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Irena Juki? Jasna Bingulac-Popovi? Vesna ?ogi? Ivana Babi? Jelena Culej Maja Tomi?i? Tomislav Vuk Dorotea ?arlija Melita Balija 《Croatian medical journal》2009,50(6):550-558
Aim
To assess the association between ABO blood group genotypes and genetic risk factors for thrombosis (FV Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations) in the Croatian population and to determine whether genetic predisposition to thrombotic risk is higher in non-OO blood group genotypes than in OO blood group genotypes.Methods
The study included 154 patients with thrombosis and 200 asymptomatic blood donors as a control group. Genotyping to 5 common alleles of ABO blood groups was performed by polymerase chain reaction with sequence specific primers (PCR-SSP). FV Leiden was determined by PCR-SSP, while prothrombin and methylenetetrahydrofolate reductase were determined by PCR and restriction fragment length polymorphism (PCR-RFLP).Results
There was an association between non-OO blood group genotypes and the risk of thrombosis (odds ratio [OR] 2.08, 95% confidence interval [CI], 1.32-3.27). The strongest association with thrombotic risk was recorded for A1B/A2B blood group genotypes (OR, 2.73; 95% CI, 1.10-6.74), followed by BB/O1B/O2B (OR, 2.29; 95% CI, 1.25-4.21) and O1A1/O2A1 (OR, 1.95; 95% CI, 1.15-3.31). FV Leiden increased the risk of thrombosis 31-fold in the group of OO carriers and fourfold in the group of non-OO carriers. There was no significant difference in the risk of thrombosis between OO and non-OO blood groups associated with prothrombin mutation. Non-OO carriers positive for methylenetetrahydrofolate reductase had a 5.7 times greater risk of thrombosis than that recorded in OO carriers negative for methylenetetrahydrofolate reductase.Conclusion
Study results confirmed the association of non-OO blood group genotypes with an increased risk of thrombosis in Croatia.ABO gene is located on chromosome 9 and its inheritance is explained by the Mendel and Bernstein three-allele theory. Methods of serologic typing allow the determination of 6 main phenotypes: A, B, A2, A2B, AB, and O. Methods of molecular biology allow the differentiation of 5 common alleles: O1, O2, A1, A2, and B; and 15 genotypes. ABO system is very well characterized by more than 165 alleles. Population studies have documented different frequencies of particular ABO genotypes worldwide (1). Also, there have been reports on a lower or higher association between ABO blood groups and cardiovascular, gastrointestinal, and infectious diseases (2).The association of ABO blood groups and diseases resulting in coagulation impairment and venous thrombus formation was first described by Jick et al (3). Most studies performed to date have generally agreed that non-OO blood group carriers have a higher risk of thrombosis than OO blood group carriers (4-7). Wu et al (8) believe that the introduction of ABO typing in the evaluation of thrombophilia patients should be considered in A1A1/A1B and BB genotypes with elevated von Willebrand factor (vWF) antigen levels in particular.Bezemer and Rosendaal (9) investigated new predictive genetic variants for venous thrombosis and identified ABO blood groups, fibrinogen gene haplotypes, factor V, factor VIII, and factor XIII Val34Leu polymorphisms as the possible new predictive variants for the disease development.Blood group O shows a tendency to bleeding and blood group A to clotting, due to the higher level of coagulation factors VIII and vWF in these individuals. The ABO blood groups also determine plasma levels of vWF, which is by 25-30% lower in O blood group than in non-O blood group. This occurs due to the direct functional impact of ABO locus; however, the exact mechanism has not yet been elucidated. Theoretically, ABO blood group can modify the rate of vWF synthesis or its secretion within endothelial cells, or act upon vWF catabolism, ie, proteolysis and/or plasma clearance (10).Venous thrombosis and disorders associated with coronary artery disease are vascular diseases in which both inherited and acquired factors are involved. It is of utmost importance to identify the risk factors implicated in the disease development and the candidates eligible for anticoagulant therapy to prevent recurrent thrombotic episodes. The most common inherited prothrombotic risk factors with significant impact on the development of thrombosis are mutations of the genes encoding proteins involved in the coagulation cascade, such as FV Leiden mutation and G20210A mutation of the prothrombin gene (11). In addition to coagulation factors, mutation of the methylenetetrahydrofolate reductase gene, known to influence the development of atherosclerosis and vascular diseases, has also been extensively investigated (12). It should be noted that the thrombogenic impact of homozygosity for methylenetetrahydrofolate reductase C677T mutation is only pronounced in case of its association with mild or moderate hyperhomocysteinemia and the genetic mutations mentioned above (13,14).The aim of this study was to define ABO genotypes in the population of Croatian blood donors and to assess the impact of ABO blood group genotypes and FV Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations on thrombosis development in the Croatian population. In addition, we investigated whether predisposition to thrombosis was higher in non-OO genotype carriers than in OO genotype carriers. Genotyping at 5 common alleles (O1, O2, A1, A2, and B) was used for ABO blood group determination because it provides more information on homozygous and heterozygous carriers of A, B, and O alleles than serotyping. The risk of thrombosis caused by a combination of multiple genetic factors (interaction of 2 risk factors) was also assessed. 相似文献4.
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HLA typing was done on 2,956 healthy, unrelated individuals living in four areas in Bulgaria. Of these, 163 had G6PD deficiency. The persons examined lived in villages situated at different altitudes. A low degree of correlation was found only for HLA-Al, -Aw23, -Bw35 and -B40 in the selected group with G6PD deficiency. The decrease of phenotype frequency of each HLA antigen was found to be directly proportional to the decrease of G6PD deficiency frequencies and related to environmental altitude, which is very typical for this selected group of carriers of this deficiency. 相似文献
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Barisić M Korać J Pavlinac I Krzelj V Marusić E Vulliamy T Terzić J 《Journal of human genetics》2005,50(11):547-549
Glucose-6-phosphate dehydrogenase (G6PD) deficiency protects from severe forms of malaria. It is interesting therefore to analyze the molecular basis underlying G6PD deficiency in regions such as the Mediterranean basin where malaria was present for a long time in history. Here we report on the genetic characterization of G6PD deficiency among inhabitants of one Mediterranean region-the Dalmatian region of south Croatia. We analyzed 24 unrelated G6PD-deficient male subjects. Molecular testing revealed several different mutations: G6PD Cosenza 9, G6PD Mediterranean 4, G6PD Seattle 3, G6PD Union 3, and G6PD Cassano 1. Furthermore, we have identified one novel G6PD variant that we named G6PD Split. This variant is caused by a nucleotide change 1442 C-->G leading to the amino acid substitution 481 Pro-->Arg and is characterized by moderate enzyme deficiency (class III variant). This study reveals a higher prevalence (37.5%) of the Cosenza mutation in the Dalmatian region than anywhere else previously investigated and overall shows the considerable molecular heterogeneity underlining G6PD deficiency that can be observed in Mediterranean populations. 相似文献
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Glucose-6-phosphate dehydrogenase (G6PD) mutations in Myanmar: G6PD Mahidol (487G>A) is the most common variant in the Myanmar population 总被引:4,自引:2,他引:4
Matsuoka H Wang J Hirai M Arai M Yoshida S Kobayashi T Jalloh A Lin K Kawamoto F 《Journal of human genetics》2004,49(10):544-547
We conducted a survey of malaria diagnoses and treatments in remote areas of Myanmar. Blood specimens from more than 1,000 people were collected by the finger-prick method, and 121 (11%) of these people were found to be glucose-6-phosphate dehydrogenase (G6PD) deficient. Of these 121, 50 consented to analysis of the G6PD genome. We read the G6PD sequences of these subjects and found 45 cases of G6PD Mahidol (487G>A), two of G6PD Coimbra (592C>T), two of G6PD Union (1360C>T), and one of G6PD Canton (1376G>T). Taken together with data from our previous report, 91.3% (73/80) of G6PD variants were G6PD Mahidol. This finding suggests that the Myanmar population is derived from homogeneous ancestries and are different from Thai, Malaysian, and Indonesian populations. 相似文献
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Matsuoka H Nguon C Kanbe T Jalloh A Sato H Yoshida S Hirai M Arai M Socheat D Kawamoto F 《Journal of human genetics》2005,50(9):468-472
We conducted a survey of malaria diagnoses and glucose-6-phosphate dehydrogenase (G6PD) testing in remote areas of Cambodia. Blood specimens from 670 people were collected by the finger-prick method. Of these people, 24.9% were found to have malaria, and 7.0% of people were G6PD deficient. In the Khmer, the largest ethnical population in Cambodia, the G6PD deficiency rate of males was 12.6% (25/199) whereas the rates in the minorities of the Tum Pun and the Cha Ray were 1.1% (1/93) and 3.2% (2/63), respectively. Of the G6PD-deficient subjects, 97.9% (46/47) were G6PD Viangchan (871G>A), and only one case (2.1%) was G6PD Union (1360C>T). Since G6PD Mahidol (487G>A) is common in Myanmar according to our previous study, the current finding suggests that the Cambodian population is derived from homogeneous ancestries and is different from the Myanmar population. All G6PD Viangchan cases were linked to two other mutations of 1311C>T and IVS-11 nt93T>C in the G6PD gene. 相似文献
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Glucose‐6‐phosphate dehydrogenase (G6PD) deficiency is the most common hereditary disorder in humans. Through a population study for G6PD deficiency using a cord blood quantitative G6PD assay in Bangkok, Thailand, we found that the prevalence of G6PD deficiency is 11.1% in Thai male (N=350) and 5.8% in female (N=172) cord blood samples. Among the neonates with hyperbilirubinemia, the prevalence of G6PD deficiency is 22.1% in males (N=140) and 10.1% in females (N=89). We developed a PCR‐restriction enzyme‐based method to identify G6PD Viangchan (871G>A), and searched for this and 9 other mutations in DNA from G6PD deficient blood samples. G6PD Viangchan (871G>A) was the most common mutation identified (54%), followed by G6PD Canton (1376G>T; 10%), G6PD Mahidol (487G>A; 8%), G6PD Kaiping (1388G>A; 5%), G6PD Union (1360C>T; 2.6%) and “Chinese‐5” (1024C>T; 2.6%). Among 20 neonates with hyperbilirubinemia, G6PD Viangchan was also most frequently identified (60%), followed by G6PD Canton (10%), G6PD Mahidol, G6PD Union, and G6PD Kaiping (5% each). G6PD Viangchan appears from this study to be the most common G6PD mutation in the Thai population, bringing into question previous reports that G6PD Mahidol is most prevalent. G6PD Viangchan, together with G6PD Mahidol and G6PD Canton, are responsible for over 70% of G6PD deficiency in this study of Thais. With the data from other Southeast Asian ethnic groups such as Laotians, G6PD Viangchan (871G>A) is probably the most common variant in non‐Chinese Southeast Asian population.© 2002 Wiley‐Liss, Inc. 相似文献
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Clones overexpressing clinical glucose 6-phosphate dehydrogenase (G6PD) mutants Union (c.1360C>T/p.Arg454Cys) and Andalus (c.1361G>A/p.Arg454His), have been constructed. These abolish a salt bridge between Arg454 and Asp 286. One mutant is reportedly a Class II clinical variant and the other a Class I. Kinetic studies of the purified proteins reveal that, for both mutants, kcat is about 10-fold decreased, thus giving a 90% decrease in the WHO assay, and also presumably under physiological conditions. In contrast with unfavourable changes in Vmax for both mutants, Km values for both G6P and NADP+ are decreased approximately 5-fold. Measurements with alternative substrates confirm that G6PD Union, like the wild-type enzyme, follows a rapid-equilibrium random-order mechanism, allowing calculation of enzyme-substrate dissociation constants from initial-rate parameters. The mutations result in several-fold tighter binding of glucose 6-phosphate to the free enzyme. Binding, however, is clearly less productive than with normal enzyme. G6PD mutations are thought to cause haemolytic anaemia by compromising enzyme stability. Both these mutants indeed show somewhat decreased thermostability. However, at 37 degrees C and with NADP+, the stability differences are only moderate. Decreased catalytic efficiency clearly contributes to the disease phenotype of these two mutants, entirely accounting for reported decrease in leukocyte G6PD levels, though not for still lower levels in erythrocytes. Neither the kinetic nor the stability effects appear to justify the different clinical classification of these mutations. 相似文献
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中山市PKU、CH、G6PD缺乏三种疾病新生儿筛查结果分析 总被引:6,自引:3,他引:6
目的 建立中山市新生儿疾病筛查方法 ,了解PKU、CH、G6PD缺乏的新生儿发病率。方法 10 783例新生儿分别在出生时采脐血肝素抗凝和出生后 4 8h~ 72h采足跟血制成滤纸干血斑。G6PD缺乏的筛查采用脐血荧光斑点定性试验测定G6PD活性 ,PKU筛查采用荧光定量法检测滤纸干血斑中Phe含量 ,CH筛查采用DELFIA法检测滤纸干血斑中TSH含量。结果 CH发病率 1/ 2 6 96 ,G6PD缺乏检出率 3 4 6 % ,未检出PKU。结论 新生儿筛查是PKU、CH、G6PD缺乏患儿得到早期诊治避免发生体格和智能发育障碍的有效手段 ,是提高人口素质的重要措施。 相似文献
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National G6PD neonatal screening program in Gaza Strip of Palestine: rationale,challenges and recommendations
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Congenital genetic disorders affecting neonates or young children can have serious clinical consequences if undiagnosed and left untreated. Early detection and an accurate diagnosis are, therefore, of major importance for preventing negative patient outcomes. Even though the occurrence of each specific metabolic disorder may be rare, their collective impact of preventable complications may be of considerable importance to the public health. Our previous studies showed that glucose‐6‐phosphate dehydrogenase (G6PD) deficiency is a problem of public health importance that has been shown to be a predominant cause of acute hemolytic anemia requiring hospitalization in Palestinian young children in Gaza Strip. Intriguingly, the majority of these children had one of the three variants, Mediterraneanc.563T, African G6PD A?c.202A/c.376G and heretofore unrecognized as a common G6PD‐deficient variant G6PD Cairoc.404C. The high prevalence of G6PD deficiency, as well as dietary factors in the region that precipitate anemia, argues for a need to protect the Palestinian children from a treatable and manageable genetic and metabolic disorder. This work reviews and discusses rationales and challenges of G6PD screening program in Gaza Strip. We advocate adopting a national neonatal G6PD screening program in Gaza Strip to identify children at risk and promote wellness and health for Palestine. 相似文献
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R. C. Stocco dos Santos O. C. O. Barretto K. Nonoyama N. H. C. Castro O. P. Ferraz J. Walter-Moura C. C. S. Vescio W. Beak 《American journal of medical genetics. Part A》1991,39(2):133-136
An apparently new X-linked syndrome is presented. It occurred in four male first cousins. The main manifestations of this syndrome are severe mental retardation, bilateral congenital hip luxation, and short stature. Three of the affected males showed a new glucose-6-phosphate dehydrogenase variant. 相似文献
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In an attempt to investigate the molecular mechanism underlying human glucose-6-phosphate dehydrogenase (G6PD) deficiency caused by two mutations, G6PD(Plymouth) (G163D) and G6PD(Mahidol) (G163S), the two variants were constructed by site-directed mutagenesis and expressed in G6PD-deficient E. coli DF 213 cells. A first indication of impaired folding came from problems in expressing these clinical mutants, which were only overcome by lowering the growth temperature or co-expressing with molecular chaperones (GroEL and GroES). Both strategies significantly increased soluble expression of recombinant G6PD(Plymouth) and G6PD(Mahidol), judged by both G6PD activity in extracts and the amount of immunoreactive protein. Using a modified 3-step protocol, the two mutant enzymes were successfully purified for the first time. Steady-state kinetic parameters (K(m) for NADP(+), K(m) for G6P and k(cat)) of the two mutants are very similar to the wild-type values, indicating that the catalytic efficiency of the two mutants remains unchanged. The two mutants are, however, markedly less stable than wild-type G6PD in both thermostability and urea-induced inactivation tests. In a typical experiment at 37 degrees C and pH 7.2 after 24h G6PD WT, G6PD(Mahidol) and G6PD(Plymouth) retained 58.3%, 27.0% and 3.9%, respectively, of their corresponding initial activity. The stability of all three enzymes is enhanced by addition of NADP(+). According to unfolding and refolding experiments, the two mutants are impaired in their folding properties. Thus structural instability appears to be the molecular basis of the clinical phenotype in G6PD(Plymouth) and G6PD(Mahidol) and in particular of the differing clinical severity of the two mutations. The 3-D structure solved for G6PD(Canton) allows an interpretation of these effects in terms of steric hindrance. 相似文献