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On certain genetic and metabolic risk factors for carotid stenosis and stroke
Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The present study evaluated genetic and metabolic factors influencing the risk of acute cerebrovascular disease (CVD) and internal carotid artery stenosis (ICA stenosis) in a Swedish community. The threonine (T) containing protein of the FABP2 A54T gene polymorphism has a greater affinity for long chain fatty acids (FFAs) than the alanine (A) containing protein. This altered affinity for FFAs has been shown to affect the intestinal absorption of fatty acids and consequently the fatty acid composition of serum lipids, in particularly postprandially. Endothelium derived NO is a potent vasodilator and antiatherogenic agent. Asymmetric dimethyl arginine (ADMA) is an endogenous competitive inhibitor of endothelial nitric oxide synthase (eNOS). ADMA has been shown to be involved in the pathogenesis of atherosclerotic disease, and ADMA inhibits eNOS by displacement of L-arginine from the enzyme, which in turn is believed to affect the amount of NO available within the endothelium.

The FABP2 A54T gene polymorphism was analyzed in 407 patients with acute CVD and also in a subset of these patients whose carotids had been evaluated with ultrasound. Both the FABP2 polymorphism and a common polymorphism of the eNOS gene, Glu298Asp, were analyzed in a different population consisting of 54 matched pairs of patients with ICA stenosis and controls. ADMA levels were measured in both study populations.

We found that the T54 allele was more frequent in patients with transient ischaemic attacks (TIA), and that the TT genotype was more prevalent in young, non-smoking patients with CVD than in controls.

Increased concentrations of ADMA were observed in cardio-embolic infarction and TIA, but not significantly in non-cardio-embolic infarction nor in haemorrhagic stroke. In multivariate logistic regression models, CVD increased across quartiles of ADMA in all subgroups, but this association was only significant in the TIA group. A decreased arginine/ADMA ratio, a measure of NO availability was associated with CVD in the entire study population. Patients with severe carotid stenosis had significantly higher ADMA levels than the controls. Allele and genotype frequencies of the FABP2 and eNOS polymorphisms did not differ between patients with ICA stenosis and controls.

Our results indicate that ADMA is a strong marker for TIA and severe ICA stenosis, and that relative defiency of arginine, measured as L-arginine/ADMA, is present in acute CVD.

We also conclude that a common polymorphism of the FABP2 gene increases susceptibility to ischaemic stroke and TIA.

Place, publisher, year, edition, pages
Institutionen för medicin och vård , 2006.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 942
Series
Keyword [en]
Carotid artery diseases, Carrier proteins, genetics, Cerebrovascular accident, Cerebrovascular disorders, Genetic predisposition to disease, Polymorphism, genetic
National Category
Clinical Science
Identifiers
URN: urn:nbn:se:liu:diva-7467ISBN: 91-85497-77-0 (print)OAI: oai:DiVA.org:liu-7467DiVA: diva2:22459
Public defence
2006-04-27, Berzeliussalen, Campus US, Linköpings Universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Note
Figure 4 on page 17 is publshed with kind permisson from The Journal of Physiology (http://jp.physoc.org/).Available from: 2006-09-28 Created: 2006-09-28 Last updated: 2009-06-08
List of papers
1. The FABP2 gene polymorphism in cerebrovascular disease
Open this publication in new window or tab >>The FABP2 gene polymorphism in cerebrovascular disease
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2004 (English)In: Acta Neurologica Scandinavica, Vol. 110, no 6, 355-360 p.Article in journal (Refereed) Published
Abstract [en]

Objective – Earlier studies have shown that the fatty acid binding protein 2 (FABP2) T54 allele is associated with dyslipidemia, which in turn correlates with the incidence of cerebrovascular disease (CVD). To assess whether the FABP2 gene A54T polymorphism is associated with an increased risk of CVD we undertook a case–control study.

Materials and methods – A total of 407 patients diagnosed with acute CVD and 158 control subjects were genotyped for the A54T polymorphism using a PCR-RFLP method.

Results – Allele and genotype frequencies of the FABP2 A54T polymorphism did not differ between subjects with acute CVD (TT, 9.6%; TA, 41.0%; AA, 49.4%) and controls (TT, 7.6%; TA, 41.1%; AA, 51.3%; P = ns) or in the following subgroups of CVD compared with controls: non-cardioembolic infarction (n = 252), intracerebral hemorrhage (n = 23), and cardioembolic infarction (n = 91). In transient ischemic attacks (TIAs) (n = 41) the combined TT and TA genotype frequency (TT + TA, 65.9%) was more frequent than in controls (48.7%) (P = 0.05). Furthermore, the TT genotype was more frequent in non-smoking patients under the age of 70 (n = 77) with a non-cardioembolic infarction (TT, 18.2%) compared with controls (7.6%) (P = 0.024).

Conclusions – Our findings suggest an involvement of the FABP2 (A54T) gene polymorphism in the pathogenesis of CVD. The FABP2 T54 allele appears to be a genetic susceptibility marker for TIA and non-cardioembolic infarction at younger onset.

Keyword
FABP2, polymorphism, stroke, genetics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14007 (URN)10.1111/j.1600-0404.2004.00335.x (DOI)
Available from: 2006-09-28 Created: 2006-09-28
2. Genetic variation of the intestinal fatty acid-binding protein 2 gene in carotid atherosclerosis
Open this publication in new window or tab >>Genetic variation of the intestinal fatty acid-binding protein 2 gene in carotid atherosclerosis
2005 (English)In: Vascular Medicine, ISSN 1358-863X, Vol. 10, no 2, 103-108 p.Article in journal (Refereed) Published
Abstract [en]

The alanine (A) to threonine (T) substitution at codon 54 of the intestinal fatty acid-binding protein 2 (FABP2) has been associated with dyslipidaemia and other characteristics of the metabolic syndrome, which in turn is a risk factor for cerebrovascular disease. The aim of this study was to investigate whether the A54T polymorphism in the FABP2 gene is associated with internal carotid artery (ICA) stenosis in stroke patients. Swedish subjects initially diagnosed with acute cerebrovascular disease (n = 196) that had been assessed with ultrasound of the carotid arteries were identified and grouped depending on whether a stenosis was found. The subjects were genotyped for the A54T polymorphism using a PCR-RFLP method. In a multivariate logistic-regression analysis, where known risk factors for atherosclerosis were fixed (diabetes, systolic blood pressure, age and smoking), having the FABP2 T allele was a significant risk factor for ICA stenosis (odds ratio 2.9; 95% confidence interval, 1.1-7.7; p = 0.04) together with diabetes (odds ratio 4.9; 95% confidence interval, 1.8-14; p < 0.01). Age, smoking and blood pressure did not reach statistical significance. In conclusion, our result supports the hypothesis that the FABP2 A54T polymorphism is associated with ICA stenosis.

Keyword
carotid atherosclerosis, FABP2, genetics, polymorphism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14008 (URN)10.1191/1358863x05vm609oa (DOI)
Available from: 2006-09-28 Created: 2006-09-28 Last updated: 2010-08-20
3. Asymmetric dimethylarginine (ADMA) as a risk marker for stroke and TIA in a Swedish population
Open this publication in new window or tab >>Asymmetric dimethylarginine (ADMA) as a risk marker for stroke and TIA in a Swedish population
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2006 (English)In: Atherosclerosis, ISSN 0021-9150, Vol. 185, no 2, 271-277 p.Article in journal (Refereed) Published
Abstract [en]

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, has been shown to be involved in the pathogenesis of atherosclerosis. The present study was initiated to investigate the role of ADMA as a risk marker of acute cerebrovascular disease (CVD).

We examined 363 CVD patients and 48 controls. The ADMA concentration (mean ± S.D., μmol/L) in controls was 0.50 ± 0.06. Compared to controls, increased concentrations of ADMA were observed in cardio-embolic infarction (0.55 ± 0.08; p < 0.001; n = 71), and TIA (0.54 ± 0.05; p < 0.001; n = 31), but not in non-cardio-embolic infarction (0.51 ± 0.07; p = 0.56; n = 239) and haemorrhagic stroke (0.51 ± 0.11; p = 0.77; n = 22). In multivariate logistic regression models, CVD increased across quartiles of ADMA in all subgroups, but this association was only significant in the TIA group (odds ratio for highest versus lowest quartile 13.1; 95% CI: 2.9–58.6; p trend 0.001) A decreased arginine/ADMA ratio was significantly associated with CVD in the entire study population (p < 0.01). Our results indicate that ADMA is a weak independent marker for acute stroke and a strong marker for TIA and that relative arginine deficiency, measured as the l-arginine/ADMA ratio, is present in acute CVD.

Keyword
Asymmetric dimethylarginine; Arginine; Atherosclerosis; Stroke; TIA
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14009 (URN)10.1016/j.atherosclerosis.2005.06.033 (DOI)
Available from: 2006-09-28 Created: 2006-09-28 Last updated: 2009-06-08
4. Asymmetric dimethylarginine and polymorphisms of fatty acid-binding protein 2 and endothelial nitric oxide synthase genes in carotid atherosclerosis
Open this publication in new window or tab >>Asymmetric dimethylarginine and polymorphisms of fatty acid-binding protein 2 and endothelial nitric oxide synthase genes in carotid atherosclerosis
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Manuscript (Other academic)
Identifiers
urn:nbn:se:liu:diva-14010 (URN)
Available from: 2006-09-28 Created: 2006-09-28 Last updated: 2010-01-13

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