Bedside testing of CYP2C19 gene for treatment of patients with PCI with antiplatelet therapy

BACKGROUND: To mitigate the risk of stent thrombosis, patients treated by percutaneous coronary intervention (PCI) are administered dual anti-platelet therapy comprising aspirin and a platelet P2Y12 receptor inhibitor. Clopidogrel is a prodrug requiring activation by the cytochrome P450 enzyme, CYP2C19. In Saudi Arabia, it has been reported that approximately 26% of the population carries CYP2C19*2 and/or *3 loss-of-function polymorphisms in addition to a high prevalence of CVD. METHODS: This prospective (April 2013-December 2020) parallel assignment clinical trial focuses on ST-Elevation Myocardial Infarction (STEMI) patient outcomes. The clinical trial includes 1500 STEMI patients from two hospitals in the Eastern Province of Saudi Arabia. Patients are assigned to one of two groups; the control arm receives conventional therapy with clopidogrel, while in the active arm the Spartan RX CYP2C19 assay is used to determine the *2 genotype. Carriers of a CYP2C19*2 loss-of-function allele receive prasugrel or ticagrelor, while non-carriers are treated with clopidogrel. Follow-up is one year after primary PCI. The primary end point is the number of patients who develop an adverse major cardiovascular event, including recurrent MI, non-fatal stroke, cardiovascular death, or major bleeding one year after PCI. DISCUSSION: The risk of stent thrombosis in PCI patients is usually reduced by dual anti-platelet therapy, comprising aspirin and a P2Y12 inhibitor, such as clopidogrel. However, clopidogrel requires activation by the cytochrome P450 enzyme, CYP2C19. Approximately 20% of the population are unable to activate clopidogrel as they possess the CYP2C19*2 loss-of function (LoF) allele. The primary goal of this trial is to study the benefits of treating only those patients that cannot activate clopidogrel with an alternative that has shown to be a more effective platelet inhibitor and does not require bioactivation by the cytochrome P450 enzyme. We expect an improvement in net clinical benefit outcome in the active arm patients, thus supporting pharmacogenetic testing in PCI patients post STEMI. TRIAL REGISTRATION: Trial registration name is "Bedside Testing of CYP2C19 Gene for Treatment of Patients with PCI with Antiplatelet Therapy" (number NCT01823185) retrospectively registered with clinicaltrials.gov on April 4, 2013. This trial is currently at the patient recruitment stage

Uncovering myocardial infarction genetic signatures using GWAS exploration in Saudi and European cohorts

Genome-wide association studies (GWAS) have yielded significant insights into the genetic architecture of myocardial infarction (MI), although studies in non-European populations are still lacking. Saudi Arabian cohorts offer an opportunity to discover novel genetic variants impacting disease risk due to a high rate of consanguinity. Genome-wide genotyping (GWG), imputation and GWAS followed by meta-analysis were performed based on two independent Saudi Arabian studies comprising 3950 MI patients and 2324 non-MI controls. Meta-analyses were then performed with these two Saudi MI studies and the CardioGRAMplusC4D and UK BioBank GWAS as controls. Meta-analyses of the two Saudi MI studies resulted in 17 SNPs with genome-wide significance. Meta-analyses of all 4 studies revealed 66 loci with genome-wide significance levels of p 12% MAF). In conclusion, our results replicated many MI associations, whereas in Saudi-only GWAS (meta-analyses), several new loci were implicated that require future validation and functional analyses

Investigation of KIF6 Trp719Arg gene polymorphism in a case-control study of coronary artery disease and non-fatal myocardial infarction in the Eastern Province of Saudi Arabia

BACKGROUND: Kinesin-like protein 6 (KIF6), a member of the kinesin superfamily, is involved in intracellular transport. A few prospective studies have shown the KIF6 variant Trp719Arg (rs20455) to be associated with coronary artery disease (CAD) in Caucasian populations. However, recent genome-wide association studies on CAD have not proven these associations. OBJECTIVES: Since the role of KIF6 719Arg allele in other ethnic populations is largely unknown, we sought to determine whether the KIF6 719Arg allele is associated with CAD in an ethnic Middle Eastern population. DESIGN: Case-control study. SETTING: CAD patients and control subjects from King Fahd Hospital of the University, Al-Khobar, Saudi Arabia. PATIENTS AND METHODS: The study population included angiographically defined CAD patients (n=1002) and controls (n=984) with a normal electrocardiogram. MAIN OUTCOME MEASURE(S): Association of KIF6 Trp719Arg mutation with CAD. RESULTS: The KIF6 Trp719Arg polymorphism was not associated with CAD (OR 0.976, 95% CI 0.861-1.105; P=.704). In addition, KIF6 Trp719Arg polymorphism showed a lack of association even in stratified myocardial infarction patients (n=802) (OR 1.006, 95% CI 0.881-1.148; P=.929) in comparison to controls. CONCLUSIONS: The absence of Trp719Arg polymorphism association with CAD and CAD in stratified myocardial infarction cases indicates that the polymorphism is not associated with an increased risk among CAD patients from the Eastern Province of Saudi Arabia. LIMITATIONS: Unavailability of data on statin usage among the patient population

Investigation of KIF6 Trp719Arg gene polymorphism in a case-control study of coronary artery disease and non-fatal myocardial infarction in the Eastern Province of Saudi Arabia

BACKGROUND: Kinesin-like protein 6 (KIF6), a member of the kinesin superfamily, is involved in intracellular transport. A few prospective studies have shown the KIF6 variant Trp719Arg (rs20455) to be associated with coronary artery disease (CAD) in Caucasian populations. However, recent genome-wide association studies on CAD have not proven these associations. OBJECTIVES: Since the role of KIF6 719Arg allele in other ethnic populations is largely unknown, we sought to determine whether the KIF6 719Arg allele is associated with CAD in an ethnic Middle Eastern population. DESIGN: Case-control study. SETTING: CAD patients and control subjects from King Fahd Hospital of the University, Al-Khobar, Saudi Arabia. PATIENTS AND METHODS: The study population included angiographically defined CAD patients (n=1002) and controls (n=984) with a normal electrocardiogram. MAIN OUTCOME MEASURE(S): Association of KIF6 Trp719Arg mutation with CAD. RESULTS: The KIF6 Trp719Arg polymorphism was not associated with CAD (OR 0.976, 95% CI 0.861-1.105; P=.704). In addition, KIF6 Trp719Arg polymorphism showed a lack of association even in stratified myocardial infarction patients (n=802) (OR 1.006, 95% CI 0.881-1.148; P=.929) in comparison to controls. CONCLUSIONS: The absence of Trp719Arg polymorphism association with CAD and CAD in stratified myocardial infarction cases indicates that the polymorphism is not associated with an increased risk among CAD patients from the Eastern Province of Saudi Arabia. LIMITATIONS: Unavailability of data on statin usage among the patient population

Assessing known chronic kidney disease associated genetic variants in Saudi Arabian populations

Abstract Background Genome wide association studies of patients with European descent have identified common variants associated with risk of reduced estimated glomerular filtration rate (eGFR). A panel of eight variants were selected to evaluate their association and prevalence in a Saudi Arabian patient cohort with chronic kidney disease (CKD). Methods Eight genetic variants in four genes (SHROOM3, MYH9, SLC7A9, and CST3) were genotyped in 160 CKD patients and 189 ethnicity-matched healthy controls. Genetic variants were tested for association with the development of CKD (eGFR < 60 ml/min/1.73m2) and effects were compared with results obtained from 133,413 participants in the CKD genetics consortium. Multivariable regression was used to evaluate the role of these eight variants in improving prediction of CKD development. Results All eight variants were present in Saudi populations with minor allele frequency ranging from 16 to 46%. The risk variant in all four genes demonstrated the same direction of effect as observed in European populations. One variant, rs4821480, in MYH9 was significantly associated with increased risk of development of CKD (OR = 1.69, 95% CI 1.22–2.36, P = 0.002), but the additional variants were not statistically significant given our modest sample size. Conclusions CKD risk variants identified in European populations are present in Saudis. We did not find evidence to suggest heterogeneity of effect size compared to previously published estimates in European populations. Multivariable logistic regression analysis showed a statistically significant improvement in predicting the CKD using models with either FGF23 and vitamin D or FGF23, vitamin D level, and MYH9 genotypes (AUC = 0.93, 95% CI 0.90–0.95, P <  0.0001)