Background: Coronary artery disease (CAD) is a complex metabolic disorder in which lifestyle and genetic factors are known to play key roles in pathogenesis. The paraoxonase 1 (PON1) enzyme has a defensive effect against CAD progression, as it safeguards low-density lipoproteins (LDLs) from oxidative modifications. The most extensively studied genetic variants in the PON1 gene are Q192R and L55M, which have been related with LDL antioxidative activity and risk of CAD. Objective: The present case-control study intended to examine the Q192R and L55M polymorphisms and their association with the risk of CAD patients in north Indians. Methods: A total of 872 subjects (412 CAD patients and 460 controls) were recruited from north India. The PON1 gene was amplified and genotypes were studies using PCR-RFLP. χ2 analysis was performed to compare genotype/allele frequencies in patients and controls. Results: The present study indicated abdominal obesity, elevated body mass index, and dyslipidemia with increased levels of total cholesterol and triglycerides as well as reduced high-density lipoprotein cholesterol in CAD subjects compared to healthy controls (p < 0.05). Logistic regression analysis of the data revealed an association of the RR genotype of the Q192R polymorphism with an about 2-fold elevated risk of CAD (OR = 2.23, 95% CI = 1.47–3.37, p = 0.0001). Contrariwise, the L55M polymorphism did not show significant association with CAD (OR = 1.81, 95% CI = 0.66–4.95, p = 0.326). Conclusions: The Q192R polymorphism in the PON1 gene may be a susceptibility gene associated with increased risk of CAD in an Asian Indian population.

Cardiovascular diseases (CVDs), including coronary artery disease (CAD) and stroke, have emerged as major health conditions associated with high mortality and pronounced socioeconomic burden in the developing countries. Currently in India, there are 270 deaths/10,000 people from CVDs [1]. Recent estimates predict that India lost about USD 237 billion on healthcare expenditure in the last decade (2005–2015) due to the exponential increase in the burden of CVDs [2]. CAD is a multifactorial disease in which interactions among various environmental and genetic determinants play a critical role in pathophysiology [3, 4]. Recent studies revealed an association of single nucleotide polymorphisms (SNPs) in various genes with the augmented risk of developing CAD in many populations. Serum paraoxonase 1 (PON1) is one of the susceptibility genes which play a significant role in vascular pathology, and thus is regarded as an emergent biomarker of CAD. It is a 44-kDa Ca2+-dependent glycoprotein enzyme produced in the liver and bound to the surface of high-density lipoproteins (HDLs). PON1 is released into the blood by the liver, where it associates primarily with HDL [5] and is regarded to be a key factor for the antioxidative activity of HDL [6]. The PON1 gene has several SNPs [7]; however, the extensively studied SNPs are those in the coding regions, i.e., Q192R (rs662) and L55M (rs854560) [8]. The Q192R polymorphism, represented by an exchange of glutamine (Q) to arginine (R), may disturb the antioxidative potential of Arg192 and lead to greater risk of developing CAD [9]. There is another polymorphism of the PON1 gene, L55M, in which leucine to methionine substitution occurring at amino acid 55 has been associated with reduced PON1 activity [10]. Earlier studies showed that L55M genetic polymorphism may be related with cerebrovascular disease and CAD [11]. Some studies have been reported in Asian Indians, but were concentrated on the other parts of India. So, the present study was devised to examine the genetic interplay of PON1 gene polymorphisms (Q192R and L55M) and modifiable lifestyle-related factors associated with the risk of CAD in an Asian Indian population.

Study Subjects

The present study included 872 human subjects, among whom 460 were healthy controls and 412 were angiographically confirmed CAD patients. All these subjects were a part of our ongoing study on diabetes and CVD [12]. In brief, this study was launched in year 2011 to inspect the susceptibility genes and their association with the pathophysiology of metabolic disorders, including type 2 diabetes and CVDs, in an Asian Indian population. CAD was diagnosed by a cardiologist from the medical records showing medical indications, disturbed cardiac enzymes, ECG variations, and the outcomes of angiography and/or echocardiography. The study was explained to each participant and then information was collected regarding age, sex, educational qualifications, physical inactivity, diet, family history of CAD, smoking, alcohol consumption, etc.

Inclusion/Exclusion Criteria

Individuals aged > 35 years, irrespective of their disease status, were involved in this study. Participants belonging to north Indian states only (Punjab, Haryana, and Chandigarh) were included in this study. Controls having a family history of CVD, type 2 diabetes, osteoporosis, other bone disorders, or cancer were excluded from the study.

Anthropometric and Clinical Measurements

Standard anthropometric measurements including height, weight, as well as waist and hip circumference were performed in all participants using standard procedures. Blood pressure was measured using an Omron blood pressure meter. Fasting blood samples were collected for clinical estimations, including serum glucose, total cholesterol, triglyceride, HDL, and creatinine levels using standard kits. All derived measures, including body mass index (BMI), body fat percentage, low-density lipoprotein (LDL) cholesterol, and very-low-density lipoprotein (VLDL) cholesterol, were calculated using standard formulae. Phenotypic characterizations, such as hypertension, obesity, and dyslipidemia, were completed according to the values recommended for Asian Indians only.

Genotyping of the PON1 Gene

Genomic DNA was extracted from nucleated blood cells using phenol/chloroform/isoamyl alcohol. The PON1 gene was amplified to detect the Q192R polymorphism using the following primers: forward, 5′-TTG AAT GAT ATT GTT GCT GTG GGA CCT GAG-3′; reverse, 5′-CGA CCA CGC TAA ACC CAA ATA CAT CTC CCA GAA-3′. The amplification was done in 20 µL reaction mixture containing 100–200 ng genomic DNA, 1× Taq DNA polymerase buffer, 2.5 mM of MgCl2, 10 pmol of each primer, 200 µmol/L of dNTPs, and 1 U of Taq DNA polymerase enzymes (Thermo) using a thermal cycler (Eppendorf). The PCR conditions were: initial denaturation at 94°C for 5 min, followed by 35 cycles of denaturation at 94°C for 45 s; annealing at 60°C for 45 s; and then extension at 72°C for 45 s, with a final extension step at 72°C for 10 min. Figure 1 (right side) shows the amplified PCR products of 111 bp digested with restriction enzyme – HinfI (New England Biolabs) – and then resolved on 3% agarose gel electrophoresis for the Q192R ge­notypes (QQ [111 bp], QR [111 and 77 bp], and RR [77 bp]).

Fig. 1.

Digested PCR product of the PON1 (Q192R and L55M) gene polymorphism with HinfI restriction enzyme. Lane M: 100-bp marker ladder; lanes 1, 2: 144 bp (MM); lanes 3, 4: 122 bp (LL); lanes 5, 6: 144 bp and 122 bp (LM); lanes 7, 8: 111 bp (QQ); lanes 9–11: 111 bp and 77 bp (QR); lane 12: 77 bp (RR). PON1, paraoxonase 1.

Fig. 1.

Digested PCR product of the PON1 (Q192R and L55M) gene polymorphism with HinfI restriction enzyme. Lane M: 100-bp marker ladder; lanes 1, 2: 144 bp (MM); lanes 3, 4: 122 bp (LL); lanes 5, 6: 144 bp and 122 bp (LM); lanes 7, 8: 111 bp (QQ); lanes 9–11: 111 bp and 77 bp (QR); lane 12: 77 bp (RR). PON1, paraoxonase 1.

Close modal

For detection of the L55M gene polymorphism, we used the following primers: forward, 5′-GAG TGA TGT ATA GCC CCA GTT TC-3′; reverse, 5′-AGT CCA TTA GGC AGT ATC TCC G-3. We amplified the L55M gene polymorphism using similar PCR conditions in a 20-µL reaction mixture. The amplified PCR product of 144 bp was then digested with HinfI restriction enzyme at 37°C overnight. Figure 1 (left side) shows the digested product resolved on 3% agarose gel electrophoresis. The three genotypes were as follows: MM (144 bp), LM (144 and 122 bp), and LL (122 bp).

Statistical Analysis

Quantitative measures were expressed as mean ± standard deviation. One-way ANOVA was applied to compare the normally distributed variables among various genotypes. Categorical variables were presented as percentage of cases and analyzed with Pearson’s χ2 test. p values < 0.05 (two-tailed) were considered significant. Logistic regression analysis was done to associate various clinical parameters with genotypes. ORs were calculated with 95% CIs. All statistical analyses were carried out using the Statistical Package for the Social Sciences for Windows (SPSS), version 20.0 (IBM, Chicago, IL, USA).

Baseline Characteristics of the Study Population

Of the 872 participants included in this study, 412 were angiographically proven CAD patients and 460 were healthy subjects. Smoking and alcohol consumption were significantly higher in CAD subjects compared to controls (p < 0.001). Table 1 summarizes the anthropometric and clinical characteristics of the study subjects. The mean age of healthy controls and CAD patients was 56.21 ± 12.78 and 56.81 ± 10.55 years, respectively. Controls showed significantly higher BMI values compared to CAD patients (25.69 ± 4.64 vs. 24.51 ± 4.1, p < 0.001). Central obesity, revealed by higher waist circumference and waist to hip ratio, was significantly prominent in CAD patients compared to controls, even at normal BMI values recommended for Asian Indians (Table 1). Significantly higher values of body fat percentage as well as systolic and diastolic blood pressure were observed in CAD patients compared to controls (p < 0.001). More than 85% of CAD patients were regularly taking lipid-lowering drugs to maintain their adverse lipid profile, due to which CAD patients might show normal values of total cholesterol, LDL, VLDL, and total lipids. Contrariwise, significantly lower HDL cholesterol, total cholesterol/HDL, and LDL/HDL ratio were found in CAD patients compared to controls. Creatinine levels were significantly higher in CAD subjects than controls, indicating some nephrological complications. Although fasting glucose levels in both controls and CAD cases were normal, elevated fasting blood glucose values were observed in CAD subjects compared to healthy controls.

Table 1.

Anthropometric and clinical parameters in CAD patients and controls

 Anthropometric and clinical parameters in CAD patients and controls
 Anthropometric and clinical parameters in CAD patients and controls

Genotype Distribution in CAD Patients and Healthy Controls

The distribution of genotypes and allelic frequencies for the Q192R polymorphism of the PON1 gene are shown in Table 2. The frequencies of the QQ, QR, and RR genotypes of the PON1 gene Q192R polymorphism in CAD patients and controls were 37.6, 44.9, and 17.5% vs. 51.1, 38.3, and 10.7%, respectively. A significantly higher frequency of RR genotype was observed in CAD patients than in controls (p < 0.0001). Logistic regression analysis of the data revealed that the heterozygous genotype (QR) in the PON1 gene might be associated with an about 1.6 fold augmented risk of developing CAD in an Indian population (odds ratio [OR] = 1.59, 95% CI = 1.19–2.12, p < 0.0001), whereas the QR genotype might be associated with an about 2.2-fold augmented risk (OR = 2.23, 95% CI = 1.47–3.37, p < 0.0001). When the data were stratified according to the anthropometric and biochemical characteristics of all the subjects according to the genotypes QQ, QR, and RR of the PON1 Q192R polymorphism, no significant differences were observed between the genotype in CAD patients and that in controls (Table 3). Although an uneven distribution of some of the clinical parameters was observed in both cases and controls, all were nonsignificant.

Table 2.

Distribution of genotype and allele frequencies of PON1 (Q192R and L55M) polymorphisms in CAD patients and controls

 Distribution of genotype and allele frequencies of PON1 (Q192R and L55M) polymorphisms in CAD patients and controls
 Distribution of genotype and allele frequencies of PON1 (Q192R and L55M) polymorphisms in CAD patients and controls
Table 3.

Distribution of metabolic characteristics in controls and CAD patients according to the genotypes of the Q192R polymorphism in the PON1 gene

 Distribution of metabolic characteristics in controls and CAD patients according to the genotypes of the Q192R polymorphism in the PON1 gene
 Distribution of metabolic characteristics in controls and CAD patients according to the genotypes of the Q192R polymorphism in the PON1 gene

The distribution of genotype and allelic frequencies for the L55M polymorphism of the PON1 gene is illustrated in Table 2. The frequencies of the MM, LM, and LL genotypes of PON1 gene L55M polymorphism in controls versus CAD patients were 2.4, 31.5, and 66.1% versus 1.5, 25.7, and 72.8%, respectively. No significant differences were prominent in the distribution of L55M ge­notypes among the controls and CAD patients. The frequency of the L allele was higher than that of the M allele in both CAD patients and controls. Logistic regression data analysis did not establish a significant association of the LL genotype with CAD (OR = 1.81, 95% CI = 0.66–4.95, p = 0.326). Similar to the Q192R polymorphism, we stratified all anthropometric and biochemical characteristics of the CAD patients and controls according to the genotypes LL, LM, and MM of the PON1 L55M polymorphism, but did not observe significant differences among the various genotypes in CAD patients or controls (Table 4).

Table 4.

Distribution of metabolic characteristics in controls and CAD patients according to the genotypes of the L55M polymorphism in the PON1 gene

 Distribution of metabolic characteristics in controls and CAD patients according to the genotypes of the L55M polymorphism in the PON1 gene
 Distribution of metabolic characteristics in controls and CAD patients according to the genotypes of the L55M polymorphism in the PON1 gene

The escalation of incidence and prevalence of CVDs in India has become a major public health issue associated with social, personal, and economic burden for individuals, families, and state healthcare system [1]. A recent study established a higher risk of developing CVD among north Indians compared to inhabitants of other parts of India [13]. There are many risk factors which contribute to the present epidemic situation of CVDs in Indian populations. Various studies reported an association of environmental risk factors with the development of CVDs [14, 15]. In our previous study, we presented abdominal obesity, even at normal BMI, dyslipidemia, family history of CAD, and cigarette smoking as independent risk factors for CAD in north Indians [16]. It was evident from earlier studies that Asian Indians develop CAD in the most dynamic period of their life and at least a decade earlier than Caucasians [17].

Several studies have documented the role of SNPs in various genes in the escalating risk of CAD [18, 19]. PON1 is known to play important roles such as an antioxidant, anti-inflammatory, and antiatherosclerotic functions by preventing LDL oxidation [20]. Moreover, PON1 inhibits the accumulation of oxidized LDL and speeds up cholesterol efflux from macrophages [21, 22]. Some studies extensively studied the Q192R and L55M polymorphisms in PON1 in different populations and exhibited the pathogenesis of CVDs [23]. PON1 may be atheroprotective [24, 25], and genetic variations in the PON1 gene may affect its ability to protect against CVDs. The present study established an association of the RR genotype of the Q192R polymorphism with a two-fold amplified risk of CAD in a north Indian population. Also, the frequency of mutant allele (R) in the 192R-PON1 gene among CAD patients was comparable to that in previous studies conducted in Indian populations. Our results are in line with an earlier study done in a northwest Punjabi population where the QR and RR genotypes contributed to increased CAD development [26]. Many other studies documented a relationship of the Q192R polymorphism with an increased risk of CAD in Asian Indian populations [10, 27‒31], Caucasians [9, 32], and Japanese [33], but negative results have been reported in Korean [34], Spanish [35], Italian [36], British Caucasian [37, 38], and Polish [39] populations. Meta-analyses of various studies also confirmed an association of the 192R variant with the risk of CAD development [40, 41]. However, no significant association of the 192R genotype with CAD was reported in a Taiwanese population [42]. Interestingly, various Asian, Indian, European Caucasian, and Saudi Arabian populations revealed comparable frequency of the alleles [43], while some African black populations have a significantly higher frequency of the PON1 192Q allele [44]. These inconsistencies in the association of the Q192R genotype with high CAD risk may be due to sample size, differences in ethnicity, genotyping methods, as well as gene-gene and gene-environment interactions [43]. We did not find any significant association of the RR genotype in the PON1 gene with metabolic traits in CAD patients or controls. However, previous findings proved an association between serum triglyceride levels and RR genotype [45‒47]. It is not clearly ascertained by which mechanism PON1 polymorphisms affect the level of serum triglycerides.

The present study did not show a significant association of PON1 (L55M) polymorphism with the risk of CAD in Asian Indians. Our results agreed with earlier studies showing that PON1-55 independently has no consequence on CAD [10, 30, 40]. Contrariwise, a study proposed the protective effect of the M allele of PON1 against CAD [48]. The LL genotype was observed to be a genetic risk factor for carotid atherosclerosis [49]. Another study observed a higher frequency of the PON1 L allele in CAD patients, thus establishing a significant connection of PON1 L55M polymorphism with CAD [50]. Some of the studies that were accomplished to demonstrate the relationship between the PON1-L55M polymorphism and CAD showed conflicting results [51]. In an Austrian population, it was seen that the L55M polymorphism was linked with CAD [49], whereas studies in other populations showed inconsistent results [30]. Our study showed a negative correlation between the L55M locus and CAD risk, and only the M allele was concluded to be a risk allele.

The present study demonstrated a significant association of the Q192R polymorphism in the PON1 gene with an increased risk of CAD, whereas no significant association was observed between the L55M polymorphism and CAD. Furthermore, metabolic traits were unaffected by variants of the PON1 gene in Asian Indians.

This study was financially supported by University Grants Commission (UGC), New Delhi under a Maulana Azad National Fellowship awarded to S. Kaur.

Informed written consent was obtained from all participants. The study was approved by the institutional ethics committees of Panjab University, Chandigarh and Post Graduate Institute of Medical Education and Research, Chandigarh, India. All procedures were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

The authors have no conflicts of interest to declare.

Study design and implementation: R. Tewari and J.S. Bhatti. Data collection and analysis: S. Kaur, G.K. Bhatti, R. Vijayvergiya, P. Singh, and S.S. Mastana. Manuscript drafting: S. Kaur, G.K. Bhatti, and J.S. Bhatti. Manuscript revision: all authors.

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