Showing papers by "Nilesh J. Samani published in 2004"

The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke

Abstract: We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13. A four-marker single-nucleotide polymorphism (SNP) haplotype in this locus spanning the gene ALOX5AP encoding 5-lipoxygenase activating protein (FLAP) is associated with a two times greater risk of myocardial infarction in Iceland. This haplotype also confers almost two times greater risk of stroke. Another ALOX5AP haplotype is associated with myocardial infarction in individuals from the UK. Stimulated neutrophils from individuals with myocardial infarction produce more leukotriene B4, a key product in the 5-lipoxygenase pathway, than do neutrophils from controls, and this difference is largely attributed to cells from males who carry the at-risk haplotype. We conclude that variants of ALOX5AP are involved in the pathogenesis of both myocardial infarction and stroke by increasing leukotriene production and inflammation in the arterial wall.

A multi-centre randomised controlled trial of minimally invasive direct coronary bypass grafting versus percutaneous transluminal coronary angioplasty with stenting for proximal stenosis of the left anterior descending coronary artery.

Abstract: OBJECTIVES: To compare the clinical- and cost-effectiveness of minimally invasive direct coronary artery bypass grafting (MIDCAB) and percutaneous transluminal coronary angioplasty (PTCA) with or without stenting in patients with single-vessel disease of the left anterior descending coronary artery (LAD). DESIGN: Multi-centre randomised trial without blinding. The computer-generated sequence of randomised assignments was stratified by centre, allocated participants in blocks and was concealed using a centralised telephone facility. SETTING: Four tertiary cardiothoracic surgery centres in England. PARTICIPANTS: Patients with ischaemic heart disease with at least 50% proximal stenosis of the LAD, suitable for either PTCA or MIDCAB, and with no significant disease in another vessel. INTERVENTIONS: Patients randomised to PTCA had local anaesthetic and underwent PTCA according to the method preferred by the operator carrying out the procedure. Patients randomised to MIDCAB had general anaesthetic. The chest was opened through an 8-10-cm left anterior thoracotomy. The ribs were retracted and the left internal thoracic artery (LITA) harvested. The pericardium was opened in the line of the LAD to confirm the feasibility of operation. The distal LITA was anastomosed end-to-side to an arteriotomy in the LAD. All operators were experienced in carrying out MIDCAB. MAIN OUTCOME MEASURES: The primary outcome measure was survival free from cardiac-related events. Relevant events were death, myocardial infarction, repeat coronary revascularisation and recurrence of symptomatic angina or clinical signs of ischaemia during an exercise tolerance test at annual follow-up. Secondary outcome measures were complications, functional outcome, disease-specific and generic quality of life, health and social services resource use and their costs. RESULTS: A total of 12,828 consecutive patients undergoing an angiogram were logged at participating centres from November 1999 to December 2001. Of the 1091 patients with proximal stenosis of the LAD, 127 were eligible and consented to take part; 100 were randomised and the remaining 27 consented to follow-up. All randomised participants were included in an intention-to-treat analysis of survival free from cardiac-related events, which found a non-significant benefit from MIDCAB. Cumulative hazard rates at 12 months were estimated to be 7.1 and 9.2% for MIDCAB and PTCA, respectively. There were no important differences between MIDCAB and PTCA with respect to angina symptoms or disease-specific or generic quality of life. The total NHS procedure costs were 1648 British pounds and 946 British pounds for MIDCAB and PTCA, respectively. The costs of resources used during 1 year of follow-up were 1033 British pounds and 843 British pounds, respectively. CONCLUSIONS: The study found no evidence that MIDCAB was more effective than PTCA. The procedure costs of MIDCAB were observed to be considerably higher than those of PTCA. Given these findings, it is unlikely that MIDCAB represents a cost-effective use of resources in the reference population. Recent advances in cardiac surgery mean that surgeons now tend to carry out off-pump bypass grafting via a sternotomy instead of MIDCAB. At the same time, cardiologists are treating more patients with multi-vessel disease by PTCA. Future primary research should focus on this comparison. Other small trials of PTCA versus MIDCAB have now finished and a more conclusive answer to the original objective could be provided by a systematic review.

Genotypes and haplotypes predisposing to myocardial infarction: a multilocus case-control study.

Abstract: Aim To identify polymorphisms and haplotypes in candidate genes that predispose to myocardial infarction (MI) using a multilocus approach. Methods and results 1052 subjects, comprising 547 acute MI cases and 505 controls were studied. The association between MI and 58 SNPs in 35 candidate genes (generating 61 016 individual genotypes), and between MI and estimated haplotypes at 14 loci encompassing 16 genes was investigated. Two individual gene variants and haplotypes at two loci showed statistical association with MI. The α-adducin 460trp variant (OR 0.73, 95% CI 0.59–0.91, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(P=0.006\) \end{document}) and the cholesteryl ester transfer protein –629A variant (OR 0.82, 95% CI 0.68–0.97, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(P=0.025\) \end{document}) were both associated with a significant protective effect on MI, as was the paraoxonase 1/paraoxonase 2 haplotype comprising met55 and gln192 in paraoxonase 1 and cys311 in paraoxonase 2 (OR 0.52, 95% CI 0.39–0.77, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(P=0.001\) \end{document}). The apolipoprotein C III haplotypes CCTTCG and ATCCCG at positions –641\*–482\*–455\*1100\*3175*3206 were associated with an increased risk of MI, odds ratios 1.41 (95% CI 1.06–1.76, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(P=0.023\) \end{document}) and 1.71 (95% CI 1.28–2.14, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(P=0.038\) \end{document}), respectively. Conclusions We report associations of two polymorphisms and haplotypes at two loci with risk of MI that warrants testing in future studies. Furthermore, we demonstrate the application of a multilocus assay in the setting of a large association study and the additional benefit gained from the study of haplotypes to identify variants influencing risk of coronary heart disease.

Dimorphism in the P2Y1 ADP Receptor Gene Is Associated With Increased Platelet Activation Response to ADP

Abstract: Objective— The platelet ADP receptors P2Y1 and P2Y12 play a pivotal role in platelet aggregation. There is marked interindividual variation in platelet response to ADP. We studied whether genetic variants in the P2Y1 or P2Y12 genes affect platelet response to ADP. Methods and Results— The P2Y1 and P2Y12 genes were screened for polymorphisms. Associations between selected polymorphisms and the platelet response to ADP (0.1, 1.0, and 10 μmol/L), assessed by whole blood flow cytometric measurement of fibrinogen binding to activated glycoprotein IIb-IIIa, were then determined in 200 subjects. Five polymorphisms were found in the P2Y1 gene and 11 in the P2Y12 gene. All polymorphisms were silent. A P2Y1 gene dimorphism, 1622A〉G, was associated with a significant ( P =0.007) effect on platelet ADP response, with a greater response in carriers of the G allele (frequency 0.15). The effect was seen at all concentrations of ADP but greatest at 0.1 μmol/L ADP, where the response in GG homozygotes was on average 130% higher than that seen in AA homozygotes ( P =0.006). Conclusions— A common genetic variant at the P2Y1 locus is associated with platelet reactivity to ADP. This genotype effect partly explains the interindividual variation in platelet response to ADP and may have clinical implications with regard to thrombotic risk.

Exon repetition: a major pathway for processing mRNA of some genes is allele‐specific

Abstract: Exon repetition describes the presence of tandemlyrepeated exons in mRNA in the absence of duplica-tions in the genome. Its existence challenges ourunderstanding of gene expression, because thelinear organization of sequences in apparently nor-mal genes must be subverted during RNA synthesisor processing. It is restricted to a small number ofgenes in some of which over half of the mRNA con-tains specific patterns of repetition. Although it issometimes assumed to arise by trans-splicing, thereis no evidence of this and the efficiency is verymuch higher than for examples of bona fide trans-splicing in mammals. Furthermore, a potentiallyubiquitous reaction such as trans-splicing is notconsistent with a phenomenon that involves such ahigh proportion of the products of so few genes.Instead, it seems more probable that exon repetitionis caused by a specific trans-acting factor. We havetested this and demonstrate for the two best charac-terized examples that the property is restricted tospecific alleles of the affected genes and is deter-mined in cis. It is not determined by exonic splicingsignals, as had been suggested previously. In het-erozygotes, RNA transcribed from the two alleles ofan affected gene can have fundamentally differentfates.INTRODUCTIONThe discovery of exon repetition suggested that somethingextraordinary can happen during RNA processing (1,2).Tandem repeats of specific exons were found originally in amajority of the mRNA from two rat genes, COT (carnitineoctanoyl transferase) and Sa (a medium-chain acyl-CoAsynthetase) (1,2), although in the case of Sa the repeats wereseen only in mRNA from the kidney of specific rat strains (2).Since these reports, exon repetition has been observed inmRNA from a small number of other rat and human genes (3–7). In most cases, the repeats were detected by RT–PCR andconfirmed by direct analysis of the mRNA (1,2,4,5,7). Inprinciple, exon repetition might arise from duplications in thegenome or unusual RNA processing reactions. Duplications ofthe repeated exons in the genome have been excluded(1,2,4,5,7). Tandem duplication of the entire gene mightallow run-through transcription and splicing, but this too wasexcluded in the case of Sa (2). Hence, it was inferred that exonrepetition must take place at the level of the RNA, and it wasthe first example of heterogeneity in natural mammalianmRNA that did not arise from the use of alternative signals inlinear, contiguous sequences.The only reaction known at present that might explain exonrepetition is intragenic trans-splicing. However, the prece-dents in mammals do not support this. Most examples of trans-splicing in mammalian cells have involved pairs of partialgenes in which transcripts began or ended within the introns(which therefore became ‘outruns’), such that there wereunpaired splice sites (8–10). There is no evidence ofappropriate internal promoters in the Sa or COT genes.Trans-splicing of intact genes has been reported very rarely,perhaps in part because it could be detected only if it wereinterallelic, meaning that the mRNA contains sequencesoriginating from two distinguishable alleles, or intergenic,containing sequences from two different genes. A compre-hensive analysis of protocadherin gene expression excludedthe existence of trans-splicing between transcripts originatingfrom different alleles, although there was evidence of a verylow level of probable trans-splicing between tandem geneclusters on the same chromosome (11). The only precedent forefficient trans-splicing between transcripts from one intactgene comes from Drosophila, in which splicing involvesalleles of lola on paired homologous chromosomes (12).However, it seems that lola splicing might depend upon theuse of alternative promoters to produce transcripts with partialterminal introns (12). We infer that, even if trans-splicing ofintact genes were a ubiquitous side-reaction, it could accountfor neither the high level of exon repetition nor its restrictionto so few genes. Exon repetition is clearly special.If exon repetition is not an occasional aberration of RNAprocessing, but efficient, it is unclear why it should berestricted to so few genes. The absence of exon repetition in SamRNA from one strain of rat suggests that there is a strain-specific trans-acting factor that promotes exon repetition inthe mRNA from specific genes. The existence of such a factorwould be a strong indication that exon repetition had abiological function. We have investigated exon repetition ofthe Sa and COT genes, and conclude that it is tightly restrictedand not determined by a common trans-acting factor;