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

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 < or = 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.

Novel platelet membrane glycoprotein VI dimorphism is a risk factor for myocardial infarction.

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, the 13254CC genotype was more common among cases who were female (OR, 4.52; 95% CI, 1.23 to 16.64; P=0.029), nonsmokers (OR, 2.50; 95% CI, 0.98 to 6.38; P=0.048), aged >/=60 years (OR, 6.48; 95% CI, 1.47 to 28.45; P=0.009) or carried the beta-fibrinogen -148T allele associated with increased fibrinogen levels (OR, 10.49; 95% CI, 1.32 to 83.42; P=0.02). In logistic regression analysis that took other cardiovascular risk factors into account, the interactions of GP VI genotype with age (P=0.005) and beta-fibrinogen genotype (P=0.035) remained significant. CONCLUSIONS: The GP VI 13254CC genotype increases the risk of MI, particularly in older individuals, and the interaction of the GP VI 13254C allele with other candidate risk alleles may accentuate this risk.

Influence of the -675 4G/5G dimorphism of the plasminogen activator inhibitor 1 promoter on thrombotic risk in patients with factor V Leiden.

Elevated plasminogen activator inhibitor 1 (PAI-1) levels are associated with venous thromboembolism, although their significance is unclear. PAI-1 levels are influenced by a PAI-1 promoter dimorphism (4G/5G), the 4G allele being associated with increased PAI-1 activity. We investigated whether the 4G allele influenced thrombotic risk by studying 99 symptomatic factor V (FV) Leiden heterozygotes and 99 healthy subjects. The 4G allele was more prevalent among cases than among healthy subjects (chi2 = 8.00, P = 0.005) and the odds ratio (OR) for thrombosis associated with either heterozygosity or homozygosity for the 4G allele was 2.43 (P = 0. 011). We conclude that carriership of the 4G allele was more prevalent in patients who already carried factor V Leiden than in control subjects without factor V Leiden.

The GPIa C807T dimorphism associated with platelet collagen receptor density is not a risk factor for myocardial infarction.

The platelet collagen receptor, GPIa/IIa, is an important mediator of platelet adhesion to fibrillar collagens at sites of vascular injury. Recently, a dimorphism at nucleotide 807 of the GPIa cDNA (TTC/TTT in codon 224) was shown to be associated with variation in GPIa/IIa receptor density on the platelet surface. We conducted a case-control study to determine if the 807T allele, linked with increased GPIa/IIa density, contributed to risk of myocardial infarction (MI). DNA from 546 acute MI cases and 507 controls, all aged <75 years, was genotyped for the C807T dimorphism using the TaqManTM system of allelic discrimination. The allelic odds ratio (OR) for MI in the complete cohort was 0.88 (95% CI 0.74-1.05, P = 0.17), indicating that the 807T allele was not associated with an increased risk of MI. There was also no increased risk of MI associated with the homozygous 807TT (P = 0.22) or heterozygous 807CT (P = 0.24) genotypes or for carriers of the 807T allele in any cohort subgroup analysed. We conclude that the GPIa 807T allele is not a risk factor for MI in our population either alone or in combination with other major cardiovascular risk factors.

The prothrombin 20210A allele and its association with myocardial infarction.

The relationship between the prothrombin (PT) 20210A allele and arterial disease is controversial. We conducted a case-control study to assess its contribution to risk of myocardial infarction (MI). Five hundred and thirty-nine acute MI patients and 498 control subjects aged <75 years were studied. Two percent of cases carried the PT20210A allele compared to 2.8% of controls. The odds ratio for MI was 0.72 (95% CI 0.32-1.60) indicating that the PT20210A allele confers no increased risk for MI. Subgroup analysis showed no association between the PT20210A allele and either premature MI or MI in females. We conclude the PT20210A allele is not a risk factor for MI and suggest that discrepancies in studies relating the PT20210A allele to MI may be due to difficulties in estimating its low allelic frequency in the general population and thus random differences in the observed frequencies in the control populations studied.

Uptake of ethylenediamine tetramethylene phosphonic acid in normal bone after multiple applications. A non-human primate study.

Palliation of bone pain in patients with bone metastases has previously been evaluated using 153Sm (samarium) complexed to bone seeking ethylenediamine tetramethylene phosphonic acid (CAS 1429-50-1, EDTMP). Repeated application of the radioligand as needed was found progressively less effective. This study questions whether EDTMP exerts a blocking function, limiting access to bone or osseous tumours with successive administration. The pharmacokinetics and biodistribution of 153Sm-EDTMP in the normal experimental baboon (n = 6) during three successive applications (6 weekly) each with two different concentrations of EDTMP (0.7 and 1.4 mg/kg b.wt.) were investigated using bone scintigraphy. 153Sm-EDTMP (111 MBq) was injected in each case and monitored for 5 h. Curves of tracer kinetics and bone to background uptake were obtained, also blood and cumulative urine curves. Comparisons were statistically assessed in each group between successive applications and between EDTMP concentrations. Partial blocking with the low EDTMP concentration reached statistical significance after the third application. The first application of the high EDTMP concentration yielded lower uptake in the bone than did low EDTMP pointing to blocking by the high concentration, but not seen with repeated applications. Continual application of high concentration EDTMP could lead to a reduced level of calcium in serum and increased parathyroid hormone levels which might trigger osteoblastic activity and bone remodelling. This would partially affect the blocking which was thus more obvious at the low EDTMP concentration.

Technetium-99m-HMPAO, technetium-99m-ECD and iodine-123-IMP cerebral blood flow measurements with pharmacological interventions in primates.

UNLABELLED: Technetium-99m-bicisate ethyl cysteinate dimer (ECD) presents a different pattern from cerebral blood flow (CBF) in the subacute phase of cerebral infarction, as measured by PET, perhaps due to lack of oxygen and enzyme activity; this pattern is contrary to that of hexamethyl-propyleneamine oxime (HMPAO) but similar to that of N-isopropyl-[123I]beta-iodoamphetamine ([123I]IMP). This study explores possible CBF differences among HMPAO, ECD and IMP, with various relevant drug interventions. METHODS: Anesthetized adult baboons were used in these SPECT studies. Four studies (n = 6 baboons for each study), one control study and three intervention studies involving intravenous acetazolamide, nimodipine infusion and intramuscular sumatriptan, were followed with 99mTc-HMPAO, 99mTc-ECD and [123I]IMP. The split-dose method was used as follows. For each tracer, intervention data from the second SPECT (SPECT-2) after the second tracer injection (444 MBq) reflected a change in CBF with respect to the baseline SPECT (SPECT-1) data from the initial injection (222 MBq). These changes as a ratio, R (R = SPECT-2/SPECT-1), for each study, and the R values for each tracer were compared to R values from the corresponding control studies, yielding a quantitative estimate of drug effects. RESULTS: There were no significant differences (p > 0.05) between HMPAO and ECD for the control, acetazolamide and sumatriptan studies, but there was indeed a difference between the two for the nimodipine study, indicating a nimodipine-dependent underestimation of CBF with ECD (and also with IMP), with respect to HMPAO. A further significant difference was that larger CBF increases were observed with acetazolamide, as measured with [123I]IMP. CONCLUSION: This is a crucial observation for the clinical interpretation of CBF SPECT data and should direct the choice of tracer for a specific examination.