothesis being that genetic factors could be used to find more coherent pathogenetical subgroups to the ischemic cerebrovascular disease complex to facilitate a more individual treatment and prophylaxis. During the first phase of the project three suspected susceptibility genes were examined in a smaller cohort (<200) of patients, namely lipoprotein lipase (LPL), methylene-tetrahydrofolate reductase (MTHFR) and angiotensin-converting enzyme (ACE). We concluded that LPL and MTHFR polymorphisms did not contribute greatly to the overall risk of ICVD or CS. In the examination of ACE we found a significant difference for the presumed susceptibility allele in patients with CS compared to healthy controls and age-matched non-CS ICVD patients. We concluded that the ACE gene polymorphism is a risk factor for the development of CS.
In the last phase of the project we expanded the material to more than 1000 patients with ICVD and phenotyped the subjects in detail including subtyping by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. We went on to examine PDE4D and ALOX5AP, genes discovered by linkage analysis on Iceland. We were not able confirm the association between the ALOX5AP HapA haplotype and ICVD, but a non-significant risk was observed in the large artery atherosclerosis (LAA) TOAST subtype. Our PDE4D findings although non-significant considering the number of markers and phenotypes tested, were consistent with the original Icelandic association, with a trend in the whole ICVD group, strengthened in LAA and the combined group of LAA and cardio embolic (CE) subtypes.
In the last study we examined 100 polymorphisms in 47 suspected susceptibility genes and found three polymorphisms to be weakly associated with ICVD after correction for age and gender (LPL, angiotensinogen and guanine nucleotide-binding protein beta-3). These markers were differently prevalent in the subtypes examined. Factor VII, apolipoprotein E and two renin polymorphisms were significantly more frequent in patients with evidence of CS compared to non-CS patients.
In conclusion we have found weak associations to some candidate genes and by subdividing ICVD patients by presence of CS the patterns of association change. We therefore conclude that larger well phenotyped ICVD cohorts are needed.
The South Stockholm Ischemic Stroke Study (SSISS) was started in 1996 to study genetic associations of ICVD and predisposing carotid stenosis (CS), the hypothesis being that genetic factors could be used to find more coherent pathogenetical subgroups to the ischemic cerebrovascular disease complex to facilitate a more individual treatment and prophylaxis. During the first phase of the project three suspected susceptibility genes were examined in a smaller cohort (<200) of patients, namely lipoprotein lipase (LPL), methylene-tetrahydrofolate reductase (MTHFR) and angiotensin-converting enzyme (ACE). We concluded that LPL and MTHFR polymorphisms did not contribute greatly to the overall risk of ICVD or CS. In the examination of ACE we found a significant difference for the presumed susceptibility allele in patients with CS compared to healthy controls and age-matched non-CS ICVD patients. We concluded that the ACE gene polymorphism is a risk factor for the development of CS.
In the last phase of the project we expanded the material to more than 1000 patients with ICVD and phenotyped the subjects in detail including subtyping by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. We went on to examine PDE4D and ALOX5AP, genes discovered by linkage analysis on Iceland. We were not able confirm the association between the ALOX5AP HapA haplotype and ICVD, but a non-significant risk was observed in the large artery atherosclerosis (LAA) TOAST subtype. Our PDE4D findings although non-significant considering the number of markers and phenotypes tested, were consistent with the original Icelandic association, with a trend in the whole ICVD group, strengthened in LAA and the combined group of LAA and cardio embolic (CE) subtypes.
In the last study we examined 100 polymorphisms in 47 suspected susceptibility genes and found three polymorphisms to be weakly associated with ICVD after correction for age and gender (LPL, angiotensinogen and guanine nucleotide-binding protein beta-3). These markers were differently prevalent in the subtypes examined. Factor VII, apolipoprotein E and two renin polymorphisms were significantly more frequent in patients with evidence of CS compared to non-CS patients.
In conclusion we have found weak associations to some candidate genes and by subdividing ICVD patients by presence of CS the patterns of association change. We therefore conclude that larger well phenotyped ICVD cohorts are needed.
List of papers:
I. Huang P, Kostulas K, Huang WX, Crisby M, Kostulas V, Hillert J. (1997). Lipoprotein lipase gene polymorphisms in ischaemic stroke and carotid stenosis. Eur J Clin Invest. 27(9): 740-2.
Fulltext (DOI)
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II. Kostulas K, Crisby M, Huang WX, Lannfelt L, Hagenfeldt L, Eggertsen G, Kostulas V, Hillert J. (1998). A methylenetetrahydrofolate reductase gene polymorphism in ischaemic stroke and in carotid artery stenosis. Eur J Clin Invest. 28(4): 285-9.
Pubmed
View record in Web of Science®
III. Kostulas K, Huang WX, Crisby M, Jin YP, He B, Lannfelt L, Eggertsen G, Kostulas V, Hillert J. (1999). An angiotensin-converting enzyme gene polymorphism suggests a genetic distinction between ischaemic stroke and carotid stenosis. Eur J Clin Invest. 29(6): 478-83.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Kostulas K, Gretarsdottir S, Kostulas V, Manolescu A, Helgadottir A, Thorleifsson G, Gudmundsson LJ, Thorsteinsdottir U, Gulcher JR, Stefansson K, Hillert J. (2007). PDE4D and ALOX5AP genetic variants and risk for Ischemic Cerebrovascular Disease in Sweden. J Neurol Sci. 263(1-2): 113-7.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Kostulas K, BrophyVH, MoraitisK, ManolescuA, KostulasV, Gretarsdottir S, Cheng S, Hillert J. (1970). Genetic Profile of Ischemic Cerebrovascular Disease and Carotid Stenosis. Acta Neurologica Scandinavica. [Accepted]
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Huang P, Kostulas K, Huang WX, Crisby M, Kostulas V, Hillert J. (1997). Lipoprotein lipase gene polymorphisms in ischaemic stroke and carotid stenosis. Eur J Clin Invest. 27(9): 740-2.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Kostulas K, Crisby M, Huang WX, Lannfelt L, Hagenfeldt L, Eggertsen G, Kostulas V, Hillert J. (1998). A methylenetetrahydrofolate reductase gene polymorphism in ischaemic stroke and in carotid artery stenosis. Eur J Clin Invest. 28(4): 285-9.
Pubmed
View record in Web of Science®
III. Kostulas K, Huang WX, Crisby M, Jin YP, He B, Lannfelt L, Eggertsen G, Kostulas V, Hillert J. (1999). An angiotensin-converting enzyme gene polymorphism suggests a genetic distinction between ischaemic stroke and carotid stenosis. Eur J Clin Invest. 29(6): 478-83.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Kostulas K, Gretarsdottir S, Kostulas V, Manolescu A, Helgadottir A, Thorleifsson G, Gudmundsson LJ, Thorsteinsdottir U, Gulcher JR, Stefansson K, Hillert J. (2007). PDE4D and ALOX5AP genetic variants and risk for Ischemic Cerebrovascular Disease in Sweden. J Neurol Sci. 263(1-2): 113-7.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Kostulas K, BrophyVH, MoraitisK, ManolescuA, KostulasV, Gretarsdottir S, Cheng S, Hillert J. (1970). Genetic Profile of Ischemic Cerebrovascular Disease and Carotid Stenosis. Acta Neurologica Scandinavica. [Accepted]
Fulltext (DOI)
Pubmed
View record in Web of Science®
Issue date: 2007-11-16
Rights:
Publication year: 2007
ISBN: 978-91-7357-395-5
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