Investigation of the association between genetic and activity polymorphisms of paraoxonase 1 and ischemic stroke risk

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2007

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Demirdöğen Can, Birsen

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Stroke is the third leading cause of death. Atherosclerosis in the carotid arteries is a risk factor for ischemic stroke. Oxidized low density lipoprotein (LDL) plays a central role in the progression of atherosclerosis. Human paraoxonase 1 (PON1), a high-density lipoprotein (HDL) associated serum esterase/lactonase, protects HDL and LDL from oxidative modifications. Thus, PON1 is protective against the development of atherosclerosis. PON1 gene has two functional coding region (192Q/R and 55L/M) and one promoter region (107T/C) polymorphism that affect the catalytic efficiency and levels of the enzyme, respectively. In this study, the aim was to determine the importance of PON1 genetic polymorphisms and activity as risk factors for ischemic stroke. The study population was comprised of 172 unrelated adult Caucasian patients with acute hemispheric ischemic stroke and 105 symptom-free controls. Serum and total blood samples were obtained from Gülhane Military Medical Academy Hospital Neurology Department, Ankara. Hypertension and diabetes were 2 times more common and HDL-C was significantly lower among patients compared to controls. Logistic regression analysis revealed hypertension and smoking to be significant predictors of stroke. Serum PON1 activities towards three substrates, paraoxon (paraoxonase activity; PON), phenyl acetate (arylesterase activity; ARE) and diazoxon (diazoxonase activity), which were measured by spectrophotometric methods, were found to be lower in stroke patients compared to controls. PON and PON/ARE were negatively associated with ischemic stroke by use of logistic regression analysis. PON/ARE was 1.26 times protective against stroke. The frequencies of the risky alleles 192R, 55L and 107T were increased in the patient group. Frequency of the 55L allele of PON1 was significantly increased among patients (0.690) compared to controls (0.628; P=0.003). Logistic regression analysis revealed PON1 55LL genotype to be associated with a 1.8-fold increase in the risk of ischemic stroke versus control status. Prevalence of triple combined haplotype QRLMTC was significantly lower in stroke patients (4.1%) when compared to controls (11.4%; P=0.019). The combined heterozygote haplotype had around 7 times increased protective effect against stroke in the overall population and 10 times protective effect in the elderly population. The low expressor genotype 107TT was associated with almost 2 times increased risk for stroke in elderly. 192R allele of PON1 represented 1.554 times increased risk for ischemic stroke in hypertensives relative to normotensives. Furthermore, the risk of hypertensive individuals having ischemic stroke was highest in the 192RR group (Odds Ratio; OR=7), followed by 192QR heterozygotes (OR=2.18), and the risk decreased to insignificant levels in 192QQ individuals. 192R allele constituted a 1.55 times increased risk in diabetics. 55L allele was associated with a 1.66 times increased risk of stroke in hypertensives and a 2.6 times increased risk for stroke in diabetics relative to non-diabetics. PON1 107T allele also represented a 1.35 times risk for stroke in hypertensives.

Subject Keywords

Genetics.

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http://etd.lib.metu.edu.tr/upload/3/12609213/index.pdf
https://hdl.handle.net/11511/17486

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Graduate School of Natural and Applied Sciences, Thesis

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Citation Formats

B. Demirdöğen Can, “Investigation of the association between genetic and activity polymorphisms of paraoxonase 1 and ischemic stroke risk,” Ph.D. - Doctoral Program, Middle East Technical University, 2007.