The controversial association of ABCB1 polymorphisms in refractory epilepsy: an analysis of multiple SNPs in an Irish population.

Controversy has surrounded the reported association of the single nucleotide polymorphism (SNP) C3435T of the ATP-binding cassette subfamily B member 1 (ABCB1, MDR1) gene, with refractory epilepsy. Here we examine this question by: (1) attempting to replicate the original association, (2) assessing the association of other variants in high linkage disequilibrium (LD) with C3435T, and (3) evaluating and comparing our findings with other published studies. We defined drug-responsiveness as seizure freedom or a 50% or more reduction in seizure frequency in the preceding year. Drug resistance was defined as a less than 50% reduction in seizure frequency in the preceding year. We used a combination of map-based (tagging SNPs) and direct sequence-based methods allowing a comprehensive assessment of variation across the associated interval. Genotypic data on 8 SNPs was collected on 440 patients, of whom 242 were drug-responsive and 198 were drug-resistant. We were unable to observe the original association of drug-resistant epilepsy with C3435T, nor any association with other functional variants at SNP or haplotype level in the ABCB1 gene. Evaluation of other attempted replication studies suggest that if the original C3435T association is indeed real, it would appear highly sensitive to the phenotype used. Alternatively, the discrepant results of this and other association attempts may be indicative of the original report of the CC genotype at C3435T in ABCB1 being a false positive finding. Variability in phenotypic descriptions in genetic association studies may partly explain the inconsistency of attempted replications.

Genetic variability in the extracellular matrix as a determinant of cardiovascular risk: association of type III collagen COL3A1 polymorphisms with coronary artery disease.

Although common genetic variants in platelet collagen receptors influence platelet activation and thrombosis, the impact of polymorphisms in collagen genes on cardiovascular disease is unknown. To evaluate this, we genotyped a highly polymorphic intronic tandem repeat of the COL3A1 gene, encoding collagen type III, alpha 1. This revealed 4 common alleles (COL3A1-1, -2, -3, and -4). The 2 populations studied were as follows: (1) a cross-sectional study of 703 acute coronary syndrome (ACS) patients with myocardial infarction (MI) and unstable angina, and (2) a prospective study of 924 Caucasian patients from the OPUS (Orbofiban in Patients with Unstable coronary Syndromes)-TIMI-16 trial of the oral GPIIb/IIIa antagonist orbofiban. In addition, we studied 306 control subjects and 224 patients with stable angina. In the case-control population, COL3A1-4 carriers were protected against ACS (odds ratio [OR] = 0.57, 95% CI = 0.35-0.91, P =.02) and stable angina (OR = 0.35, 95% CI = 0.16-0.74, P =.006). In the OPUS population, allele 4 again appeared protective against composite end points (death, MI, stroke, recurrent ischemia, and urgent rehospitalization) (relative risk [RR] = 0.41, 95% CI = 0.17-1.00). There were significant interactions between COL3A1-1 and -3 variants and treatment. Allele COL3A1-3 was associated with an increased risk of the composite end point (RR = 1.65, 95% CI = 1.07-2.55) in patients randomized to orbofiban, but appeared protective in placebo patients (RR = 0.53, 95% CI = 0.28-0.98). We conclude that variants in the COL3A1 gene, the product of which is a vessel-wall protein and platelet ligand, modulate the risk of coronary artery disease and could also modulate the response to antithrombotic therapy. This is the first reported association between polymorphisms of extracellular matrix components and cardiovascular risk.

Platelet glycoprotein Ib alpha receptor polymorphisms and recurrent ischaemic events in acute coronary syndrome patients.

AIMS: To examine the relationship between polymorphisms in the platelet receptor glycoprotein (GP) Ib(alpha) and recurrent ischaemic events, and assess their impact on response to anti-platelet treatment. METHODS AND RESULTS: 1014 patients presenting with unstable coronary syndrome were recruited from the OPUS-TIMI 16 clinical trial of the platelet GPIIb/IIIa antagonist, orbofiban. The subjects were genotyped for two polymorphisms in the gene for GPIb(alpha). These were a T-5C polymorphism in the 5' untranslated Kozak region of the GPIb(alpha) gene, and the variable number of tandem repeats (VNTR) in the macroglycopeptide region.165 patients had events (recurrent ischaemia, urgent revascularisation, myocardial infarction (MI), stroke and death). There was no effect of the number of -5C alleles on composite endpoint frequency among Caucasian subjects (test for trend, p = 0.47). However, MI risk increased with the number of -5C alleles carried, with MI occurring in 2.3% of patients with the -5T/-5T genotype, 5.0% of -5T/-5C, and 16.7% of -5C/-5C (p < 0.01). The effect of treatment on MI outcome was not significantly modified by genotype (test for interaction, p = 0.10). The overall risk of bleeding was not strongly influenced by either the -5C or the VNTR polymorphisms. CONCLUSION: In an unstable coronary syndrome population the T-5C polymorphism in GPIb(alpha) influences risk of subsequent MI.