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Subjects Heterozygous (subject + heterozygous)
Selected AbstractsAnalysis of TPI gene promoter variation in three sub-Saharan Africa population samplesAMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 1 2009Licínio Manco Population samples from Angola, Mozambique, and S. Tomé e Príncipe were screened for the TPI gene promoter variants -5A,G, -8G,A and -24T,G. Three haplotypes were identified in the three populations: the haplotype -5A-8G-24T (average frequency 65.3%) and two less common haplotypes -5G-8G-24T (average frequency 24.7%) and -5G-8A-24T (average frequency 10.0%). A population sample from Central Portugal showed the haplotype -5A-8G-24T in 139 chromosomes and one subject heterozygous for haplotype -5G-8A-24G. The exact test of sample differentiation among three groups of malaria-infected individuals classified according to the severity of the disease showed no significant differences. We confirmed TPI gene diversity in sub-Saharan Africa, but we could not detect any association between TPI promoter variation and a malarial protective effect. Larger scale epidemiological studies are thus required to clarify this putative mechanism of natural host defense against this worldwide public health problem. Am. J. Hum. Biol., 2009. © 2008 Wiley-Liss, Inc. [source] The c.43_44insCTG variation in PCSK9 is associated with low plasma LDL-cholesterol in a Caucasian population,,HUMAN MUTATION, Issue 5 2006Pin Yue Abstract The genetic etiology of familial hypobetalipoproteinemia (FHBL) is unclear in the majority of cases. Mutations in apolipoprotein B (APOB) are the only confirmed causes of FHBL. Recently, loss-of-function mutations of PCSK9 gene have been shown to be associated with the hypocholesterolemia phenotype. Our primary goal was to confirm that mutations in PCSK9 could be another cause of FHBL. Using the sequencing approach, we found that the c.43_44insCTG variation in PCSK9, a common in-frame insertion in both African American and Caucasian populations, is associated with the hypocholesterolemia phenotype in three FHBL families. Then we tested whether this variation could be associated with lower cholesterol levels in the general population. A total of 403 subjects from a Caucasian population, in which hypobetalipoprotein (HBL) and normal groups were classified using standard criteria, were sequenced for this variation. The allele frequency of this variation in the HBL group was 0.186, but was only 0.128 in the normal lipid group. The mean plasma low-density lipoprotein (LDL)-cholesterol level in subjects heterozygous for this variant is significantly lower than that in the normal group (p<0.01). Heterozygous subjects also had higher high-density lipoprotein (HDL)-cholesterol levels (p<0.01). In general, LDL-cholesterol concentration in individuals with PCSK9 c.43_44insCTG variation was ,10,15 mg/dL lower than that in normal individuals. We conclude that the c.43_44insCTG variant plays a role in lowering cholesterol in the general population. Hum Mutat 27(5), 460,466, 2006. Published 2006 Wiley-Liss, Inc. [source] Separation of haemoglobin HbE and HbA2 by the fully automated, high-pressure liquid chromatography Tosoh HLC-723 G7 analyzerINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 5 2008G. LIPPI Summary High-pressure liquid chromatography instruments specifically devised for separating haemoglobin (Hb) fractions have been increasingly employed by the hospital laboratories over the recent years since they allow easy and fast screening for several Hb variants. Although such instruments may be proposed as sensitive, specific and reliable alternatives to the classic electrophoretic techniques, a major drawback of this screening strategy is the almost identical retention time of several Hb variants. In particular, at least 18 Hb variants have been reported in the same retention window as HbA2, including HbE, the second most common ,-chain variant in humans after sickle cell trait. Recently, we evaluated the performance characteristics of an improved buffer formulation originally conceived for Hb variants separation procedures on the fully automated high-pressure liquid chromatography instrument Tosoh G7. At variance with other fully automated high-pressure liquid chromatography analyzers, the elution pattern on the G7 in subjects heterozygous for HbE is characterized by the presence of four suggestive peaks (HbF, HbA, HbA2 and HbE), confirming the effective separation of HbE from HbA2. Because of its potential value in the diagnosis of the thalassaemia syndromes, the effective separation of HbA2 from HbE can provide clinical laboratories with a valuable information for the diagnostic reasoning. [source] Evaluation of a new venom-based clotting assay of protein CINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 5 2008P. C. COOPER Summary Congenital protein C deficiency significantly increases the risk of venous thromboembolism, a serious and potentially lethal condition. Protein C levels can be determined by chromogenic, clotting and antigenic assays, each type of assay has differences in specificity and sensitivity to protein C deficiency. In principle, clotting-based assays of protein C are preferred over chromogenic assays, as they can detect some rare mutations that are missed by the chromogenic assay, however, clotting-based assays may be prone to inaccuracy because of poor specificity. We have evaluated a new venom-based clotting assay of protein C, and optimized it for use on Sysmex CA-1500 analyser. The assay was linear from 0 to 130 U/dl, a normal plasma demonstrated good inter-assay precision, with a coefficient of variation of 4.8%. The assay compared well with antigenic- and venom-based chromogenic protein C assay in normal individuals, subjects with lupus anticoagulant, and subjects with FV Leiden. Median protein C levels by clotting, chromogenic and antigen for the three subject groups were 108 U/dl, 108 IU/dl and 109 IU/dl for normal subjects, 94 U/dl, 106 IU/dl and 103 IU/dl for subjects with lupus anticoagulant, and 102 U/dl, 104 IU/dl and 100 IU/dl for subjects heterozygous for FV Leiden. Comparing levels of clotting protein C with protein C antigen by ratio (clotting/antigen), the three groups showed small differences that did not quite reach statistical significance, (mean ratios ranged from 0.95 to 1.01, anovaP = 0.0561), the lowest ratio was with the lupus anticoagulant group. Comparing clotting assay with chromogenic assay by ratio (clotting/chromogenic), the three groups did show a statistically significant difference (P = 0.0033) which was due to a difference in mean ratios between normal and lupus anticoagulant groups (ratios 1.00 and 0.91, respectively, P < 0.01). There was no statistical difference in any of the groups when comparing chromogenic protein C with protein C antigen (mean ratios ranged from 1.02 to 1.05, P = 0.3925). In a normal sample, the clotting-based protein C level was unaffected by increasing FVIII level by up to 1000 IU/dl, using intermediate purity FVIII concentrate. The new assay is considered to be a suitable assay for the routine diagnosis of protein C deficiency. [source] Proplatelet formation in heterozygous Bernard-Soulier syndrome type BolzanoJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 3 2009A. BALDUINI Summary.,Background: Although mutations of GPIb, are among the most frequent causes of inherited platelet disorders, the mechanisms for the onset of thrombocytopenia and platelet macrocytosis are still poorly defined. Objective: In this work we analyzed in vitro megakaryocyte differentiation and proplatelet formation in six subjects heterozygous for the Ala156Val mutation in the GPIb, (Bolzano mutation). Methods: Human megakaryocytes were obtained by differentiation of patient cord blood-derived CD34+ cells and peripheral blood-derived CD45+ cells. Proplatelet formation was evaluated by phase contrast and fluorescence microscopy. Results: Megakaryocyte differentiation from both cord blood (one patient) and peripheral blood (five patients) was comparable to controls. However, proplatelet formation was reduced by about 50% with respect to controls. An identical defect of proplatelet formation was observed when megakaryocytes were plated on fibrinogen, von Willebrand factor or grown in suspension. Morphological evaluation of proplatelet formation revealed an increased size of proplatelet tips, which was consistent with the increased diameters of patients' blood platelets. Moreover, ,-tubulin distribution within proplatelets was severely deranged. Conclusions: Megakaryocytes from patients carrying a Bolzano allele of GPIb, display both quantitative and qualitative abnormalities of proplatelet formation in vitro. These results suggest that a defect of platelet formation contributes to macrothrombocytopenia associated to the Bolzano mutation, and indicate a key role for GPIb, in proplatelet formation. [source] The relation between two polymorphisms in the glucocorticoid receptor gene and body mass index, blood pressure and cholesterol in obese patientsCLINICAL ENDOCRINOLOGY, Issue 1 2003Anna Maria Di Blasio Summary objective ,We have recently reported that, in healthy elderly Dutch individuals, a N363S polymorphism in the glucocorticoid receptor (GR) gene is associated with higher sensitivity to low-dose dexamethasone (0·25 mg), evaluated as both cortisol suppression and insulin response, and with an increased body mass index (BMI). In the present study we investigated the role of the N363S polymorphism, and a BclI restriction site polymorphism in a group of Italian patients with severe obesity. design Two hundred and seventy-nine patients (mean BMI 45·9 ± 0·9 kg/m2) were genotyped using both PCR-restriction fragment length polymorphism analysis and Taqman Sequence Detection System. Determination of several metabolic and antropometric parameters was also performed in order to correlate them to the genotype. results In this group of obese patients, 13 subjects (eight female, five males) were heterozygous for the N363S variant (allelic frequency 2·3%) and had significantly higher BMI (P < 0·04), resting energy expenditure (P < 0·03) and food intake (P < 0·01) when compared to wild-type homozygotes. When the data were analysed according to sex, female heterozygotes for the N363S allele had significantly higher BMI (P = 0·04), resting energy expenditure (P = 0·03) and food intake (P = 0·008) than obese women with the wild-type 363 GR gene. Male carriers of this variant also had higher values for these variables although the differences did not reach statistical significance. A case,control study with homozygous wild-type obese subjects which were age-, sex- and BMI-matched, revealed no difference in resting energy expenditure and food intake. The allele frequency of the BclI variant was 27% (89 females and 41 males out of 269 subjects). No differences in anthropometric and metabolic parameters were found between subjects heterozygous or homozygous for this variant GR in this obese population. However, when we studied the effect of the presence of the BclI polymorphism and the N363S variant in the same individual, we found that the subjects who carried both polymorphisms had a tendency towards higher systolic and diastolic blood pressure and significantly higher total and LDL-cholesterol levels (P = 0·005 and P = 0·05, respectively). discussion Taking the results of this study and those obtained in the Dutch population, we speculate that heterozygous carriers of the N363S variant who develop obesity, may become even more obese, possibly because they have a hypersensitive insulin response and thus, via activation of lipogenesis, store fat more efficiently. Furthermore, these data suggest that N363S carriers who carry the BclI polymorphism as well, tend to have a slightly unfavourable cardiovascular profile. [source] | |||||||||||||