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Hereditary Factors (hereditary + factor)
Selected AbstractsCharacterization of an immunologic polymorphism (D79H) in the heavy chain of factor VJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2004M. Van Der Neut Kolfschoten Summary.,Background: During the study of a family with hereditary factor (F)V deficiency (FV Amersfoort, 1102 A > T in exon 7) we identified an individual with 5% FV heavy chain antigen (FVHC) and 50% FV light chain antigen (FVLC). Further testing revealed that apart from the FV Amersfoort allele a second variant FV allele was segregating in this family, which encodes for a FV molecule with a reduced affinity for mAb V-23 used in the FV heavy chain ELISA (ELISAHC). Objective: Identification and characterization of the molecular basis responsible for the reduced affinity of the variant FV for mAb V-23. Methods: Family members of the proband were screened for mutations in the exons coding for the heavy chain of FV, after which the recombinant variant FV could be generated and characterized. Next, the cases and controls of the Leiden Thrombophilia Study (LETS) were genotyped for carriership of the variant FV. Results: In the variant FV allele a polymorphism in exon 3 (409G > C) was identified, which predicts the replacement of aspartic acid 79 by histidin (D79H). Introduction of this mutation in recombinant FV confirmed that it reduces the affinity for binding to mAb V-23. The substitution has no effect on FV(a) stability and Xa-cofactor activity. In Caucasians the frequency of the FV-79H allele is ,5%. Analysis of the LETS revealed that the FV-79H allele is not associated with FV levels (FVLC), activated protein C sensitivity (using an activated partial thromboplastin time-based test) or risk of venous thrombosis (OR 1.07, CI 95: 0.7,1.7). Conclusion: The D79H substitution in FV should be considered as a neutral polymorphism. The monoclonal antibody V-23, which has a strongly reduced affinity for FV-79H, is not suitable for application in diagnostic tests. [source] Birth weight and cardiovascular risk factors in a cohort followed until 80 years of age: the study of men born in 1913JOURNAL OF INTERNAL MEDICINE, Issue 2 2004M. Eriksson Abstract. Objectives., To analyse whether there is a relation-ship between birth weight and cardiovascular risk factors given the influence of potential modifying factors from birth time, former generations and adult life. Design., Population-based cohort followed until 80 years of age. Setting., Sweden. Subjects., A total of 478 singleton men born in 1913 and participating in a population study in Gothenburg, Sweden, from age 50. Main outcome measures., Systolic blood pressure (SBP), antihypertensive treatment, incident diabetes mellitus, and serum total cholesterol, serum triglycerides and waist circumference as both continuous variables and in the highest quintiles of their distributions. Results., After adjustment for the influence of birth time variables, hereditary factors and anthropometric and socio-economic adult life variables, SBP decreased by 3.7 mmHg per 1000 g increase of birth weight, the prevalence of antihypertensive treatment decreased by 32%, diabetes decreased by 53%, serum total cholesterol decreased by 0.20 mmol L,1 and being in the top quintile of serum cholesterol decreased by 23%. The population risk percentage due to a birth weight ,3000 g was for all three outcomes 3.8% and for antihypertensive treatment, diabetes and cholesterol 0.2, 18 and 2.5%, respectively. Conclusions., Low birth weight thus seems to affect the development of increasing SBP, antihypertensive treatment, diabetes and high cholesterol even when potential effect modifiers from birth time, former generations and adult life were taken into account. In the general population, the risk percentage due to a birth weight ,3000 g was largest for diabetes. [source] Cardiovascular pharmacogenetics in the SNP eraJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 7 2003V. Mooser Summary., In the past pharmacological agents have contributed to a significant reduction in age-adjusted incidence of cardiovascular events. However, not all patients treated with these agents respond favorably, and some individuals may develop side-effects. With aging of the population and the growing prevalence of cardiovascular risk factors worldwide, it is expected that the demand for cardiovascular drugs will increase in the future. Accordingly, there is a growing need to identify the ,good' responders as well as the persons at risk for developing adverse events. Evidence is accumulating to indicate that responses to drugs are at least partly under genetic control. As such, pharmacogenetics , the study of variability in drug responses attributed to hereditary factors in different populations , may significantly assist in providing answers toward meeting this challenge. Pharmacogenetics mostly relies on associations between a specific genetic marker like single nucleotide polymorphisms (SNPs), either alone or arranged in a specific linear order on a certain chromosomal region (haplotypes), and a particular response to drugs. Numerous associations have been reported between selected genotypes and specific responses to cardiovascular drugs. Recently, for instance, associations have been reported between specific alleles of the apoE gene and the lipid-lowering response to statins, or the lipid-elevating effect of isotretinoin. Thus far, these types of studies have been mostly limited to a priori selected candidate genes due to restricted genotyping and analytical capacities. Thanks to the large number of SNPs now available in the public domain through the SNP Consortium and the newly developed technologies (high throughput genotyping, bioinformatics software), it is now possible to interrogate more than 200 000 SNPs distributed over the entire human genome. One pharmacogenetic study using this approach has been launched by GlaxoSmithKline to identify the approximately 4% of patients who are predisposed to developing a hypersensitivity reaction to abacavir, an anti-HIV agent. Data collected thus far on the HLA locus on chromosome 6 indicate that this approach is feasible. Extended linkage disequilibrium can be detected readily, even across several haplotype blocks, thus potentially reducing the number of SNPs for future whole-genome scans. Finally, a modest number of cases and controls appears to be sufficient to detect genetic associations. There is little doubt that this type of approach will have an impact on the way cardiovascular drugs will be developed and prescribed in the future. [source] Heritability of serum iron measures in the hemochromatosis and iron overload screening (HEIRS) family studyAMERICAN JOURNAL OF HEMATOLOGY, Issue 2 2010Christine E. McLaren Heritability is the proportion of observed variation in a trait among individuals in a population that is attributable to hereditary factors. The Hemochromatosis and Iron Overload Screening family study estimated heritability of serum iron measures. Probands were HFE C282Y homozygotes or non-C282Y homozygotes with elevated transferrin saturation (TS > 50%, men; TS > 45%, women) and serum ferritin concentration (SF > 300 ,g/L, men; SF > 200 ,g/L, women). Heritability (h2) was estimated by variance component analysis of TS, natural logarithm (ln) of SF, and unsaturated iron-binding capacity (UIBC). Participants (N = 942) were 77% Caucasians, 10% Asians, 8% Hispanics, and 5% other race/ethnicities. Average age (SD) was 49 (16) years; 57% were female. For HFE C282Y homozygote probands and their family members, excluding variation due to HFE C282Y and H63D genotype and measured demographic and environmental factors, the residual h2 (SE) was 0.21 (0.07) for TS, 0.37 (0.08) for ln SF, and 0.34 (0.08) for UIBC (all P < 0.0004 for comparisons with zero). For the non-C282Y homozygote proband group, residual h2 was significant with a value of 0.64 (0.26) for ln SF (P = 0.0096). In conclusion, serum iron measures have significant heritability components, after excluding known genetic and nongenetic sources of variation. Am. J. Hematol. 85:101,105, 2010. © 2009 Wiley-Liss, Inc. [source] Reduced Blood Platelet Sensitivity to Aspirin in Coronary Artery Disease: Are Dyslipidaemia and Inflammatory States Possible Factors Predisposing to Sub-optimal Platelet Response to Aspirin?BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 5 2006Leszek Markuszewski Platelet non-responsiveness to aspirin is associated with an increased risk of serious cardiovascular events. Several environmental and hereditary factors are reportedly involved in sub-optimal acetylsalicylic acid response. Forty-five coronary artery disease patients and 45 non-coronary artery disease controls received acetylsalicylic acid at a daily dose of 75,150 mg. Controls were examined twice: on the day of entering the study and 10 days later. Urinary 11-dehydrothromboxane B2 was assessed as the marker of platelet thromboxane generation. Aggregation was studied in platelet-rich plasma using turbidimetric aggregometry with collagen and arachidonic acid. Fifty to seventy percent of coronary artery disease patients showed an extent of collagen-induced aggregation above the upper quartile of the reference range compared with 8,15% in controls (P<0.003). For arachidonic acid-activated aggregation these proportions were 45,50% in coronary artery disease versus 7% in controls (P<0.007). In coronary artery disease patients, the acetylsalicylic acid-mediated platelet inhibition positively correlated with increased triglycerides (in arachidonic acid-stimulated platelets, r=0.30, P=0.0018), total cholesterol (r=0.33, P<0.0001 in coll and arachidonic acid-activated platelets) and elevated serum C-reactive protein (CRP) (r=0.27, P=0.0024). In coronary artery disease patients urine 11-dehydrothromboxane B2 concentrations were significantly increased compared to controls after 10 day acetylsalicylic acid intake (563; 313,728 pg/mg creatinine versus 321; 246,488 pg/mg creatinine, P=0.04). The incidence of suboptimal acetylsalicylic acid response incidence was more common in patients with coronary artery disease. Acetylsalicylic acid inhibition of blood platelet reactivity and thromboxane generation was less effective in these patients. Dyslipidaemia and chronic inflammatory states may promote suboptimal acetylsalicylic acid response in coronary artery disease patients. [source] | ||||||||||