Abstract: Background: The association of Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) common variants (rs4402960 and rs1470579) with type 2 diabetes (T2D) has been performed in different populations. The aim of this study was to evaluate the association of alternative variants of IGF2BP2; rs6777038, rs16860234 and rs7651090 with glutamic acid decarboxylase antibodies (GADA) negative diabetes in Malaysian Subjects. Methods/Principal Findings: IGF2BP2; rs6777038, rs16860234 and rs7651090 single nucleotide polymorphisms (SNPs) were genotyped in 1107 GADA negative diabetic patients and 620 control subjects of Asian from Malaysia. The additive genetic model adjusted for age, race, gender and BMI showed that alternative variants; rs6777038, rs16860234 and rs7651090 of IGF2BP2 associated with GADA negative diabetes (OR = 1.21; 1.36; 1.35, P = 0.03; 0.0004; 0.0002, respectively). In addition, the CCG haplotype and diplotype CCG-TCG increased the risk of diabetes (OR = 1.51, P = 0.01; OR = 2.36, P = 0.009, respectively).
Conclusions/Significance: IGF2BP2 alternative variants were associated with GADA negative diabetes. The IGF2BP2 haplotypes and diplotypes increased the risk of diabetes in Malaysian subject.
Abstract: OBJECTIVE: To determine the activity of paraoxonase 1 (PON1) in keratoconus in a Malaysian population in comparison with non-keratoconic subjects.
METHODS: Clinical eye examinations were performed on patients with keratoconus and non-keratoconic subjects after questionnaires were completed. Blood samples were collected and subjected to spectrophotometry analysis of paraoxonase and diazoxonase activities for the determination of the status of PON1 of every individual.
RESULTS: Of the 11 keratoconic patients and 55 non-keratoconic control samples collected, eight patients of Indian ethnicity were keratoconic (73%), whereas 33 non-Indians were non-keratoconic (60%; p = 0.047). Paraoxonase activity was lower in Indians compared to the non-Indians ie Malays and Chinese (p = 0.008). Keratoconic subjects had a lower paraoxonase activity compared to non-keratoconics (p = 0.038).
CONCLUSIONS: The reduced paraoxonase activity in keratoconic patients suggests that the keratoconic corneas were more susceptible to oxidative stress. Reduced paraoxonase activity and keratoconus status appears to be associated with ethnicity.
Abstract: Diabetic retinopathy is the most common diabetic eye disease, occurring in about 60% of type 2 diabetic patients. Other than known clinical risk factors, the influence of genes has been suggested as part of the development of diabetic retinopathy. We investigated the association of Gly82Ser, 1704G/T and 2184A/G polymorphisms in the RAGE gene with retinopathy in type 2 diabetic patients in Malaysia. Ninety-eight unrelated retinopathy patients and 185 unrelated healthy controls from all over Malaysia were recruited in this study. The allele and genotype frequencies of the three gene polymorphisms were investigated using PCR-RFLP. The allele frequency of the three polymorphisms did not differ significantly between the control and the retinopathy group (P > 0.05). Analysis of the frequency of GA+AA, GT+TT and AG+GG in the retinopathy group did not reveal significant differences (P > 0.05) compared to the control group. We conclude that RAGE gene Gly82Ser, 1704G/T and 2184A/G polymorphisms are not associated with retinopathy development in the Malaysian population.
Abstract: The role of paraoxonase 1 in cardiovascular disease complications in type 2 diabetes mellitus is not fully understood. We studied paraoxonase activity towards paraoxon in 188 non-diabetic and 140 diabetic subjects using general linear models and univariate analysis. Adjusting for age revealed a reduction in activity towards paraoxon was associated with a significant increase in risk (p=0.023) for cardiovascular disease complications in diabetic patients. Multivariate analysis of two plasma measures of paraoxonase activity using paraoxon and diazoxon also showed reduced paraoxonase activity towards paraoxon was associated with a significant increase in risk (p=0.045) for cardiovascular disease complications in diabetic patients. These analyses showed that a reduced paraoxonase activity towards paraoxon was associated with ethnicity. Based on multivariate analysis, subjects of Malay ethnic origin have significantly higher than expected activity (p=0.008, compared to Indians), towards paraoxon than subjects of Chinese origin who in turn had higher than expected paraoxonase activity (p=0.028, compared to Indians) Indian subjects.
Abstract: Human paraoxonase 1 (PON1), a High-Density Lipoprotein (HDL)-associated esterase has been implicated in slowing down the development of atherosclerosis. In the present study, kinetic and inhibition studies on PON1 were conducted to assess three parameters: the Michaelis constant (KM) and maximal rate of metabolisme (Vmax) of paraoxonase and inhibition constant (Ki) of phenylacetate. Human paraoxonase 1 (PON1) activity was measured spectrophotometrically at 405 nm, using plasma samples in basal (without added NaCl) and salt-stimulated assays with 1 M NaCl. Inhibition studies were performed using phenylacetate as an inhibitor of PON1 in basal assays, pH 8.0. Estimates of KM and Vmax were obtained from the Lineweaver-Burk plot. Estimates of Ki were obtained from the secondary plot of apparent KM (KM,app) versus inhibitor concentration. The parameter values were evaluated for the genotypes PON1192QQ, -QR, -RR. In salt-stimulated assays, the Vmax increased two-fold for the PON1192QQ samples and three to five-fold for the PON1192RR samples compared with basal assays. Similarly, it increased four-fold for PON1192QR samples. Michaelis constant (KM) was comparable with or without 1.0 M NaCl across the three genotypes. The Lineweaver-Burk and Dixon plots revealed that phenylacetate was a predominantly competitive inhibitor exhibiting linear mixed type inhibition. The Ki values were also comparable across the three genotypes. We conclude that the three kinetic parameters of PON1 in the Malaysian population estimated in the present report were comparable with those reported by other studies on PON1 from Caucasian populations.
Abstract: Paraoxonase (PON1) has been implicated to have a cardioprotective role, due to its physical attachment with high-density lipoprotein. PON1192QR is a variation of the PON1 gene, the R allele being a risk factor for cardiovascular disease. Kinetic studies resulting in a plot of paraoxon versus diazoxon hydrolysis rates may be used to accurately predict PON1192 geno-type. In this study, paraoxonase and diazoxonase activities in plasma were measured spec-trophotometrically using plasma while PCR-based PON1192 genotyping was performed us-ing polymerase chain reaction followed by restriction digestion. The two-substrate assay-derived genotypes were cross-referred with those determined by PCR-based genotyping. When results did not concur, sequencing of the 99-bp region spanning codon 192 of PON1 was performed to verify the genotype. Concordant samples with high or low activities were sequenced for comparison. In addition, the rare PON1194WX polymorphism was examined as a source of discordance. The frequency of the PON1192Q allele in a Malaysian population comprising three ethnic groups (Malays, Chinese and Indians) was estimated to be 0.46, and that of the PON1192R allele, 0.54. Discordance between the genotype and phenotype was ob-served for two samples. One of the two subjects genotyped as PON1192QR and phenotyped as PON1192QQ. The sample showed low paraoxonase and diazoxonase activities. Sequencing confirmed that the genotype was PON1192QR. The other subject was genotyped as PON1192RR but phenotyped as PON1192QR. Sequencing showed that the genotype was in fact PON1192RR, with the subject showing relative high activities. The PON1194WX mutation was not detected in the sequenced samples and was not the source for discordance.
Abstract: The role of high-density lipoprotein associated paraoxonase (PON) 1 in protection against oxidative stress associated with the development of complications in diabetes mellitus has been reported. Variations in the PON1 gene, 55LM and 192QR have been described in different populations. These variations are known to be risk factors for heart disease, especially the L and R alleles. We have investigated the prevalence of both polymorphisms in the Malaysian population comprising the three major ethnic groups: Malay, Chinese and Indian, using polymerase chain reaction followed by restriction endonuclease digestion. The results show the pooled frequencies of L and R alleles were 0.91 and 0.54, respectively, similar to those in the Asian region. The frequency of the M allele was higher in Indians (p < 0.05), whereas the R allele was higher in both the Chinese and Malays compared to Indians (p < 0.05), indicating ethnic group-dependent genetic differences. The most common genotypic combination was LL/QR, followed by LL/RR. The genotype frequencies for the total Malaysian population showed a significant departure from Hardy-Weinberg equilibrium for the 55LM (p = 0.013) but not the 192QR (p = 0.056) polymorphisms. A strong linkage disequilibrium between L/55 and R/192 alleles was also observed. In the Malaysian population as a whole, Malays and Chinese showed a higher frequency of the R allele which is a risk factor for cardiovascular diseases.
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