|Year : 2014 | Volume
| Issue : 4 | Page : 816-824
Association of lipoprotein lipase gene polymorphisms with lipid profiles in atherosclerotic coronary artery disease
Ibrahim Elmadbouh1, Maathir El-Shafiey1, Ayman A Al-Hamid1, Ahmad-Ashraf Reda2, Safaa Tayel1, Ghada MK Gaballah MBBCh, MSc 1, Tarek Abd-Elhakim1
1 Department of Biochemistry, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Cardiology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
|Date of Submission||18-Aug-2013|
|Date of Acceptance||08-Oct-2013|
|Date of Web Publication||22-Jan-2015|
Ghada MK Gaballah
Department of Biochemistry, Faculty of Medicine, Menoufia University, Yassin Abdel-Ghaffar St., Shebin El-Kom, Menoufia
Source of Support: None, Conflict of Interest: None
Coronary artery disease (CAD) is a complex disease with well-documented genetic and environmental components. Lipoprotein lipase (LPL) is considered a potential target as the variations in the LPL gene have been implicated in a number of pathophysiologic conditions associated with CAD.
The aims of this study were to determine the relationship between LPL gene polymorphisms (PvuII and S447X) and lipid profiles in patients with CAD, and to determine its role in the prediction of the severity of coronary atherosclerosis.
Patients and methods
A total of 100 individuals were classified by coronary angiography: 80 patients with CAD and 20 controls (normal coronary angiography). Clinical data, carotid sonography, blood lipid profiles, and LPL genotyping for PvuII and S447X using PCR-RFLP were assessed.
Plasma lipid profiles and carotid intima-media thickness were significantly increased in CAD patients compared with controls. LPL polymorphisms were distributed for PvuII genotypes and alleles in CAD patients versus controls as follows: CC (2.5 vs. 15%), CT (76.25 vs. 75%), and TT (21.25 vs. 10.0%) genotypes; T (59.4 vs. 47.5%) and C (40.6 vs. 52.5%) alleles. LPL S447X genotypes and alleles showed no significant difference between CAD and controls. CT genotypes of LPL PvuII were the highest in number and percentage compared with CC and TT among the CAD patients (P<0.05). However, there was a significant decrease in the systolic and diastolic velocity in CC versus CG genotypes of S447X among CAD patients (P < 0.05). Other carotid ultrasound, lipid profiles, or coronary angiography parameters were not significant in both genotypes of LPL among CAD patients.
Atherosclerotic ischemic patients showed a higher association in the number and percent of CT genotypes of PvuII LPL that may be an important diagnostic risk biomarker and may implicate a therapeutic intervention in CAD.
Keywords: Coronary artery disease, lipid profile, lipoprotein lipase polymorphism, PvuII, S447X
|How to cite this article:|
Elmadbouh I, El-Shafiey M, Al-Hamid AA, Reda AA, Tayel S, Gaballah GM, Abd-Elhakim T. Association of lipoprotein lipase gene polymorphisms with lipid profiles in atherosclerotic coronary artery disease. Menoufia Med J 2014;27:816-24
|How to cite this URL:|
Elmadbouh I, El-Shafiey M, Al-Hamid AA, Reda AA, Tayel S, Gaballah GM, Abd-Elhakim T. Association of lipoprotein lipase gene polymorphisms with lipid profiles in atherosclerotic coronary artery disease. Menoufia Med J [serial online] 2014 [cited 2020 Feb 26];27:816-24. Available from: http://www.mmj.eg.net/text.asp?2014/27/4/816/149801
| Introduction|| |
Coronary artery disease (CAD) is a leading cause of death and premature disability. CAD is a complex disorder resulting from many risk factors. Individuals with a genetic predisposition to atherosclerosis have a high risk of developing CAD, especially at an early age .
Hyperlipidemia is a major risk factor for CAD. Lipoprotein lipase (LPL) plays a pivotal role in lipoprotein metabolism . LPL is produced by many tissues, including adipose tissue, cardiac muscle, and skeletal muscle. LPL plays a key role in the metabolism of the triglyceride-rich lipoproteins by catalyzing the hydrolysis of the triacylglycerol component of circulating chylomicrons and very low-density lipoproteins (LDLs) into free fatty acids, monoglycerides, or diglycerides .
The LPL gene is located on chromosome 8p22, spans 30 kb containing 10 exons, and 100 naturally occurring mutations have been described in this gene ,.
Any disturbance in the LPL level or activity may hence alter the lipid metabolism. Metabolic and genetic factors may influence the LPL level and functions. Abnormalities in the LPL function are associated with clinical conditions including insulin resistance, obesity, hyperlipidemia, and CAD .
Several mutations of the LPL gene have been identified so far, and 20% occur in the noncoding regions. Multiple studies have associated the variants in the LPL gene with plasma lipid concentrations and clinical conditions in different populations .
The exact mechanism by which a mutation in LPL results in remnant accumulation is not clear. Mutations in LPL result in increased triglyceride levels that promote atherosclerosis by their association with small dense LDL particles, and also by influence on homeostasis or by promoting postprandial triglyceride-rich lipoproteins .
The PvuII polymorphism occurs as a result of C to T transition in the restrection site of the LPL gene sixth intron at nucleotide 497. This mutation results in the creation of a restriction site for the PvuII enzyme .
The S447X polymorphism is a consequence of C to G transversion at nucleotide 1595 in exon 9, which converts the serine 447 codon (TCA) into a premature termination codon (TGA). This mutation results in the premature truncation of LPL by two amino acids. This C-G mutation creates a MnlI recognition site .
The present study was carried out to determine the relationship of LPL polymorphisms (PvuII, Ser447X) with lipid profiles in patients with CAD defined by coronary angiography and its role in the prediction of the severity of carotid and coronary atherosclerosis.
| Participants and methods|| |
All the patients were consecutively referred to the coronary ICU of the Department of Cardiology in the Menoufia University Hospital and the Shebin El-Kom Teaching Hospital because of an acute myocardial infarction and who underwent coronary angiography in this cross-sectional study.
This study included 100 individuals: 80 patients with CAD and 20 individuals who also underwent angiography procedures and had normal coronaries (with acute chest pain other than coronary diseases) as controls.
Full assessment of history, general and heart clinical examination, carotid ultrasound, and blood samples were performed for every patient. Written informed consent was obtained from each participant before inclusion in the study. Ethical approval for this investigation was obtained from the Research Ethics Committee, Faculty of Medicine, Menoufia University. The exclusion criteria for enrollment into the study included familial hypercholesterolemia, cancer, renal disease, and any other chronic illnesses.
Carotid ultrasound examination
Carotid artery examination was performed using an ECG-triggered echo-Doppler Acuson 128 XP 10C equipped with a 7.5-MHz linear transducer. Data collected from the right common carotid artery were used for statistical analysis. Parameters such as carotid intima-media thickness (CIMT), carotid systolic and diastolic diameters, and velocities were measured for 41 patients and all control participants.
Determination of coronary artery disease severity
According to the results of the coronary angiography, the number and percentage of stenosed coronary vessels were classified. The characteristics of diseased vessels were recorded, including the severity of the most serious stenosis (<75 or ≥75%) and the number of diseased vessels (one, two, or three vessels) including the left main coronary artery (main trunk), circumflex artery, right coronary artery, and left anterior descending artery.
Lipid profiles analysis
Venous blood sample (5 ml) from a 12 h fasting patient was taken into a plain tube, left to clot, centrifuged, and the serum obtained was used for the determination of serum total cholesterol (TC), total triglyceride (TG), and high-density lipoprotein cholesterol (HDL-c) levels. Lipid profiles were measured using the standard enzymatic colorimetric kits (Spinreact, Spain). The serum LDL-cholesterol (LDL-c) was calculated using the following formula: LDL-c = TC-(TG/5+HDL-c) as the TG level did not exceed 400 mg/dl .
Venous blood sample (5 ml) was drained slowly into an EDTA tube for the isolation of peripheral blood mononuclear cells using Lymphoflot solution (Biotest AG, Germany). Briefly, patients' blood was added to an equal volume of saline and mixed carefully. This diluted blood sample was carefully layered onto the Lymphoflot solution (sodium diatrizoate 11.00% and Ficoll 6.35% w/v) so as not to mix the Lymphoflot solution and the diluted blood sample.
The mixture was centrifuged at 1500 rpm for 25 min at 20C. The upper plasma layer was drawn off, leaving the lymphocyte layer undisturbed at the interface. The lymphocyte layer at the interface was transferred to a clean centrifuge tube containing 4 ml of balanced salt solution, mixed gently, and centrifuged at 1500 rpm for 10 min at 4C. The supernatant was discarded. A volume of 1 ml of PBS was added to the lymphocytes' pellet, drawn in and out of a clean pipette, and transferred into a sterile cryotube and stored at 80C for further DNA extraction and purification. Genomic DNA was extracted from peripheral blood mononuclear cells using QIAamp DNA Blood Mini Kits (Qiagen, Germany), to yield pure DNA, and stored at 20C for direct amplification.
LPL polymorphisms were detected by the PCR using a Perkin Elmer Thermal Cycler 2400 (Perkin Elmer, USA) and then using restriction enzymes for genotyping. The DNA was amplified using the following primers (Midland, Texas, USA): forward primer for S447X: F5΄-TACACTAGCAATGTCTAGCTGAAGGCAGA-3΄. Reverse primer: R5΄-TCAGCTTTAGCCCAGAATGCTCACCc-3΄. The LPL S447X band (488 bp) was generated using the following protocol: denaturation for 5 min at 94C, annealing for 1 min at 62C, extension for 2 min at 72C, 35 cycles. For PvuII, the following primers were used (Midland, Texas, USA): Forward primer: F5΄-TACA CTAGCAATGTCTAGCTGAAGGCAGA-3΄. Reverse primer: R5΄-TCAGCTTTAGCCCAGAA TGCTCACCc-3΄. The LPL PvuII band (430 bp) was generated using the following protocol: denaturation for 3 min at 98C, annealing for 1 min at 60C, extension for 1 min at 72C, 30 cycles.
LPL S447X genotyping was performed by RFLP. The PCR bands (≈488 bp) were digested by MnlI restriction enzymes (500 U) (New England Biolabs, UK) in 20 ml of working solution containing 1 ml 10 Χ NEB 4 buffer, 0.1 ml 100 Χ BSA, 0.5 ml MnlI, 8.4 ml distilled water, and 10 ml PCR product and incubated for at least 12 h at 37C. The presence of S447X polymorphism bands was detected in 2% agarose gel electrophoresis visualized under ultraviolet light; S447X alleles appeared: the expected product for heterozygous (+,−) 290, 250, and 200 bp, for wild homozygous (−,−) 290 and 200 bp, and for mutant homozygous (+,+) 250 and 200 bp.
LPL PvuII genotyping was performed by RFLP. The PCR band (430 bp) was digested by the PvuII restriction enzyme (5000 U) (New England, Biolabs) and a working solution was prepared and incubated overnight at 37C [working solution (20 ml): 1 ml buffer, 2 ml PvuII, 7 ml distilled water, and 10 ml PCR product]. The expected product is 320, 110 bp for the homozygous mutated genotype (+,+) and 430, 320, and 110 bp for heterozygous (+,−), whereas the wild genotype (−,−) is 430 bp.
Variables are presented as numbers, percentages, or mean SD as indicated. Genotypes and allele frequencies of LPL (S447X, PvuII) were compared between CAD patients and controls using the c2 -test or Fisher's exact test. Student's t-test and analysis of variance were used to compare the means for parametric variables. All odds ratios were calculated by logistic regression. A P value of less than 0.05 was considered to be statistically significant. Results were analyzed using the statistical software package SPSS (version 11; SPSS Inc., Chicago, Illinois, USA).
| Results|| |
The present study showed significantly higher age, male, smoking, hypertension, TC, TG, LDL-c, while lower HDL-c in CAD patients versus controls [Table 1]. Also, there was a significant difference between CAD patients and controls with regard to ultrasound CIMT (P < 0.001), diastolic diameter (P = 0.001), systolic velocity (P<0.05), and plaque number (P < 0.001), whereas carotid systolic diameter (P > 0.05) and diastolic velocity (P > 0.05) were not significant between the two groups [Table 1].
|Table 1: Sociodemographics, carotid parameters, and lipid profiles in all patients|
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LPL gene polymorphism frequencies for the PvuII variant were as follows: CC was 15% in controls and 2.5% in CAD patients, CT was 75% in controls and 76.25% in CAD patients, and TT occurred in 10% of controls and 21.25% of patients. The T allele was found in 59.4% of patients and 47.5 of controls and the C allele was found in 40.6% of patients and 52.5% of controls [Table 2] and [Figure 1]a and b, whereas the frequency for LPL gene polymorphisms S447X in the control groups was as follows: 35.0% CC, 65% CG, and 0% GG, whereas in CAD patients, these were 40% CC, 60% CG, and 0% GG [Table 2] and [Figure 1]c and d.
|Figure 1: Detection of lipoprotein lipase (LPL) gene polymorphism: (a) LPL PvuII product: PvuII expected product length 430 bp. (b) PCR-REFLP analysis using LPL PvuII restriction enzyme analysis by 2% agarose gel electrophoresis. Lane 1: ladder (50 bp). Lanes 2, 3, 5, 6, 9, and 13: heterozygous (+,−) 430, 320, and 110 bp. Lanes 4, 7, 8, and 11: wild homozygous form has no restriction (−,−) 430 bp. Lanes 10 and 12 homozygous mutant form (+,+) 320 and 110 bp. (c) LPL S447X product: the expected length product is ∼488 bp. (d) LPL S447X RFLP product: 2% agarose gel electrophoresis cutting with MnlI. Lane 1: DNA molecular ladder (50 bp). Lane 2: wild homozygous 200 and 290 bp. Lane 3: heterozygosity 290, 250 and 200 bp.|
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|Table 2: Statistical comparison of lipoprotein lipase genotypes and alleles among the coronary artery disease and control groups|
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The current study showed that there was a significant difference between the control and the CAD group in the LPL gene polymorphism, PvuII variant, with a higher number and percent for the CT genotype. [Table 2] shows that the CT genotype increased the risk of CAD significantly by 4.6 folds and the T allele increased the risk of the disease nonsignificantly by 1.62 fold, whereas the CG genotype of the S447X variant and G alleles decreased the risk of CAD nonsignificantly by about 0.8 fold [Table 2].
There was no significant difference between genotypes of the LPL polymorphism in age, sex, smoking, and hypertension, whereas there was a significant increase in the number and percent of diabetes mellitus cases.
Echocardiographic data of CAD patients showed that LPL polymorphisms, PvuII genotypes and alleles, had nonsignificantly higher of CIMT. Also, there was no significant difference between different alleles in carotid diameter and velocity in systolic and diastolic phases, and number of carotid plaques [Table 3] and [Table 4]. However, there was a significant decrease in the systolic and diastolic velocity in the CC genotype compared with the CG genotype of the S447X variant in CAD patients [Table 3] and [Table 4].
|Table 3: Statistical comparison of carotid ultrasound data of different lipoprotein lipase polymorphisms PvuII and S447X groups in coronary artery disease patients|
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|Table 4: Number of carotid artery plaques in lipoprotein lipase PvuII and S447X genotype groups in coronary artery disease patients|
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In LPL polymorphisms PvuII, there was a nonsignificant increase in TC, TG, and LDL-c in the CC genotype group when compared with the CT and TT groups among CAD patients and controls, Also, the CT group showed a nonsignificant increase in HDL-c when compared with the other two groups in CAD patients and controls [Table 5]. Also, there was no significant difference in TC, TG, HDL-c, and LDL-c in CG and CC genotypes of the S447X variant in CAD patients and controls [Table 5].
|Table 3: Statistical comparison of carotid ultrasound data of different lipoprotein lipase polymorphisms and groups in coronary artery disease patients|
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The severity of CAD was analyzed, but there was no significant difference between different genotypes or alleles of the two variants of LPL polymorphisms, PvuII and S447X, in the number of stenosed vessels and the percent of stenosis or number of plaques. This table showed that there was a nonsignificant difference between CC and CT genotyping and also between CC and TT genotyping of CAD patients in stenosis of left anterior descending artery, circumflex artery, and right coronary artery. Also, it showed that the risk of single-vessel stenosis increased nonsignificantly to 2.59 folds when comparing the CC genotype group with the CT genotype group, whereas the TT and CT genotype groups tended to have multiple-vessel stenosis than the CC genotype group with an increase in risk by about 1.13 folds when TT was compared with CC [Table 6]. Also, there was no significant difference between patients with CC and CG genotyping in the number and percent of stenosed vessels. Patients with CC genotyping showed nonsignificantly higher number and percent of multiple stenosed vessel when compared with patients with CG genotyping and a nonsignificant increase in risk by 1.4 fold. Also, patients with CC genotyping showed nonsignificantly higher percent of stenosis (≥75%) when compared with patients with CG genotyping and a nonsignificant increase in risk by 2.88 folds [Table 6].
|Table 6: Different risk classifications using coronary angiography in different lipoprotein lipase PvuII and S447X genotypes groups among coronary artery disease patients|
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| Discussion|| |
The atherosclerotic process is believed to be triggered by initial damage to the arterial endothelial cells, which increases their adhesive properties and secretion of chemotactic factors, thereby causing infiltration of T lymphocytes and monocytes to the site of damage. Monocytes differentiate into macrophages, import lipoproteins, and transform into so-called foam cells, which form the fatty streak observed in early lesions . Given the importance of LPL in lipoprotein metabolism and transport, it is not surprising that the enzyme has been found to play a critical role in the pathogenesis of atherosclerosis. However, its exact role depends on the tissue/cell type that is expressing in the enzyme .
The present study was carried out to determine the relation of PvuII and S447X polymorphisms of the LPL gene and lipid profile in CAD defined by coronary angiography and its relation to the severity of disease in a small number of Egyptian CAD patients. The present study showed significantly higher age, male, smoking, hypertension, diabetes, TC, TG, and LDL-c, while lower HDL-c in CAD patients versus controls. These results were similar to those found in other studies , that reported a predominance of male sex and mean age in CAD patients. The potential differences related to sex, age, and different ethnic groups need to be explored further.
Hypertriglyceridemia is a common feature in patients with insulin resistance, diabetes, and obesity, and is correlated positively to deleterious tissue lipid deposition. Reduced whole-body LPL activity is suggested to be one mechanism resulting in impaired clearance of circulating lipoproteins, and causing hypertriglyceridemia. Hormone-responsive LPL was determined to be sensitive to changes in plasma insulin. Whether the influence on coronary LPL was an outcome of direct changes in plasma insulin or was secondary to metabolic alterations associated with insulin lack was unclear. Elevated circulating glucose, fatty acids, and TG could potentially influence the regulation of LPL at the coronary lumen ,.
The current study showed that CAD patients with and without diabetes had significantly higher TC, TG, and LDL-c and lower HDL-c as compared with the controls; these results was similar to those in other works .
When we compared CIMT in both the control and the CAD groups, we found that CIMT was significantly increased in patients and this is in agreement with those of other studies ,,.
The most relevant explanation for increased luminal diameter and decreased flow velocity may be an indicator of early-stage atherosclerosis. It is well known that atherosclerosis and atherosclerotic risk factors are associated with arterial diameter, and arterial remodeling frequently occurs in association with vulnerable plaques. The increase in arterial diameter in patients with atherosclerosis is usually compensation in relation to stenosis, an increase in vessel diameter to preserve luminal area. Large vessel diameter may lead to disturbed blood, and may thereby possibly be a factor in promoting the development of atherosclerosis .
For the PvuII polymorphism
LPL genotypes were distributed in the study sample as follows for the PvuII variant: CC was 15% in controls and 2.5% for CAD, CT was 75% in controls and 76.25% in CAD, and TT occurred in 10% of controls and in 21.25% of patients. The T allele appeared in 59.4% of patients and 47.5 of controls, and the C allele in 40.6% of patients and 52.5% of controls. The present study showed that there was a significant difference between the CAD and the control groups in PvuII genotyping distribution, with the highest number and percent of CT genotypes in the patient groups. These results were in agreement with those of other researchers who found that the CT genotype increases the risk of CAD as these several genetic studies suggest that mutation in LPL decreased the activity of the enzyme and was proved to be correlated to CAD ,,,,.
However, other investigators failed to show such a significant association between CAD and the PvuII polymorphism as the relevance of this polymorphism varies among different populations [25,26].
These conflicting results can be explained by the association between the PvuII polymorphism and other variants in LPL as HindIII, which has strong linkage disequilibrium. Paradoxically, the direction of the association with CAD differed for the two polymorphisms, with the more common allele being associated with an increased risk for HindIII but a decreased risk (trend) for the more common PvuII allele .
CAD and type 2 diabetes mellitus (T2DM) are complex diseases with many overlapping risk factors and likely have many interdependencies. This study showed a nonsignificant correlation in PvuII polymorphisms and T2DM in CAD patients.
These results are not in agreement with those of Huang et al. , who found that LPL polymorphisms as PvuII variants were associated with insulin resistance and T2MD. Huang et al.  and Goodarzi et al.  showed in their studies that LPL was significantly associated with insulin resistance and T2MD. However, Albalat et al.  found no significant association between the LPL polymorphism and diabetes mellitus.
In our study, there was no significant association between PvuII genotypes and CIMT, and also no significant difference in the number and percentage of stenosed coronary vessels, or plaque number among PvuII genotypes, in contrast to Burdon et al. , who reported the association of PvuII with carotid artery atherosclerosis.
For S447X polymorphism
S447X is the third common variant of LPL, and results in the generation of a premature stop codon, truncating the last two amino acids of the mature LPL protein. This variant has been reported at carrier frequencies of ~10-25%; the frequencies of particular single-nucleotide polymorphisms in the LPL gene vary widely between different ethnic groups [2,32].
This study showed that the distributions of the S447X variant were as follows: the CAD group had the following distribution: 40.0% CC, 60.0% CG, and no GG, whereas in the control patient group, it was as follows: 35% CC and 65% CG. The effect of the GG variant genotype could not be determined by the odds ratio as there was no GG variant genotype in the sample. The odds for CG and CC were as follows: the CG genotype decreased the risk of CAD by about 0.7 fold compared with the CC genotype. In addition, the G allele decreased the risk of CAD by 0.8 fold. We found no significant association between lipid levels and S447X in CAD patients when compared with the control group.
Clee et al.  reported that carriers of the S447X variant had decreased TG and thus decreased vascular disease compared with noncarriers; others suggest that the LPL protein may have a direct influence on the vascular wall. These results can be explained by the interactions of the LPL variants with other common polymorphisms, for example, the associations between the LPL variants, for example, S447X versus the HindIII polymorphism in intron 8. It should therefore also be taken into account that the interactions between gene products are quite important in the assessment of genetic effects .
A nonsignificant difference was found in CIMT between S447X genotype groups in CAD patients. However, there was a significant decrease in systolic and diastolic velocity in the CC genotype versus the CG genotype in CAD patients. These results were similar to those of Elousa et al. , who found no evidence for a significant association of the S447X LPL genotype and CIMT.
In our study, there was no significant difference in the number and percentage of stenosed coronary vessels among S447X genotypes; the number of occluded vessels was nonsignificantly lower in the CG genotype of the S447X variant. Also, there was no significant association between genotypes and the number of plaques .
| Conclusion|| |
The association between CAD and gene polymorphisms involved in lipid metabolism remains a subject of debate because of conflicting results. Many studies involved a limited number of participants. Furthermore, the studies varied markedly by the inclusion of different populations (e.g. age, sex, and ethnicity), sampling strategies, and genotyping procedures. Our previous study, which used the same patients with CAD, had significantly higher integration of dyslipidemia and atherogenic ApoE alleles (E2 with hypertriglyceridemia and E4 with hypercholesterolemia and higher LDL-c) with carotid and coronary atherosclerosis. Higher frequencies of E2E3 and E3E4 genotypes and ApoE4 alleles were found in severe CAD patients . These observations point to the role of the ApoE gene as a diagnostic and perhaps a prognostic marker of CAD severity, and may be implicated in therapeutic interventions in ischemic heart patients .
This study concluded that the CT genotype of PvuII increases the risk of CAD by 4.6 folds and this genotype may be an important risk biomarker, which may implicate a therapeutic intervention in atherosclerotic ischemic patients.
Coronary atherosclerosis is a multifactorial disease and there is a need for extensive and well‐funded research before genetics is introduced in everyday clinical practice. To generalize these results, a larger sample size is recommended. We believe that results from smaller studies guide the design of larger ones. To clarify the effect of certain LPL mutations, it is recommended to study the effects of many commonly associated polymorphisms and the linkage disequilibrium between them. We believe that evaluation of genetic associations with coronary atherosclerosis is a promising tool for prevention and treatment.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]