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PGM3 activity was investigated by means of horizontal starch gel electrophoresis. In the pig of the German Landrace three different phenotypes have been recognized: F, S and FS. Family studies suggest the occurrence of at least two alleles--PGM3F and the PGM3S at an autosomal locus.
Adhesion molecules are involved in the pathophysiology of respiratory syncytial virus (RSV)-associated diseases. By testing polymorphisms within ICAM-1, VCAM-1 and E-selectin, we found no evidence for association of any polymorphism with severe RSV infections. Thus, we conclude that these genes do not predispose to severe RSV-associated diseases.
AIM: To investigate whether the CYP3A5*3 polymorphism would affect cyclosporine A (CsA) metabolism in Chinese renal transplant patients. METHODS: The CYP3A5*3 genotype was determined in Chinese renal transplant recipients using polymerase chain reaction and amplification of specific alleles (PCR-ASA). The concentrations of CsA and metabolites were separately measured by fluorescence polarization immunoassay and dose-adjusted trough concentrations and metabolic ratio (MR) values were calculated. RESULTS: The trough concentrations adjusted with the dose was significantly higher in the wild allele carriers compared to both the homozygous (*3*3) and heterozygous variants (*1*3). However, no significant difference was found for the dose-adjusted metabolite concentrations. The MR values for the 3 genotype groups were as follows: 0.92+/-0.62 for CYP3A5*3/ *3 (n=14), 0.99+/-0.51 for CYP3A5*1/*3 (n=15), and 1.45+/-0.62 for CYP3A5*1/*1 (n=9), respectively. Post hoc comparisons showed that only the MR values between the CYP3A5*3/*3 group and the CYP3A5*1/*1 group were significantly different. CONCLUSION: The CYP3A5*3 polymorphism exerted little effect on cyclosporine metabolism. The MR may be a more accurate indicator for therapeutic drug monitoring, considering its integrated information on body exposure of both parent drugs and metabolites.
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The study was designed to define the contribution of cytochrome p450 2C19 (CYP2C19) and cytochrome p450 3A4 (CYP3A4) to citalopram N-demethylation and to evaluate the relationship between the disposition of citalopram and CYP2C19 genotype. A single oral 40-mg dose of citalopram was administered to eight extensive metabolizers and five poor metabolizers recruited from 77 healthy Chinese volunteers whose genotypes and phenotypes were predetermined. The plasma concentrations of citalopram and desmethylcitalopram were determined by high-performance liquid chromatography. It was found that the genotype of CYP2C19 had a significant effect on the N-demethylation of citalopram. Poor metabolizers with m1 mutation had higher area under the plasma concentration versus time curve (AUC0--> infinity ) values than did extensive metabolizers. Terminal elimination half-life (t1/2) values of citalopram in poor metabolizers were significantly higher than the values in extensive metabolizers who were either homozygous or heterozygous with CYP2C19*1. The oral clearance (CLoral) of citalopram in poor metabolizers was significantly lower than that of extensive metabolizers. The AUC0--> infinity and maximum plasma concentration (Cmax) of desmethylcitalopram in poor metabolizers were significantly lower than the values of extensive metabolizers. The results show that CYP3A4 is not the major enzyme in the N-demethylation of citalopram among extensive metabolizers. The polymorphism of CYP2C19 plays an important role in the N- demethylation of citalopram in vivo. The extensive metabolizers and poor metabolizers of CYP2C19 had significant difference in disposition of citalopram in vivo.
The human proton-dependent dipeptide transporter (PEPT1, gene SLC15A1) is important for intestinal absorption of di- and tripeptides and a variety of peptidomimetic compounds. Using a DNA polymorphism discovery panel of 44 ethnically diverse individuals, nine nonsynonymous and four synonymous coding-region single-nucleotide polymorphisms (SNPs) were identified in PEPT1. HeLa cells were transiently transfected with plasmids constructed by site-directed mutagenesis for each of the nine nonsynonymous variants. Quantitative polymerase chain reaction showed that the mRNA transcription level of all of the mutants was comparable with the mRNA transcription level of the reference sequence in transfected HeLa cells. Functional analysis in transiently transfected HeLa cells revealed that all nonsynonymous variants retained similar pH-dependent activity and K(t) values for [glycyl-1,2-(14)C]glycylsarcosine (Gly-Sar) uptake as the reference PEPT1. In addition, a group of seven peptide-like drugs showed inhibitory effect on Gly-Sar uptake by these variants comparable with the reference, suggesting conserved drug recognition. Of the nine nonsynonymous SNPs, a single SNP (P586L) demonstrated significantly reduced transport capacity as evidenced by a much lower V(max) value. This was consistent with lower immunoactive protein level (Western analysis) and lower plasma membrane expression (immunocytochemical analysis). Therefore, Pro(586) may have profound effect on PEPT1 translation, degradation, and/or membrane insertion.
Population frequencies of the two patterns of pepsinogen excretion (with and without pepsinogen 5) and family studies indicate that pepsinogen 5 is controlled by a pair of genes, Pg(a) and Pg(b), at a single autosomal locus and that Pg(a) is dominant.
In a survey of 860 unselected human placental extracts, three variants of mitochondrial glutamic oxaloacetic transaminase were found, all of which were common enough to be considered polymorphisms. Family studies showed that this enzyme is under the control of nuclear rather than mitochondrial DNA.
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Thirteen experimenital populationis of Drosophila willistoni were maintained in cages, in some of which the environments were relatively constant and in others varied. After 45 weeks, the populations were assayed by gel electrophoresis for polymorphisms at 22 protein loci. The average heterozygosity per individual and the average unmber of alleles per locus were higher in populations maintained in heterogeneous environments than in populations in more constant enviroments.
In randomly collected saliva samples from 120 Caucasians, 79 Blacks, and 40 Chinese, three phenotypes were observed by electrophoresis in alkaline slab polyacrylamide gels. The proteins showing polymorphism were identical with four previously characterized proline-rich proteins. Inheritance is controlled by two autosomal codominant alleles. The gene frequencies were for Caucasians, Pr(l)=0.73, Pr(2)=0.27; for Blacks, Pr(1)=0.80, Pr(2)=0.20; for Chinese, Pr(l)=0.84, Pr(2)=0.16.
Resistance to antimalarial drugs is a public health problem worldwide. Molecular markers for drug-resistant malaria, such as pfcrt and pfmdr1 polymorphisms, could serve as useful surveillance tools. To evaluate this possibility, sequence polymorphisms in pfcrt (position 76) and pfmdr1 (positions 86, 184, 1034, 1042, and 1246) and in vitro drug sensitivities were measured for 65 Plasmodium falciparum isolates from Thailand, Myanmar, Vietnam, and Bangladesh. The pfcrt Thr76 polymorphism was present in 97% of samples, consistent with observations that chloroquine resistance is well established in this region. Polymorphisms in pfmdr1 clustered into four specific patterns: the wild type (category I), a Tyr86 polymorphism only (category II), a Phe184 polymorphism only (category III), and Phe184 in combination with Cys1034 and/or Asp1042 (category IV). Isolates in categories I and III were more sensitive to chloroquine and more resistant to mefloquine, artesunate, and artemisinin than isolates in categories II and IV (P </= 0.01). Mefloquine resistance was significantly more common in category I and III isolates than in category II and IV isolates, with a prevalence ratio of 14.95 (95% confidence interval, 3.88 to 57.56). These categories identified mefloquine resistance with a sensitivity and a specificity of 94 and 91%, respectively. The pfmdr1 gene copy number was measured by real-time PCR as a ratio of the amount of pfmdr1 DNA to the amount of lactate dehydrogenase (ldh) DNA. Eight samples had pfmdr1 DNA/ldh DNA ratios >/=3. The isolates in all 8 samples fell into categories I and III and were significantly more resistant to mefloquine, quinine, artemisinin, and artesunate and more sensitive to chloroquine than the isolates in the 57 samples with <3 copies of the gene (P </= 0.001). Thus, measurement of pfmdr1 mutations and gene copy number may be useful for surveillance of mefloquine-resistant malaria in Southeast Asia.
mtp40 was originally identified as a short genomic region that was found in strains of Mycobacterium tuberculosis but not in Mycobacterium bovis. Subsequent studies have revealed that the sequence is part of the mpcA gene, which encodes a phospholipase C. To investigate further the distribution of the mtp40 sequence, we analyzed strains of the M. tuberculosis complex by PCR and were able to amplify the mtp40 sequence in 90 of 94 strains of M. tuberculosis and in 2 strains of Mycobacterium microti but not in M. bovis or M. bovis BCG. Based on this, we developed a dot blot assay using genomic DNA which allows M. bovis to be distinguished from the majority of M. tuberculosis strains. We also probed Southern blots of 140 clinical isolates of M. tuberculosis to determine the frequency of strains lacking mtp40. This revealed an unexpected polymorphism in the phospholipase region. Two fragments were detected in 57% of samples. The expected fragment of 0.75 kbp corresponds to the region of mpcA containing mtp40. A 2.1-kbp fragment was observed to belong to a recently discovered second phospholipase gene, mpcB. In addition, some strains appeared to lack both genes, while others showed only the presence of mpcA. A few strains had additional bands, suggesting the existence of other homologs to the two phospholipase genes. We also detected the insertion of IS6110 in the mpcA coding region of one strain. The absence of these genes in some clinical isolates raises questions about their function during infection and in the development of tuberculosis disease in humans.
Polymorphisms in the coding sequences of CCR5 and CXCR4 were studied in a group of human immunodeficiency virus (HIV)-infected long-term nonprogressors. Two different point mutations were found in the CXCR4 coding sequence. One of these CXCR4 mutations was silent, and each was unique to two nonprogressors. The well-described 32-bp deletion within the CCR5 coding sequence (CCR5-Delta32) was found in 4 of 13 nonprogressors, and 12 different point mutations were found scattered over the CCR5 coding sequence from 8 nonprogressors. Most of the mutations created either silent or conservative changes in the predicted amino acid sequence: only one of these mutations was found in more than a single nonprogressor. All nonsilent mutations were tested in an HIV envelope-dependent fusion assay, and all functioned comparably to wild-type controls. Polymorphisms in the CXCR4 and CCR5 coding sequences other than CCR5-Delta32 do not appear to play a dominant mechanistic role in nonprogression among HIV-infected individuals.
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Data are presented on a group of cases of primary carcinoma of the bladder, detailing red cell surface blood group antigenic phenotypes, serum haptoglobin phenotypes, and some red cell isoenzyme phenotypes. Account is taken of the stage of the disease at presentation. The results are compared with corresponding phenotype frequencies in groups of presumed healthy persons originating either in Yorkshire or County Durham. Differences in relative incidences were found in the haptoglobin, phosphoglucomutase (PGM), and some other systems. These are both differences between all cases and controls and between particular stages at presentation and controls.
OBJECTIVES: To evaluate possible influences of CCG and delta2642 glutamic acid polymorphisms adjacent to the (CAG)n trinucleotide repeat in Huntington's disease gene IT15 on some clinical features (age and symptoms) at onset. METHODS: 84 patients and a control group of 68 unaffected relatives were studied. Patients all belonged to a group of affected persons tested for molecular confirmation of Huntington's disease. The length of the CAG repeat sequence in the IT15 gene and the adjacent CCG and delta2642 polymorphisms were determined by quantitative polymerase chain reaction. RESULTS: Two intragenic polymorphisms were studied: (CCG)n and delta2642 glutamic acid. Patients were classified firstly according to the size of the CCG rich segment adjacent to the CAG repeat into genotype groups CCG 7/7, 7/8, 7/9, 7/10, and 10/10 and then according to delta2642 polymorphism into genotype groups A/A (absence of the delta2642 deletion), A/B, and B/B (presence of the delta2642 deletion in respectively one and two alleles). The presence of delta2642 mutation was associated with a significant decrease in age at onset, although there was no significant increase in CAG size. A good correlation was found between the (CAG)n trinucleotide repeat size and the age at onset in patients with genotype AA (r2=0.72). Within patients of the A/B genotype group however, a significant correlation was found but with a drop of the r2 value to 0.44. No association was found between age at onset and the CCG polymorphism. Although an increased percentage of patients within the A/A genotype group had a neurological onset, we found no overall significant association between CCG or delta2642 polymorphisms and the nature of symptoms at onset. CONCLUSIONS: The delta2642 glutamic acid polymorphism did not affect CAG repeat size nor the nature of symptoms at onset but seems to influence the age at onset in patients with Huntington's disease.