A synergic effect between CYP2C19*2, CYP2C19*3 loss-of-function and CYP2C19*17 gain-of-function alleles is associated with Clopidogrel resistance among Moroccan Acute Coronary Syndromes patients.

OBJECTIVE: The main objective of our study was to investigate the association of CYP2C19*2 and CYP2C19*3 loss-of-function and CYP2C19*17 gain-of-function variants of CYP2C19 gene with Clopidogrel resistance in a sample of Moroccan Acute Coronary Syndromes patients. RESULTS: Our results showed the existence of a synergic effect between the three alleles, statistically very significant, on Clopidogrel resistance among the treated patients (P = 0.0033). For the three variants of the CYP2C19 gene, the heterozygous and homozygous mutant genotypes were the most frequent among ACS patients (CYP2C19*2: 82.76% GA and 10.35% AA; CYP2C19*3: 76.67% GA and 18.33% AA; CYP2C19*17: 66.67% CT and 18.66% TT). Allelic frequencies were 51.73% vs 48.27% (P < 0.001); 56.67% vs 43.33% (P < 0.001); and 52% vs 48% (P = 0.01) for the mutant and wild type alleles of the CYP2C19*2, CYP2C19*3 and CYP2C19*17 variants respectively. Our results support a role of CYP2C19 gene variants as a potential marker of Clopidogrel response. Understanding the functional and clinical consequences of these variants may help for treating patients more effectively, they could be genetically screened and appropriate dose adjustments could be made on the basis of their CYP2C19 genotype.

Impact of I/D polymorphism of angiotensin-converting enzyme (ACE) gene on myocardial infarction susceptibility among young Moroccan patients.

OBJECTIVE: Our case-control study aimed to access the potential association of insertion/deletion (I/D) ACE (angiotensin converting enzyme) gene polymorphism with myocardial infarction (MI) risk of occurrence among a sample of Moroccan patients, especially young ones. RESULTS: Distribution of I/D ACE gene variant among cases vs controls, showed that healthy controls carried out higher frequency of wild type allele I compared to cases (23.5% vs 21.79% respectively), when cases were carrying higher frequency of mutant allele D (78.21% vs 76.5% for controls). Patients were-after this- divided into two groups of < 45 and > 55 years of age, to investigate whether or not younger patients carried out higher frequency of the mutant allele D, than older ones. As expected, < 45 years old patients carried out more DD genotype than older ones (68.9% vs 54.6% respectively), and higher frequency of mutant allele D (81.08% vs 75% respectively). Besides, a tendency to a positive association was found under the recessive genetic transmission model (OR [95% CI] = 1.85 [0.93-3.69], P = 0.08), suggesting that the I/D ACE polymorphism may be associated with MI occurrence among younger patients (< 45 years of age).

Does i-T744C P2Y12 Polymorphism Modulate Clopidogrel Response among Moroccan Acute Coronary Syndromes Patients?

Background. An interindividual variability in response to Clopidogrel has been widely described in patients with acute coronary syndromes (ACS). The contribution of genetics on modulating this response was widely discussed. The objective of our study was to investigate the potential effect of i-T744C P2Y12 polymorphism on Clopidogrel response in a sample of Moroccan ACS patients. We tried also to determine the frequency of this polymorphism among Moroccan ACS compared to healthy subjects. Methods and Results. 77 ACS patients versus 101 healthy controls were recruited. DNA samples were genotyped by PCR-RFLP method. The VerifyNow assay was used to evaluate platelet function among ACS patients. Our results show that the mutant allele C was more frequent among ACS ST (+) than ST (-) patients (39% versus 19.8%, resp.), when the wild-type allele was more represented in the ACS ST (-) group (80.2%). The C allele frequency was higher among resistant than nonresistant patients (30% versus 20.8%, resp.). Comparison of ACS patients and healthy controls shows higher frequency of mutant C allele among cases compared to controls (22.73% versus 19.31%, resp.); there was a statistically significant association of the recessive and additive transmission models with the ACS development risk (OR [95% CI] = 1.78 [1.58-5.05], P = 0.01 and OR [95% CI] = 1.23 [0.74-2.03], P < 0.001, resp.), increasing thus the association of this polymorphism with the pathology. Conclusion. Our results suggest that this polymorphism may have a potential effect on Clopidogrel response among our Moroccan ACS patients and also on ACS development.

G2691A and C2491T mutations of factor V gene and pre-disposition to myocardial infarction in Morocco.

Coagulation factor Leiden mutation has been described as a common genetic risk factor for venous thrombosis; however, this mutation was reported to be practically absent in an African population. Recently, a novel non-sense mutation in the gene encoding factor V has been associated with the risk of occurrence of cardio-cerebrovascular diseases such as stroke and venous thrombosis. The aim of the present study was to investigate whether the factor V Leiden (FVL) and C2491T non-sense mutations are associated with the risk of developing myocardial infarction. Genotyping of FVL and C2491T FV was performed using the polymerase chain reaction restriction fragment length polymorphism method on a sample of 100 patients with myocardial infarction as well as 211 controls. In the study population, the frequency of the FVL mutation was practically zero. However, with regard to the C2491T mutation, the TT genotype was associated with an increased risk of myocardial infarction [odds ratio (OR)=3.16, 95% confidence interval (CI): 1.29-7.71, P=0.03]. A significant association between the C2491T FV mutation and the risk of myocardial infarction was identified using recessive (OR=2.74, 95% CI: 1.14-6.58, P=0.04), dominant (OR=1.85, 95% CI: 1.13-3.04, P=0.02) and additive (OR=1.88, 95% CI: 1.25-2.80, P=0.004) models. Furthermore, a positive correlation was found between the presence of the C2491T FV mutation and hypertension (P=0.02), which is associated with myocardial infarction. In conclusion, the results of the present study suggested that the C2491T non-sense mutation of the FV gene may be a risk factor for myocardial infarction in a Moroccan population.

Association of C677T MTHFR and G20210A FII prothrombin polymorphisms with susceptibility to myocardial infarction.

Myocardial infarction (MI) is a common complex pathology, localized in the main leading causes of mortality worldwide. It is the result of the interaction of genetic and environmental factors. The aim of the present study was to investigate the potential association of C677T 5,10-methylenetetrahydrofolate reductase (MTHFR) (rs1801133) and G20210A factor II prothrombin (FII) (rs1799963) polymorphisms with the susceptibility of MI. Following extraction by the standard salting-out procedure, DNA samples of 100 MI patients and 182 apparently healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism using HinfI and HindIII restriction enzymes, respectively. The results show a significant association of the G20210T FII polymorphism with the MI risk. The frequencies of the heterozygote genotype GA, homozygous mutated AA and the G20210A allele was higher among patients compared to controls (GA: 59 vs. 5.5%, P<0.001; AA: 10 vs. 0%, P=0.003; and 20210A: 39.5 vs. 2.7%, P<0.003), suggesting that this polymorphism may be a potential genetic marker for MI. No significant association was observed between the C677T MTHFR and MI occurrence, and there was more heterozygote CT in the patient group compared to the controls. As a multifactorial disease, the development of MI may be the result of numerous factors that influence synergistically its occurrence. Thus, further studies are merited to try to better assess these associations (gene-gene and gene-environment interactions).

Genetic polymorphisms of T-1131C APOA5 and ALOX5AP SG13S114 with the susceptibility of ischaemic stroke in Morocco.

Ischaemic stroke is a multifactorial disease. Genetic polymorphisms involved in lipid, inflammatory and thrombotic metabolisms play an important role in the development of ischaemic stroke. The present study aimed to assess the relationship between T1131C APOA5 and SG13S114 ALOX5AP polymorphisms and the risk of ischemic stroke in 175 cases and 201 controls. Genotyping was performed by high resolution melting and polymerase chain reaction restriction fragment length polymorphism methods. In the case of T-1131C APOA5, a modest risk of ischaemic stroke was noticed with CC (OR: 2.86; 95% CI = 1.24-6.58; Pc = 0.039) and C allele (OR: 1.54; 95% CI = 1.01-2.33; Pc = 0.014). For SG13S114 ALOX5AP, a significant association was observed among subjects with TT (OR: 2.57; 95% CI =1.49-4.83; Pc = 0.009) and T allele (OR: 1.59; 95% CI = 1.16-2.19; Pc = 0.008). According to the risk factors of ischaemic stroke, a positive correlation was observed only between SG13S114 variant of ALOX5AP gene and hypertension (Pc = 0.026). Despite lower sample size, T-1131C APOA5 and SG13S114 variants could be considered an independent genetic risk factor of ischaemic stroke in Moroccan population.

Association of G894T eNOS, 4G/5G PAI and T1131C APOA5 polymorphisms with susceptibility to myocardial infarction in Morocco.

BACKGROUND: Myocardial infarction (MI) is a common multifactorial disease. Numerous studies have found that genetic plays an essential role in MI occurrence. The main objective of our case-control study is to explore the association of G894T eNOS (rs1799983), 4G/5G PAI (rs1799889) and T1131C APOA5 (rs662799) polymorphisms with MI susceptibility in the Moroccan population. METHODS AND RESULTS: 118 MI patients were recruited vs 184 healthy controls. DNA samples were genotyped by PCR-RFLP method using MboI, BslI and MseI restriction enzymes respectively for the G894T eNOS, 4G/5G PAI and T1131C APOA5 polymorphisms. Our results show that the G894T eNOS was significantly associated with increased risk of MI under the three genetic transmission models (dominant: OR = 1.64, 95% CI = 1.05-2.58, P = 0.003; recessive: OR = 2.15, 95% CI = 0.74-6.16, P = 0.03; additive: OR = 1.54, 95% CI = 1.06-2.23, P = 0.001). The T1131C APOA5 polymorphism was associated to MI risk in recessive and additive models (OR = 1.53, 95% CI = 0.72-3.2, P = 0.04 and OR = 1.78, 95% CI = 1.26-2.51, P = 0.03 respectively). For the 4G/5G PAI variant, even the cases and controls groups were not in Hardy-Weinberg Equilibrium (HWE), the dominant and additive models show a statistically significant association with MI risk (OR = 7.96, 95%CI = 3.83-16.36, P = 0.01 and OR = 1.96, 95% CI = 1.4-2.72, P = 0.03 respectively). CONCLUSION: Our results suggest that G894T eNOS and T1131C APOA5 polymorphisms may be considered as genetic markers of MI among the Moroccan population. Further studies including larger sample sizes and exploring more genetic associations are needed to confirm our results and to better understand the susceptibility to MI.