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PubMedDate not supplied

Antigenic differences between normal human albumin and a genetic variant.

Agglutinating antisera were induced in rabbits against a purified genetic variant of human albumin and against normal albumin. These antisera had different specificities, as determined by inhibition experiments with the purified variant and normal albumin. The results suggest that genetic variants of human albumin differ antigenically from the normal protein. It is conceivable that antibodies against normal human albumin could be induced following albumin administration to individuals homozygous for an albumin variant.

Aged↗
PubMed1984

Isolation and characterization of a genetic variant of bovine proinsulin.

A genetic variant of bovine proinsulin has been isolated using preparative reverse-phase HPLC. The new proinsulin (bovine proinsulin II) differs from the known proinsulin (bovine proinsulin I) by a single amino acid residue at position C-48 in the connecting peptide. The amino acid replacement is a leucine substitution for proline. The two proinsulins were found in a ratio of approximately 9:1, proinsulin I: proinsulin II. No chemical or biological differences were observed for the two proinsulins other than their different elution times on reverse-phase HPLC.

Amino Acid Sequence↗
PubMed1994

Genetic variants of human serum albumin in Italy: point mutants and a carboxyl-terminal variant.

Of the > 50 different genetic variants of human serum albumin (alloalbumins) that have been characterized by amino acid or DNA sequence analysis, almost half have been identified in Italy through a long-term electrophoretic survey of serum. Previously we have reported structural studies of 11 Italian alloalbumins with point mutations, 2 different carboxyl-terminal variants, and 1 case of analbuminemia in an Italian family. This article describes confirmation by DNA sequencing of mutations previously inferred from protein sequencing of 4 of the above alloalbumins; it also reports the mutations identified by protein and DNA sequence analysis of 4 other Italian alloalbumins not previously recorded: albumin Larino, His3-->Tyr; Tradate-2 (protein sequencing only), Lys225-->Gln; Caserta, Lys276-->Asn; and Bazzano, a carboxyl-terminal variant. The first 3 have point mutations that produce a single amino acid substitution, but a nucleotide deletion causes a frameshift and an altered and truncated carboxyl-terminal sequence in albumin Bazzano. In these 4 instances the expression of the alloalbumin is variable, ranging from 10% to 70% of the total albumiN, in contrast to the usual 50% each for the normal and mutant albumin. The distribution of point mutations in the albumin gene is nonrandom; most of the 47 reported point substitutions involve charged amino acid residues on the surface of the molecule that are not concerned with ligand-binding sites.

Amino Acid Sequence↗
PubMedDate not supplied

Pesticides and susceptible populations: people with butyrylcholinesterase genetic variants may be at risk.

Butyrylcholinesterase (BChE) scavenges low doses of organophosphorus (for example, paraoxon) and carbamate pesticides (for example, carbaryl) and in this way protects people from the toxic effects of these poisons. The protective role of BChE is demonstrated by the finding that pesticide applicators can have reduced BChE activity with no clinical signs of poisoning. The question has arisen whether people with genetic variants of BChE are less protected. Seventy-six percent of the population is homozygous for wild-type BChE, while 24% carry at least one genetic variant allele. Most genetic variants of BChE have reduced activity. The clinically most important variant is atypical (D70G) BChE because people with this variant have 2 hours of apnea after receiving a dose of succinylcholine that is intended to paralyze muscles for 3-5 minutes. In test tube experiments the atypical variant reacts more slowly with all positively charged compounds (for example physostigmine, echothiophate). This leaves more toxin available for reaction with acetylcholinesterase in nerve synapses and predicts that people with atypical BChE will be less protected. Variants with low activity, such as silent BChE, are predicted to be at increased risk from organophosphorus pesticides based on experiments in monkeys and rodents where injection of purified BChE protected animals from the toxic effects of nerve agents. More studies are needed to strengthen the hypothesis that people with genetic variants of BChE are at higher risk of intoxication from pesticides.

Animals↗
PubMed2000

New genetic variants identified in donkey's milk whey proteins.

Novel genetic variants for donkey milk lysozyme and beta-lactoglobulins I and II have been identified by the combined use of peptide mass mapping and sequencing by tandem mass spectrometry in association with database searching. The novel donkey lysozyme variant designated as lysozyme B (Mr 14,631 Da) differed in three amino acid exchanges, N49 --> D, Y52 --> S, and S61 --> N, from the previously published sequence. Three novel genetic variants for donkey beta-lactoglobulins were identified. One of them is a type beta-lactoglobulin I with three amino acid exchanges at E36 --> S, S97 --> T, and V150 --> I (beta-lactoglobulin I B, Mr 18,510 Da). The two others are type beta-lactoglobulins II with two amino acid exchanges at C110 --> P and M118--> T (beta-lactoglobulin II B, Mr 18,227 Da) and with three amino acid exchanges at D96 --> E, C110 --> P, and M118 -->T (beta-lactoglobulin II C, Mr 18,241 Da). All these primary structures are closely related to those of homologous proteins in horse milk (percent identity >96%).

Amino Acid Sequence↗
PubMed1993

Protein and gene structure analysis of an albumin genetic variant: proalbumin Wu Yang (-2 Arg-->His).

An electrophoretically slow genetic variant of human serum albumin was isolated from a patient with bis-albuminemia in Xin Jiang who originated in the province of He Nan, county Wu Yang. Based on the FPLC-CNBr peptide profiles of the variant and normal albumins, the mutated CNBr peptide of the variant was found. Both the mutated and corresponding normal CNBr peptides were further subjected to trypsin digestion. An additional peptide peak from the mutated CNBr peptide was found in the HPLC mapping. The amino acid sequence of this peptide was determined to be Gly-Val-Phe-His-Arg corresponding to the fragment of albumin propeptide from position -5 to -1 with an -2 Arg-->His mutation. The N-terminal sequence of the mutated CNBr peptide was also determined to be Arg-Gly-Val-Phe-His*-Arg-Asp-Ala-His-Lys-, namely the N-terminal part of the mutated proalbumin. According to the known genomic structure of proalbumin, the gene fragments neighbouring the propeptide DNA sequences of the normal and variant albumins were amplified in vitro by polymerase chain reaction. The PCR products with 390 bp were then cloned into M13 vector, respectively. The nucleotide sequence analyses demonstrated that the codon CGT for -2 Arg was mutated to CAT for His. Thus, the point substitution was confirmed both at protein and gene levels. The above genetic variant of albumin was named proalbumin Wu Yang (-2 Arg-->His) being the first instance of the Lille type found in China.

Adolescent↗
PubMed2000

Expression of the genetic variants of human alpha-1-acid glycoprotein in cancer.

OBJECTIVES: We have investigated the AAG and its genetic variants concentrations in plasma samples of 61 patients suffering from different types of cancers. DESIGN AND METHODS: The patients were shared out in three groups, breast, lung, and ovary cancers groups. AAG concentration was measured by an immunonephelometric method and the phenotype was determined, after desialylation of plasma by analytical isoelectric focusing. Detection of AAG variants was made by immunoblotting and their proportions were determined by laser densitometry analysis. A population of 74 healthy individuals served as controls. RESULTS: The plasma concentrations of AAG in the breast and lung cancer groups were 2.5 times increased, while in the ovary cancer group, the concentrations were 1.6 times increased. AAG concentrations in the cancer population ranged between 0.45 and 2.85 g/L (mean value 1.12 +/- 0.51 g/L). The proportions of the ORM1 and ORM2 variants were similar to those in the healthy population. In breast and lung cancer groups, the relative concentrations of genetic variants were increased more than 2.5 fold, whereas a 1. 6-fold increase was observed in the ovary cancer group. CONCLUSIONS: These results show that AAG plasma concentrations are increased in these types of cancers and that changes in the expression of the genetic variants of AAG could also occur according to the type of cancer.

Adult↗
PubMed2004

An asthma-associated genetic variant of STAT6 predicts low burden of ascaris worm infestation.

Th-2 immune mechanisms are involved in the pathology of asthma and in the protective immune response to parasitic worms. Common upregulating genetic variants of Th-2 immune signalling are risk factors for asthma, and we tested whether they may confer a counteradvantage in protecting against parasitic worms. We examined the intensity of infection by the parasitic worm, Ascaris lumbricoides, by microsopic counting of ascaris eggs in the stool of 614 schoolchildren from an area of endemic ascaris infection in China. We investigated the relationship between the intensity of ascaris infection and common, asthma-associated genetic variants of Th-2 and Th-1 immune signalling. Ascaris egg counts per gram of stool (epg), mean 1068 epg, ranged from barely detectable (<240 epg) to heavy (approximately 9600 epg) in a skewed distribution. Logistic regression, after exploratory discriminant analysis, showed a major association between a common genetic variant of the 3'-UTR regulatory elements of the signal transducer and transactivating factor (STAT6) (P=0.0002) and egg counts, at the 77 th centile. Linear regression after log transformation of egg counts confirmed a highly significant association with this STAT6 variant (P=0.001). Thus, a common, asthma-associated, genetic variant of the pivotal transduction and transactivating factor for Th-2 immune signalling, STAT6, predicts increased resistance to ascaris worm infection. The evolution of enhanced resistance to parasitic worm infection, through human genetic variation in Th-2 immune signalling, may represent one origin for asthma.

3' Untranslated Regions↗
PubMed2006

Biantennary glycans as well as genetic variants of alpha1-acid glycoprotein control the enantioselectivity and binding affinity of oxybutynin.

PURPOSE: The purpose of this study was to investigate the role of biantennary branching glycans of alpha1-acid glycoprotein (AGP) and its genetic variants in the enantioselective binding of oxybutynin (OXY). METHOD: Human native AGP was separated using imminodiacetate-copper (II) affinity chromatography into two fractions, the A variant and a mixture of the F1 and S variants (F1-S). These fractionated AGPs were further separated by concanavalin A affinity chromatography into two fractions, with and without biantenarry glycans. An on-line high-performance liquid chromatography (HPLC) system consisting of a high-performance frontal analysis column, an extraction column, and an analytical HPLC column was developed to determine the binding affinities of OXY enantiomers for respective AGP species. RESULTS: The total binding affinity as well as the enantiomeric selectivity of OXY in the F1-S mixed variant was significantly higher than that for the A variant, indicating that the chiral recognition ability of native AGP for the OXY enantiomers highly depends on the F1-S mixed variant. Furthermore, not only the genetic variants but also bianntenary glycans of AGP affect the binding affinity of OXY and are also responsible for the enantioselectivity. CONCLUSIONS: Both genetic variants and glycan structures significantly contribute to the enantioselectivity and the binding affinity of OXY.

Carbohydrate Conformation↗
PubMed1987

Amino acid substitutions in genetic variants of human serum albumin and in sequences inferred from molecular cloning.

The structural changes in four genetic variants of human serum albumin were analyzed by tandem high-pressure liquid chromatography (HPLC) of the tryptic peptides, HPLC mapping and isoelectric focusing of the CNBr fragments, and amino acid sequence analysis of the purified peptides. Lysine-372 of normal (common) albumin A was changed to glutamic acid both in albumin Naskapi, a widespread polymorphic variant of North American Indians, and in albumin Mersin found in Eti Turks. The two variants also exhibited anomalous migration in NaDodSO4/PAGE, which is attributed to a conformational change. The identity of albumins Naskapi and Mersin may have originated through descent from a common mid-Asiatic founder of the two migrating ethnic groups, or it may represent identical but independent mutations of the albumin gene. In albumin Adana, from Eti Turks, the substitution site was not identified but was localized to the region from positions 447 through 548. The substitution of aspartic acid-550 by glycine was found in albumin Mexico-2 from four individuals of the Pima tribe. Although only single-point substitutions have been found in these and in certain other genetic variants of human albumin, five differences exist in the amino acid sequences inferred from cDNA sequences by workers in three other laboratories. However, our results on albumin A and on 14 different genetic variants accord with the amino acid sequence of albumin deduced from the genomic sequence. The apparent amino acid substitutions inferred from comparison of individual cDNA sequences probably reflect artifacts in cloning or in cDNA sequence analysis rather than polymorphism of the coding sections of the albumin gene.

Amino Acid Sequence↗
PubMed2006

The role of endothelial nitric oxide synthase (eNOS) genetic variants in European patients with intracranial aneurysms.

The endothelial nitric oxide synthase (eNOS) gene harbors three well-characterized genetic variants, which have been reported to be associated with various vascular diseases. Recently, conflicting results have been published relating to the role of these genetic variants in the pathogenesis of intracranial aneurysms (IA). Therefore, we analyzed these variants in a large European population of IA patients and controls. In all, 142 patients with IA and 190 controls were enrolled in our study. The -786T>C and 894G>T single-nucleotide polymorphisms (SNPs) were analyzed by direct sequencing of the corresponding sections in the genomic DNA. A variable number tandem repeat (VNTR) located in intron 4 of the gene and consisting of either four or five 27-base pair (bp) repeats was analyzed by polymerase chain reaction amplification and electrophoresis using ALF sequencertrade mark equipment. Genotype and allele frequencies were determined, and the frequencies in cases and controls were compared. In addition, haplotypes were constructed. There were no deviations from Hardy-Weinberg equilibrium. Genotype and allele frequencies did not differ significantly between cases and controls in any sample group or after stratification for multiple IA or aneurysm size. No single haplotype was significantly associated with the phenotype of an IA. The -786T>C, 894G>T, and 27-bp VNTR genetic variants of the eNOS gene are not associated with IA in the European population.

Adult↗
PubMed1979

Quantitative studies of the interaction of cholecalciferol ((vitamin D3) and its metabolites with different genetic variants of the serum binding protein for these sterols.

Cholecalciferol (vitamin D3) and its 25-hydroxy metabolite are transported in plasma bound to a specific protein, the binding protein for cholecalciferol and its metabolites (DBP). DBP is identical with the group-specific component (Gc) proteins, which are known to display genetic polymorphism. Studies were conducted to explore whether or not major differences in the transport of cholecalciferol and its biological metabolites might exist among persons with different Gc phenotypes. Detailed quantitative studies were first carried out on the interaction of 25(OH)D3 with DBP in 21 different samples of serum, representing eight different Gc phenotypes. The studies used a filter disc assay method that provided highly reproducible quantitative results with cholecalciferol-related sterols. The Gc phenotypes studied included the three common types (Gc 1-1, 2-1, and 2-2) and several uncommon genetic variants (Gc Ab-Ab, Ab-1, Ab-2, Chip-1, and Chip-2). The binding affinities for 25(OH)D3 observed with these different sera were all fairly similar to each other. More extensive studies were then conducted to compare the binding of four cholecalciferol-related sterols to each of three genetic variants of DBP, by using sera from homozygous persons with the Gc 1-1, Gc 2-2 and Gc Ab-Ab phenotypes. The ligands tested included cholecalciferol, 25(OH)D3, 1,25(OH)2D3, and 24(R) 25(OH)2D3. The affinities of the three genetic types of DBP/Gc protein were found to be similar for each of the four cholecalciferol-related sterols. The apparent association constants for 25(OH)D3 and 24,25(OH)2D3 were similar (approx. 1--2 x 10(8) M-1); lesser affinities were observed for 1,25(OH)2D3 (kA approx. 1 x 10(7) M-1) and for cholecalciferol (kA approx. 3--4 x 10(5) M-1). Thus the common genetic variants of DBP/Gc protein, and the uncommon genetic variants studied here, all appear to have similar binding properties for cholecalciferol and its several metabolites.

Alpha-Globulins↗
PubMed1977

Genetic studies of the Macushi and Wapishana Indians. I. Rare genetic variants and a "private polymorphism' of esterase A.

Blood samples from 509 Macushi and 623 Wapishana Amerindians of of Northern Brazil and Southern Guyana have been analyzed with reference to the occurrence of rare variants and genetic polymorphisms of the following 25 systems: (i) Erythrocyte enzymes: acid phosphatase-1, adenosine deaminase, adenylate kinase-k, carbonic anhydrase-1, carbonic anhydrase-2, esterase A1,2,3, esterase D, galactose-1-phosphate uridyltransferase, isocitrate dehydrogenase, lactate dehydrogenase, malate dehydrogenase, nucleoside phosphorylase, peptidase A, peptidase B, phosphoglucomutase 1, phosphoglucomutase 2, phosphogluconate dehydrogenase, phosphohexoseisomerase, triosephosphate isomerase and (ii) Serum proteins: albumin, ceruloplasmin, haptoglobin, hemoglobin A2 and transferrin. Fifteen different rare variants were detected, involving 11 of these systems. In addition, a previously undescribed variant of ESA 1,2,3 which achieves polymorphic proportions in both these tribes is described. Excluding this variant, the frequency of rare variants is 1.1/1000 in 12510 determinations in the Macushi and 4.7/1000 in 15396 determinations in the Wapishana. The ESA 1,2,3 polymorphism was not observed in 382 Makiritare, 232 Yanomama, 146 Piaroa, 404 Cayapo, 190 Kraho and 112 Moro. Irregularities in the intratribal distribution of this polymorphism in the Macushi and Wapishana render a decision as to the tribe of origin impossible at present. Gene frequencies are also given for previously described polymorphisms of 5 systems: haptoglobin, phosphoglucomutase 1, erythrocyte acid phosphatase, esterase D, and galactose-1-phosphate-uridyl-transferase.

Blood Proteins↗
PubMed2001

Surfactant protein A and B genetic variants and respiratory distress syndrome: allele interactions.

The contribution of multiple genetic components in disease pathogenesis is relevant to both diseases of multifactorial and/or multigenic etiology such as the respiratory distress syndrome (RDS) and to diseases where a single gene has been identified as the disease-causing gene. An example of the latter is cystic fibrosis (CF) where the disease-causing gene has been clearly identified as the CF transmembrane conductance regulator gene, but genetic variants of the mannose binding protein and surfactant protein A have been associated with disease severity in CF. The overall rationale for considering genetic contribution to disease pathogenesis is based on the premise that all diseases or deaths (except perhaps those resulting from trauma) have a genetic component. The difference in genetic contribution among various diseases is the percent contribution and the number of factors that make this contribution. Therefore, if the number of genetic contributors is small and the percentage of genetic contribution is high it may be less challenging to identify such factors. In this paper we summarize allele associations and discuss allele interaction of the surfactant protein genes in relation to RDS (the term allele and genetic variant will be used interchangeably).

Alleles↗
PubMed2006

Association between well-characterized lipoprotein-related genetic variants and carotid intimal medial thickness and stenosis: The Framingham Heart Study.

OBJECTIVE: To determine the association of well-characterized lipoprotein-related genetic variants with carotid intimal medial thickness (IMT) and stenosis. METHODS: 3380 men and women from the Framingham Offspring Study underwent carotid ultrasound to determine carotid IMT and stenosis>/=25%. We genotyped 12 variants in 10 lipoprotein-related genes known to be associated with significant differences in lipoprotein levels. RESULTS: For most of the variants, there was no association with carotid IMT. In multivariable, sex-specific analyses, the rare allele of the cholesterol ester transfer protein (CETP) TaqIB variant was associated with lower ICA IMT in men. Hypertension was associated with higher ICA IMT only in male carriers of the rare allele of the APOCIII Sst-1 variant (p for the interaction=0.041). In analyses of carotid stenosis in male, carriers of the lipoprotein lipase (LPL) N291S rare variant showed a higher risk of carotid stenosis (OR=2.59, 95% confidence interval: 1.11-6.02, p=0.028) compared to NN genotype. CONCLUSIONS: While there is no evidence for a significant association of several common lipoprotein-related genetic variants with carotid IMT, our results are consistent with the previously reported role of CETP and LPL genetic variants in cardiovascular risk and the possible modulation of the association between hypertension and carotid IMT by APOCIII Sst-1 variant.

Adolescent↗
PubMed2005

Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations.

This work describes an approach to characterize the clinical significance of genetic variants detected during the genetic testing of BRCA1 in patients from hereditary breast/ovarian cancer families. Results from transgenic mice and extensive clinical testing support the hypothesis that biallelic BRCA1 mutations result in embryonic lethality. Therefore, it is reasonable to conclude that variants of uncertain clinical significance found to reside in trans with known deleterious mutations impart reduced risk for cancer. This approach was applied to a large data set of 55,630 patients who underwent clinical BRCA1 screening by whole gene direct DNA sequencing. Fourteen common single nucleotide polymorphisms (SNPs) were used to assign 10 previously defined common, recurrent, or canonical haplotypes in 99% of these cases. From a total of 1,477 genetic variants detected in these patients, excluding haplotype-tagging SNPs, 877 (59%) could be unambiguously assigned to one or more haplotypes. In 41 instances, variants previously classified as being of uncertain clinical significance, mostly missense variants, were excluded as fully penetrant mutations due to their coincidence in trans with known deleterious mutations. From a total of 1,150 patients that harbored these 41 variants, 956 carried one as the sole variant of uncertain clinical significance reported. This approach could have widespread application to other disease genes where compound heterozygous mutations are incompatible with life or result in obvious phenotypes. This largely computational technique is advantageous because it relies upon existing clinical data and is likely to prove informative for prevalent genetic variants in large data sets.

Alleles↗
PubMed2006

Persistence of genetic variants of the arctic fox strain of Rabies virus in southern Ontario.

Genetic-variant analysis of rabies viruses provides the most sensitive epidemiologic tool for following the spread and persistence of these viruses in their wildlife hosts. Since its introduction by a southern epizootic movement that began in the far north, the arctic fox (AFX) strain of Rabies virus has been enzootic in Ontario for almost 50 y. Prior genetic studies identified 4 principal genetic variants (ONT.T1 to ONT.T4) that were localized to different regions of the province; furthermore, these viruses could be distinguished from the variant circulating in northern regions of Quebec, Newfoundland, and arctic zones, ARC.T5. Despite an intensive provincial control program undertaken over the last decade that involved aerial distribution of baits laden with rabies vaccine to combat fox rabies throughout the enzootic zone of Ontario, pockets of rabies activity persist. Re-evaluation of the genetic characteristics of the viral variants circulating in these areas of persistence has been undertaken. These data demonstrate that the recent outbreaks are, with 1 exception, due to persistence of the regional variant first identified in the area in the early 1990s. In contrast, the disease in the Georgian Bay area is a consequence of the incursion of a variant previously found further south. An outbreak that occurred in northern Ontario north and west of North Bay and in the neighboring border areas of Quebec in 2000-2001 was due to renewed incursion of the ARC.T5 variant from more northerly areas.

Animals↗
PubMed2004

High-throughput association testing on DNA pools to identify genetic variants that confer susceptibility to acute myeloid leukemia.

We have evaluated the use of allele-specific PCR (AS PCR) on DNA pools as a tool for screening inherited genetic variants that may be associated with risk of adult acute myeloid leukemia (AML). Two DNA pools were constructed, one of 444 AML cases, and another of 823 matched controls. The pools were validated using individual genotyping data for GSTP1 and LTalpha variants. Allele frequencies for variants in GSTP1 and LTalpha were estimated using quantitative AS PCR, and when compared to individual genotyping data, a high degree of concordance was seen. AS primer pairs were designed for nine candidate genetic variants in DNA repair and cell cycle/apoptotic regulatory genes, including Cyclin D1 [codon 870 splice site variant (A>G)]; BRCA1, P871L; ERCC2, K751Q; FAS -1377 (G>A); hMLH1 -93 (G>A) and V219I; p21, S31R; and the XRCC1 R194W and R399Q variants. For six of these assays, there was at least 95% concordance between AS PCR genotyping and an alternative approach carried out on individual samples. Furthermore, these six AS PCR assays all accurately estimated allele frequencies in the pools that had been calculated using individual genotyping data. A significant disease association was seen with AML for the -1377 variant in FAS (odds ratio 1.76, 95% confidence interval 1.26-2.44). These data suggest that quantitative AS PCR can be used as an efficient screening technique for disease associations of genetic variants in DNA pools made from case-control studies.

Base Sequence↗