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Genetic and Nongenetic Factors Affecting Clopidogrel Response in the Egyptian Population.

ABSTRACT: Aspirin and clopidogrel are the mainstay oral antiplatelet regimens, yet a substantial number of major adverse cardiac events (MACE) still occur. Herein, we investigated genetic and nongenetic factors associated with clopidogrel response in Egyptians. In all, 190 Egyptians with acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI), treated with clopidogrel (75 mg/day) for at least a month, were genotyped for CYP2C19 *2, *3, *6, *8, *10, and *17, CES1 G143E and ABCB1*6 and *8. These variants along with nongenetic factors were tested for association with the risk of having MACE in clopidogrel-treated patients. CYP2C19 loss-of-function (LOF) alleles carriers had increased risk of MACE vs. noncarriers (odds ratio 2.52; 95% confidence interval 1.23-5.15, P = 0.011). In a logistic regression, CYP2C19 LOF variants (P = 0.011), age (P = 0.032), and body mass index (BMI, P = 0.039) were significantly associated with the incidence of MACE in patients taking clopidogrel. CYP2C19 genetic variants, age, and BMI are potential predictors associated with variability to clopidogrel response in Egyptians.

SUBMITTER: Khalil BM

PROVIDER: S-EPMC4760893 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Genetic and Nongenetic Factors Affecting Clopidogrel Response in the Egyptian Population.

Khalil B M BM Shahin M H MH Solayman M H M MH Langaee T T Schaalan M F MF Gong Y Y Hammad L N LN Al-Mesallamy H O HO Hamdy N M NM El-Hammady W A WA Johnson J A JA

Clinical and translational science 20160112 1

Aspirin and clopidogrel are the mainstay oral antiplatelet regimens, yet a substantial number of major adverse cardiac events (MACE) still occur. Herein, we investigated genetic and nongenetic factors associated with clopidogrel response in Egyptians. In all, 190 Egyptians with acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI), treated with clopidogrel (75 mg/day) for at least a month, were genotyped for CYP2C19 *2, *3, *6, *8, *10, and *17, CES1 G143E and ABCB1*6 and ...[more]

PMID: 26757134

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Project description:BACKGROUNDRBC transfusion effectiveness varies due to donor, component, and recipient factors. Prior studies identified characteristics associated with variation in hemoglobin increments following transfusion. We extended these observations, examining donor genetic and nongenetic factors affecting transfusion effectiveness.METHODSThis is a multicenter retrospective study of 46,705 patients and 102,043 evaluable RBC transfusions from 2013 to 2016 across 12 hospitals. Transfusion effectiveness was defined as hemoglobin, bilirubin, or creatinine increments following single RBC unit transfusion. Models incorporated a subset of donors with data on single nucleotide polymorphisms associated with osmotic and oxidative hemolysis in vitro. Mixed modeling accounting for repeated transfusion episodes identified predictors of transfusion effectiveness.RESULTSBlood donor (sex, Rh status, fingerstick hemoglobin, smoking), component (storage duration, γ irradiation, leukoreduction, apheresis collection, storage solution), and recipient (sex, BMI, race and ethnicity, age) characteristics were associated with hemoglobin and bilirubin, but not creatinine, increments following RBC transfusions. Increased storage duration was associated with increased bilirubin and decreased hemoglobin increments, suggestive of in vivo hemolysis following transfusion. Donor G6PD deficiency and polymorphisms in SEC14L4, HBA2, and MYO9B genes were associated with decreased hemoglobin increments. Donor G6PD deficiency and polymorphisms in SEC14L4 were associated with increased transfusion requirements in the subsequent 48 hours.CONCLUSIONDonor genetic and other factors, such as RBC storage duration, affect transfusion effectiveness as defined by decreased hemoglobin or increased bilirubin increments. Addressing these factors will provide a precision medicine approach to improve patient outcomes, particularly for chronically transfused RBC recipients, who would most benefit from more effective transfusion products.FUNDINGFunding was provided by HHSN 75N92019D00032, HHSN 75N92019D00034, 75N92019D00035, HHSN 75N92019D00036, and HHSN 75N92019D00037; R01HL126130; and the National Institute of Child Health and Human Development (NICHD).

Project description:Study designCohort study.ObjectiveWe aimed to evaluate the associations of genetic and nongenetic factors with degenerative cervical myelopathy (DCM).Summary of background dataThere is mounting evidence for an inherited predisposition for DCM, but uncertainty remains regarding specific genetic markers involved. Similarly, nongenetic factors are thought to play a role.Materials and methodsUsing diagnosis codes from hospital records linked to the UK Biobank cohort, patients with cervical spondylosis were identified followed by the identification of a subset with DCM. Nongenetic variables evaluated included age, sex, race, Townsend deprivation index, body mass index, occupational demands, osteoporosis, and smoking. Genome-wide association analyses were conducted using logistic regression adjusted for age, sex, population principal components, and follow-up.ResultsA total of 851 DCM cases out of 2787 cervical spondylosis patients were identified. Several nongenetic factors were independently associated with DCM including age [odds ratio (OR)=1.11, 95% CI=1.01-1.21, P =0.024], male sex (OR=1.63, 95% CI=1.37-1.93, P <0.001), and relative socioeconomic deprivation (OR=1.03, 95% CI=1.00-1.06, P =0.030). Asian race was associated with lower DCM risk (OR=0.44, 95% CI=0.22-0.85, P =0.014). We did not identify genome-wide significant (≤5×10 -8 ) single-nucleotide polymorphisms (SNPs) associated with DCM. The strongest genome-wide signals were at SNP rs67256809 in the intergenic region of the genes LINC02582 and FBXO15 on chromosome 18 ( P =1.12×10 -7 ) and rs577081672 in the GTPBP1 gene on chromosome 22 ( P =2.9×10 -7 ). No SNPs reported in prior DCM studies were significant after adjusting for replication attempts.ConclusionsIncreasing age, male sex, and relative socioeconomic deprivation were identified as independent risk factors for DCM, whereas Asian race was inversely associated. SNPs of potential interest were identified in GTPBP1 and an intergenic region on chromosome 18, but these associations did not reach genome-wide significance. Identification of genetic and nongenetic DCM susceptibility markers may guide understanding of DCM disease processes, inform risk, guide prevention and potentially inform surgical outcomes.Level of evidencePrognostic level III.

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Genetic and Nongenetic Factors Affecting Clopidogrel Response in the Egyptian Population.

Publications

Genetic and Nongenetic Factors Affecting Clopidogrel Response in the Egyptian Population.

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