Abstract
Background and Objective
Pulmonary embolism (PE) is caused by some genetic factors for more than half patients. Paraoxonase 1 (PON1) has significant anti‐oxidative and anti‐inflammatory effects. According to our knowledge, there is no study researching the relation between PON 1 gene polymorphisms and PE in the literature. Therefore, it is aimed to research possible impacts of PON 1 Q192R and L55M polymorphisms on PE, considering anti‐inflammatory and anti‐oxidative effects of PON 1 in Turkish population.
Methods
One hundred and five PE patients and one hundred and seventeen controls were enrolled in this study. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses for the PON1 gene Q192R and L55M polymorphisms.
Results
Any associations were not found between clinical and demographical characteristics of PE patients and the PON1 gene Q192R polymorphism; however, there were associations between surgery, chronic renal failure, and cerebrovascular disease on the history of patients and L55M polymorphism (P = .013, P = .037, and P = .031, respectively). Genotype and allele frequencies did not show any significant differences between patients and controls according to PON1 gene Q192R and L55M polymorphisms (P > .05).
Conclusion
The results of this study suggest that there is no correlation between PE and PON 1 gene Q192R and L55M polymorphisms in the Turkish population from the Central Black Sea region. Besides, whole genotypes and alleles of Q192R and L55M are not risk factors for patients with PE in this population.
Keywords: L55M, polymorphism, PON1, pulmonary embolism, Q192R
1. INTRODUCTION
Pulmonary embolism (PE), one of the clinical manifestations of venous thromboembolism (VTE), is a multifactorial cardiovascular disease with high mortality rate.1 It is caused by genetic factors account for up to 60%.2 Most important genetic factor is deficiencies of natural anticoagulants such as protein C, S, and antithrombin.3 However, the routine screening tests on these factors are not used due to rarity in population.
It is very important to diagnose PE early for reducing morbidity and mortality rates. The clinical presentation of PE can be very different from dyspnea to syncope and it can sometimes give no symptoms according to many autopsy studies.4 Also, it is hard to decide clinically which patient will be investigated by thorax computed tomography pulmonary angiography (CTPA) despite some clinical scoring systems as Wells Score because of harmless effects of CTPA.
In the literature, there are many studies aimed finding possible genetic factors for PE.1, 5 Thus, early diagnose and treatment can be obtained for patients with PE. Also, researching genetic predispositions can supply understanding of PE pathogenesis and finding better diagnose and treatment choices.6
It is known that the pathogenesis of PE is mainly parallel with formation of thrombus. The underlying mechanisms include thrombosis and homeostasis, hypoxia, abnormal lipid metabolism, cell‐matrix adhesion, inflammation, and oxidative stress according to the literature.3, 7
Paraoxonase 1 (PON1) is a member of paraoxonase (PON) enzyme family with PON 2 and PON 3. It is the most studied PON especially on cardiovascular disease, stroke, inflammation, and oxidative stress.8 PON 1, a 45‐kDa glycoprotein, is synthesized in the liver and transfers to tissues via high‐density lipoproteins (HDL).9 There are two genetic polymorphisms of PON 1 as glutamine or arginine at position 192 (Q/R192) and methionine or leucine at position 55 (L55M).10
It is suggested that PON 1 has significant anti‐oxidative and anti‐inflammatory effects owing to activations of lactonase, peroxidase, and esterase.8 It is stated that the anti‐inflammatory effects lead to protection of mitochondria from endoplasmic reticulum stress and dysfunction.11
According to our knowledge, there is no study researching the relation between PON 1 gene polymorphisms and pulmonary embolism in the literature. Therefore, it is aimed to research possible impacts of PON 1 Q192R and L55M polymorphisms in PE, considering anti‐inflammatory and anti‐oxidative effects of PON 1, in Turkish population.
2. MATERIAL AND METHODS
2.1. Subjects
The study group consisted of 105 unrelated patients with PE (56 men and 49 women; mean age: 58.62 ± 10.760 standard deviation [SD] years) and 117 (69 men and 48 women; mean age: 56,21 ± 7.684 SD years) unrelated healthy controls. PE patients were recruited consecutively and prospectively from those whom were treated and followed up in the Emergency Medicine Department of Gaziosmanpasa University Research Hospital, Tokat, Turkey. The diagnosis of PE was confirmed with thorax computed tomography pulmonary angiography (CTPA) by experienced emergency physicians and also radiologists. All control subjects were confirmed free from VTE, coronary artery disease (CAD), malignancy, pregnancy, previous surgery, and stroke. Controls with family history of any evidence for thrombosis and women controls with prior history of abortions or other obstetric complications were excluded from the study. All participants, patients, and healthy controls were of Turkish origin, from the inner Central Black Sea region of Turkey. The healthy controls matched for age and gender with PE patients. The study protocol was approved by the Local Ethics Committee of Gaziosmanpasa University, Faculty of Medicine, and written informed consent was obtained from the study participants.
2.2. Genotyping
Genomic DNA was extracted from whole venous blood samples using a commercial DNA isolation kit (Sigma‐Aldrich, Taufkirchen, Germany). The PON1 gene Q192R and L55M polymorphisms were analyzed by polymerase chain reaction (PCR)‐based restriction fragment length polymorphism (RFLP) assay. The PON1 Q192R polymorphism was analyzed by using forward F: 5′‐TAT TGT TGC TGT GGG ACC TGA G‐3′ and reverse R: 5′‐ CAC GCT AAA CCC AAA TAC ATC TC‐3′ primers. After amplification, the 99‐bp PCR product was digested with BspPI (AlwI). The digestion products were separated on 3% agarose gels, and fragments stained with the ethidium bromide were photographed on an ultraviolet transilluminator. The Q allele remained intact, but the R allele was digested into 66‐ and 33‐bp fragments. For PON1 L55M polymorphism, amplification was carried out using F: 5′‐GAA GAG TGA TGT ATA GCC CCA G‐3′ and R: 5′‐TTT AAT CCA GAG CTA ATG AAA GCC‐3′ primers. The amplified 170‐bp product was digested with NlaIII. The L allele remained intact, but the M allele was digested into 126‐ and 44‐bp fragments.
2.3. Statistical analysis
Statistical analysis was performed using the Statistical Package for the Social Sciences (IBM SPSS Statistics, version 20) and OpenEpi Info software package version 3.01 (www.openepi.com). The Chi‐square (χ2) test was used to evaluate the Hardy‐Weinberg equilibrium (HWE) for the distribution of the genotypes of the patients and the controls. The relationships between PON1 gene Q192R and L55M polymorphisms and the clinical and demographical characteristics of patients were analyzed by using χ2 test or analysis of variance (ANOVA) statistics. χ2 test and Fisher's exact test were used to compare categorical variables appropriately. Odds ratio (OR) and 95% confidence interval (CI) were used for the assessment of risk factors. All P values were 2‐tailed and P values <.05 were considered as significant.
3. RESULTS
Clinical and demographical characteristics of PE patients (gender, age, WBC, RDW, HTC, surgery, smoking, comorbitidy, ECG abnormalities, thorax CT) stratified according to PON1 gene polymorphisms were shown in Table 1. Any associations were not found between clinical and demographical characteristics of PE patients and the PON1 gene Q192R polymorphism; however, there were associations between surgery, chronic renal failure, and cerebrovascular disease history of patients and L55M polymorphism (P = .013, P = .037 and P = .031, respectively) (Table 1). Although the number of patients with surgery, chronic renal failure, and cerebrovascular disease was small, in these patients, the frequencies of MM genotype of L55M polymorphism were significantly higher than the patients without these complications.
Table 1.
Clinical and demographical characteristics of PE patients stratified according to PON1gene polymorphisms
| Characteristics | Total n = 105 | Q192R | L55M | ||||||
|---|---|---|---|---|---|---|---|---|---|
| QQ n = 63 | QR n = 37 | RR n = 5 | P value | LL n = 49 | LM n = 43 | MM n = 13 | P value | ||
| Gender, male/female, n (%) | 56/49 (53.3/46.7) | 35/28 (55.6/44.4) | 20/17 (54.16/45.9) | 1/4 (20.0/80.0) | .307 | 28/21 (57.1/42.9) | 21/22 (48.8/51.2) | 7/6 (53.8/46.2) | .727 |
| Age, years | 58.62 ± 10.760 | 58.29 ± 10.525 | 59.70 ± 11.551 | 54.80 ± 7.855 | .591 | 60.51 ± 9.768 | 55.58 ± 11.085 | 61.54 ± 9.324 | .051 |
| WBC, per mm3 | 9876.3 ± 2723.5 | 9633.4 ± 2371.4 | 10137.9 ± 3277.9 | 10860.0 ± 2308.2 | .488 | 9802.4 ± 2669.2 | 9961.5 ± 2842.8 | 9875.0 ± 2743.3 | .964 |
| RDW, % | 16.44 ± 2.541 | 16.32 ± 2.600 | 16.85 ± 2.454 | 14.84 ± 2.025 | .218 | 16.32 ± 2.722 | 16.64 ± 2.361 | 16.26 ± 2.565 | .814 |
| HTC, % | 38.49 ± 4.296 | 38.34 ± 3.976 | 38.99 ± 4.724 | 36.66 ± 5.046 | .485 | 38.95 ± 4.782 | 37.94 ± 3.732 | 38.62 ± 4.209 | .545 |
| Surgery, n (%) | 3 (2.9) | 3 (100) | 0 | 0 | .357 | 1 (33.3) | 0 | 2 (66.7) | .013 |
| Smoking, n (%) | 59 (56.2) | 34 (57.6) | 14 (39.0) | 2 (3.4) | .550 | 28 (47.5) | 22 (37.3) | 9 (15.3) | .507 |
| Comorbitidy, n (%) | |||||||||
| Coronary artery disease | 38 (36.2) | 25 (65.8) | 11 (28.9) | 2 (5.3) | .597 | 19 (50.0) | 12 (31.6) | 7 (18.4) | .205 |
| Diabetes mellitus | 37 (35.2) | 24 (64.9) | 11 (29.7) | 2 (5.4) | .681 | 16 (43.2) | 13 (35.1) | 8 (21.6) | .102 |
| Hypertension | 56 (53.3) | 35 (62.5) | 19 (33.9) | 2 (3.6) | .763 | 28 (50.0) | 21 (37.5) | 7 (12.5) | .727 |
| Chronic renal failure | 13 (12.4) | 9 (69.2) | 4 (30.8) | 0 | .606 | 7 (53.8) | 2 (15.4) | 4 (30.8) | .037 |
| Cerebrovascular disease | 7 (6.7) | 4 (57.1) | 3 (42.9) | 0 | .782 | 3 (42.9) | 1 (14.3) | 3 (42.9) | .031 |
| Malignancy | 9 (8.6) | 6 (66.7) | 3 (33.3) | 0 | .759 | 5 (55.6) | 2 (22.2) | 2 (22.2) | .411 |
| ECG abnormalities, n (%) | |||||||||
| RBBB | 17 (16.2) | 7 (41.2) | 10 (58.8) | 0 | .068 | 7 (41.2) | 6 (35.3) | 4 (23.5) | .313 |
| Sinus tachycardia | 37 (35.2) | 19 (51.4) | 17 (45.9) | 1 (2.7) | .214 | 18 (48.6) | 11 (29.7) | 8 (21.6) | .057 |
| S1Q3T3 | 28 (26.7) | 20 (71.4) | 7 (25.0) | 1 (3.6) | .353 | 10 (35.7) | 14 (50.0) | 4 (14.3) | .395 |
| AF | 27 (25.7) | 20 (74.1) | 6 (22.2) | 1 (3.7) | .220 | 11 (40.7) | 12 (44.4) | 4 (14.8) | .757 |
| Ischemia | 15 (14.3) | 9 (60.0) | 5 (33.3) | 1 (6.7) | .927 | 8 (53.3) | 5 (33.3) | 2 (13.3) | .808 |
| Thorax CT | |||||||||
| Right main bronchus | 18 (18.0) | 13 (72.2) | 4 (22.2) | 1 (5.6) | .327 | 7 (38.9) | 11 (61.1) | 0 | .188 |
| Right distal | 26 (26.0) | 14 (53.8) | 11 (42.3) | 1 (3.8) | 9 (34.6) | 11 (42.3) | 6 (12.9) | ||
| Left main bronchus | 7 (7.0) | 5 (71.4) | 2 (28.6) | 0 | 5 (71.4) | 2 (28.6) | 0 | ||
| Left distal | 4 (4.0) | 3 (75.0) | 1 (25.0) | 0 | 1 (25.0) | 3 (75.0) | 0 | ||
| Bilateral main bronchus | 41 (41.0) | 26 (63.4) | 12 (29.3) | 3 (7.3) | 22 (53.7) | 13 (31.7) | 6 (14.6) | ||
| Bilateral distal | 4 (4.0) | 0 | 4 (100) | 0 | 2 (50.0) | 2 (50.0) | 0 | ||
AF, Atrial fibrillation; CT, Computed tomography; ECG, Electrocardiography; HTC, Hematocrit; RBBB, Right bundle‐branch block; PE, Pulmonary embolism; PON1, paraoxonase 1; RDW, Red blood cell distribution width; WBC, White blood cell.
Data were analyzed by analysis of variance or χ2 test. Mean plus standard deviation values are presented for age, WBC, RDW, HTC.
The results that are statistically significant are typed in bold.
Allelic and genotypic distributions of the PON1gene Q192R and L55M polymorphisms were shown in Table 2. Genotype and allele frequencies did not show any significant differences between patients and controls according to PON1 gene Q192R and L55M polymorphisms (P > .05) (Table 2).
Table 2.
Genotype and allele frequencies of PON1 gene polymorphisms in patient and control groups
| Polymorphism | PE patients n = 105 (%) | Healthy controls n = 117 (%) | P | OR (CI 95%) |
|---|---|---|---|---|
| Q192R | ||||
| Genotypes | ||||
| 63 (60.0) | 63 (53.8) | .648 | ||
| QR | 37 (35.2) | 48 (41.0) | ||
| RR | 5 (4.8) | 6 (5.1) | ||
| QQ: QR + RR | 63 (60.0): 42 (40.0) | 63 (53.8): 54 (46.1) | .355 | 0.78 (0.45‐1.33) |
| QQ + QR: RR | 100 (95.2): 5 (4.8) | 111 (94.8): 6 (5.1) | .900 | 0.92 (0.25‐3.26) |
| Alleles | ||||
| Q | 163 (77.6) | 174 (74.4) | .422 | 0.83 (0.53‐1.29) |
| R | 47 (22.4) | 60 (25.6) | ||
| L55M | ||||
| Genotypes | ||||
| LL | 49 (46.7) | 49 (41.9) | .663 | |
| LM | 43 (41.0) | 55 (47.0) | ||
| MM | 13 (12.4) | 13 (11.1) | ||
| LL: LM + MM | 49 (46.7): 56 (53.4) | 49 (41.9): 68 (58.1) | .473 | 0.82 (0.48‐1.40) |
| LL + LM: MM | 92 (87.7): 13 (12.4) | 104 (87.9): 13 (11.1) | .769 | 1.13 (0.49‐2.60) |
| Alleles | ||||
| L | 141 (67.1) | 153 (65.4) | .695 | 0.92 (0.62‐1.37) |
| M | 69 (32.9) | 81 (34.6) | ||
PE, Pulmonary embolism; PON1, paraoxonase 1.
Data were analyzed by χ2.
We also examined the risk associated with inheriting the combined genotypes for the two polymorphisms (Table 3). Any statistically significant differences were not observed between patients and controls according to combined genotypes. The observed and expected frequencies of both the PON1 gene polymorphism were in HWE in control and patient groups.
Table 3.
Comparative analysis of combined genotypes of PE patients and controls
| Genotypes | Patient (n = 105) | Control (n = 117) | P | ||
|---|---|---|---|---|---|
| n | % | n | % | ||
| Q192R‐L55M | |||||
| QQ‐LL | 24 | 22.9 | 19 | 16.2 | .213 |
| QR‐LL | 22 | 21.0 | 25 | 21.4 | .939 |
| RR‐LL | 3 | 2.9 | 5 | 4.3 | .844 |
| QQ‐LM | 29 | 27.6 | 36 | 30.8 | .606 |
| QR‐LM | 12 | 11.4 | 18 | 15.4 | .389 |
| RR‐LM | 2 | 1.9 | 1 | 0.9 | .918 |
| QQ‐MM | 10 | 9.5 | 8 | 6.8 | .464 |
| QR‐MM | 3 | 2.9 | 5 | 4.3 | .844 |
PE, Pulmonary embolism.
Data were analyzed by χ2 or fisher's exact test.
4. DISCUSSION
In the current study, it was found that there was no correlation between PE and PON 1 gene Q192R and L55M polymorphisms in the Turkish population from the Central Black Sea region.
Besides, it is suggested that whole genotypes and alleles of Q192R and L55M are not risk factors for patients with PE in our population. In the study of Aykal et al12, the increased activity of oxidative stress was shown in patients with VTE. They evaluated PON 1 activity with some other parameters and suggested that PON 1 levels were significantly different in patients but not reliable using for diagnosis of VTE. It supports our results. As mentioned previously, it is the first study that evaluates possible relationship between PE and both PON 1 polymorphisms. So, there is no chance to compare our results with other populations. In the literature, most of the studies about PON 1 polymorphisms are interested in CAD.13, 14, 15 Also, there are studies on stroke, migraine, dementia, and familiar Mediterranean fever etc.10, 16, 17, 18
There are many studies that present the protective effects of PON 1 on CAD. In a study of Oliveira, PON 1 L55M polymorphism suggested as an independent genetic marker and has protection against CAD.19 The exact mechanism of these protective effects is not clear yet. The correlation between PON 1 polymorphisms and CAD is explained with good resistance to oxidative stress and strong anti‐inflammatory features.15 Besides, it was suggested that PON 1 has protective effects on HDL functions and it could be admitted as an etiologic factor in the development of CAD.20 Additionally, the antioxidative effects of HDL explained via PON 1 on low‐density lipoprotein cholesterol (LDL‐C). It was suggested that PON 1 retards or reverses atherosclerosis via the prevention of LDL‐C oxidation or metabolism of oxidized LDL‐C.21 The possible mechanisms according to studies are collected in main titles as prevention of LDL and cell membrane oxidation, prevention of LDL glycation, prevention of diabetes development, reduction in macrophage oxidative stress, promotion of macrophage RCT, normalization of endothelial function, metabolism of homocysteine thiolactones, prevention of LCAT oxidative inactivation, disposal of toxic apoptosis products, prevention of apoptosis, and reduction in monocyte macrophage inflammatory response in a review of Shekhanawar.20 Inversely, in the current study, no correlation was found between the patients with a history of CAD and PON 1 polymorphisms. However, there was a relation between patients with history of cerebrovascular disease, chronic renal failure, and surgery with PON1 L55M polymorphism. According to genotype analysis, MM genotype of L55M polymorphism was found to be related to the patients with these complications. Inversely, Shenhar‐Tsarfat et al22 found that PON1 QQ192 and MM55 genotypes demonstrated lower PON acitivity on stroke patients. They suggested that PON1 activity as a potential anti‐atherogenic element proposes involvement of cholinesterase activities in its effects. Besides, it is known that acetylcholinesterase can prevent the accumulation of LDL like PON 1 by lipid preoxidation. Acetylcholinesterase can play a substitute role for PON 1 in the protection of oxidation of LDL.23 Therefore, the genetic evaluation of both PON1 and acetylcholinesterase was suggested for risk stratification of atherosclerosis.22 In the present study, the current data about patient's history were not very detailed, these mentioned relations did not find significant.
5. CONCLUSION
It is known that PE is a multifactorial disease, and there are many acquired factors next to genetics. However, researching possible other genetic risk factors next to known ones is useful on this issue for early diagnosis and risk assessment. As a result of this research, it is suggested that there is no relationship between both PON 1 polymorphisms and PE in the Turkish population.
Basol N, Karakus N, Savas AY, et al. The evaluation of two genetic polymorphisms of paraoxonase 1 in patients with pulmonary embolism. J Clin Lab Anal. 2018;32:e22455 10.1002/jcla.22455
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