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Please use this identifier to cite or link to this item: http://hdl.handle.net/1812/590

Title: Activity and polymorphism of Paraoxonase 1 in the Malaysian population
Authors: Rozaida Poh, Yuen Ying
Keywords: Paraoxonase
Premature cardiovascular disease
Diabetes mellitus
Issue Date: Jan-2009
Publisher: University Malaya
Abstract: PON1 is an esterase that is associated with HDL. Polymorphisms at positions 55 and 192 of the PON1 gene have been associated with accelerated atherosclerosis that leads to development of premature cardiovascular disease. However the role of PON1 in cardiovascular disease complications in type 2 DM has not been not fully understood. The variation in gene frequencies in a Malaysian population comprising three ethnic groups for the polymorphisms at PON1 was determined using conventional PCRbased genotyping and two-substrate activity assays. The pooled observed frequencies in a sample of 353 subjects for the L, M, Q and R alleles were 0.901, 0.099, 0.459 and 0.541, respectively. The most common genotype was LL/QR (37%) followed by LL/RR (31%). A higher frequency of the M allele was found in subjects of Indian ethnicity compared to other ethnic groups (p<0.001). A strong linkage disequilibrium between L/55 and R/192 alleles was observed (P<0.0001). These analyses suggested that polymorphisms of PON1 observed are associated with ethnicity. The association of polymorphisms in PON1 with complications in type 2 DM was examined in a sample of 188 non-diabetic and 140 diabetic subjects using association tests adjusted for age. The polymorphisms of PON1 at positions 55 and 192 were not associated with complications in type 2 DM (p=0.218, p=0.847, respectively). Univariate analysis of PON1 activity towards paraoxon in these subjects using general linear models adjusting for age revealed that reduced PON1 activity towards paraoxon was associated with increased risk of CVD complications in type 2 DM (p=0.023) compared to diabetics without complications. Multivariate analysis of two plasma measures of PON1 activity using paraoxon and diazoxon also showed that a reduced PON1 activity towards paraoxon was associated with increased risk of CVD complications in type 2 DM (p=0.045). These analyses revealed that both activity measures were independent of PON1 polymorphisms. In addition, these analyses also showed that a reduced PON1 activity towards paraoxon was associated with ethnicity. Similarly, ethnicity was associated with PON1 polymorphisms (p<0.001). Based on multivariate analysis, subjects of Malay ethnic origin were expected to have higher activity towards paraoxon than subjects of Chinese origin (p=0.008, compared to Indians). Chinese subjects in turn were expected to have higher PON1 activity than Indian subjects (p=0.028, compared to Indians). Discordance between genotype and phenotype was found in three subjects in the sample population and was resolved using DNA sequencing of the PON1 polymorphism at position 192. Hence, the PON1192Q or –R allele was predicted to be inactive in heterozygotes. The effect of PON1 polymorphisms on kinetics of PON1 was examined. KM values between genotypes was not significantly different (p>0.05). However, Vmax was significantly increased according to the polymorphisms in both basal (p<0.05) and saltstimulated assays (p<0.001). Ki was not significantly different between genotypes (p>0.05). The inhibition of paraoxon by phenylacetate was of the linear mixed type.
Description: Thesis (PhD) -- Faculty of Medicine, University of Malaya, 2009.
URI: http://dspace.fsktm.um.edu.my/handle/1812/590
Appears in Collections:PhD Theses: Medicine

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