Showing papers by "Nilesh J. Samani published in 2001"

Novel Platelet Membrane Glycoprotein VI Dimorphism Is a Risk Factor for Myocardial Infarction

Abstract: Background Glycoprotein (GP) VI plays a crucial role in platelet activation and aggregation. We investigated whether polymorphic variation at the GP VI locus confers an increased risk of myocardial infarction (MI). Methods and Results Coding and 5′ and 3′ non-coding regions of the GP VI gene were analyzed by polymerase chain reaction and conformation sensitive gel electrophoresis in 21 healthy subjects. Ten dimorphisms, 5 of which predicted amino acid substitutions (T13254C, A19871G, A21908G, A22630T, C22644A), were identified. Two core haplotypes involving 7 dimorphisms (C10781A and G10873A and all those predicting amino acid substitutions) were apparent. The contribution of the T13254C dimorphism, which predicted the substitution of serine 219 by proline, to risk of MI was assessed in 525 patients with acute MI and 474 controls, all aged <75 years. The allelic odds ratio (OR) for MI associated with the 13254C allele was 1.16 (95% CI, 0.91 to 1.46; P=0.23). Compared with corresponding control subgroups, ...

Genetic Dissection of Region Around the Sa Gene on Rat Chromosome 1: Evidence for Multiple Loci Affecting Blood Pressure

Abstract: A region with a major effect on blood pressure (BP) is located on rat chromosome 1 in the vicinity of the Sa gene, a candidate gene for BP regulation. Previously, we observed a single linkage peak for BP in this region in second filial generation rats derived from a cross of the spontaneously hypertensive rat (SHR) with the Wistar-Kyoto rat (WKY), and we have reported the isolation of the region containing the BP effect in reciprocal congenic strains (WKY.SHR-Sa) and (SHR.WKY-Sa) derived from these animals. Here, we report the further genetic dissection of this region. Two congenic substrains each were derived from WKY.SHR-Sa (WISA1 and WISA2) and SHR.WKY-Sa (SISA1 and SISA2) by backcrossing to WKY and SHR, respectively. Although there was some overlap of the introgressed regions retained in the various substrains, the segments in WISA1 and SISA1 did not overlap. Furthermore, although the Sa allele in WISA1, WISA2, and SISA2 remained donor in origin, recombination in SISA1 reverted it back to the recipient (SHR) allele. Surprisingly, all 4 substrains demonstrated a highly significant BP difference compared with that of their respective parental strain, which was of a magnitude similar to those seen in the original congenic strains. The findings strongly indicate that there are at least 2 quantitative trait loci (QTLs) affecting BP in this region of rat chromosome 1. Furthermore, the BP effect seen in SISA1 indicates that at least a proportion of the BP effect of this region of rat chromosome 1 cannot be due to the Sa gene. SISA1 contains an introgressed segment of <3 cM, and this will facilitate the physical mapping of the BP QTL(s) located within it and the identification of the susceptibility-conferring genes. Our observations serve to illustrate the complexity of QTL dissection and the care needed to interpret findings from congenic studies.

The −1185 A/G and −1051 G/A dimorphisms in the von Willebrand factor gene promoter and risk of myocardial infarction

Abstract: Elevated plasma von Willebrand factor (VWF) levels are associated with coronary artery disease, although the precise mechanism for this is unclear. Recently, four linked dimorphisms in the VWF gene promoter were demonstrated to influence plasma VWF level. We conducted a case–control study of 525 acute myocardial infarction (MI) cases and 451 control subjects, all aged 75 years, to assess the potential contribution of two of these dimorphisms (−1185 G/A and −1051 A/G) to the risk of MI. The frequency of the −1185A/−1051G haplotype, associated with elevated VWF levels, was similar in the case and control groups, yielding a haplotypic odds ratio for MI of 0·93 (95% CI 0·77, 1·12, P = 0·43), and there was no significant association between the −1185A/−1051G haplotype and the risk of MI in any subgroup analysed. We therefore conclude that possession of the −1185A/−1051G haplotype does not confer an increased risk for MI.

Professor John Douglas Swales, MD, FRCP: 1935–2000

Abstract: This communication records the immense contribution made by John Swales to clinical science and the practice of medicine, most notably in the field of hypertension. In September 2000, John suffered a cardiac arrest while browsing the local bookshop on the University of Leicester campus. He was resuscitated by colleagues but died 2 weeks later without regaining consciousness. It was a tragic, sudden, and premature end to a glorious career. John Swales was born in Leicester in 1935 and was educated at the local grammar school. His intellectual abilities were recognized early when he was awarded a major scholarship to study medicine at the University of Cambridge, from which he graduated with first class honors and the University prize. He completed his undergraduate medical education at Westminster hospital medical school, University of London, before embarking on a distinguished postgraduate medical career in London and Manchester, where Sir Douglas Black was his mentor. In 1974, he was invited to become the Foundation Professor and Chairman of Medicine at the new medical school at the University of Leicester. It was a daunting challenge, to build an academic department of medicine from scratch, and one that John could readily have avoided by accepting one of the many comfortable established positions on offer elsewhere. That was not his style, and with relish, John accepted the challenge to help build a medical school in his hometown at Leicester. He served as Chairman of Medicine from …