SEARCH · Search PubMed

Results for “Genetic variant”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 55 records · Page 3Linked to original sources

PubMed2004

Novel CYP2C9 genetic variants in Asian subjects and their influence on maintenance warfarin dose.

BACKGROUND: Commonly occurring genetic variants in CYP2C9 are known to reduce catalytic activity and are associated with enhanced patient sensitivity to warfarin. Interethnic differences in warfarin dose requirement have been described in the Asian population, and we postulate that this could be related to genetic variants of CYP2C9 that are unique to ethnic groups. METHODS: We prospectively genotyped 125 patients who were receiving a stable daily warfarin dose to maintain international normalized ratio values between 2 and 3 through comprehensive sequencing of the promoter and coding regions of the CYP2C9 gene. RESULTS: The mean weight-adjusted warfarin maintenance dose was significantly lower for Malay and Chinese subjects than Indian subjects ( P <.001 and.014, respectively). Warfarin dose negatively correlated with age (r = -0.4, P <.001) but not with sex. Multiple variants were detected in the promoter, exonic, intronic, and 3'-untranslated regions of CYP2C9, of which 16 were novel, including 7 nonsynonymous exonic variants ( 208G>C, 374G>A, 485C>A, 895A>G, 1144C>T, 1190A>C, and 1362G>C ). CYP2C9*3, but not CYP2C9*2, was found in Chinese and Malay patients, and carriers of the CYP2C9*3 variant in Chinese ( P <.01) and Indian ( P <.01) patients, but not Malay patients ( P =.77), required less warfarin. The influence of the novel exonic variants on warfarin dose requirement was unclear, because they were rare, but the lower warfarin dose requirement for Chinese and Malay patients existed despite omission of individuals with any coding region variants from analysis. CONCLUSIONS: Interethnic differences in warfarin dosing in Asian subjects may result from other genetic, dietary, or environmental influences; however, these novel variants in the gene warrant further characterization through functional studies.

Adult↗

PubMed2006

Selective binding of imatinib to the genetic variants of human alpha1-acid glycoprotein.

Imatinib is a selective tyrosine kinase inhibitor, successfully used for the treatment of chronic myelogenous leukaemia. Its strong plasma protein binding referred to alpha1-acid glycoprotein (AGP) component was found to inhibit the pharmacological activity. AGP shows genetic polymorphism and the two main genetic variants have different drug binding properties. The binding characteristics of imatinib to AGP genetic variants and the possibility of its binding interactions were investigated by various methods. The results proved that binding of imatinib to the two main genetic variants is very different, the high affinity binding belongs dominantly to the F1-S variant. This interaction is accompanied with specific spectral changes (induced circular dichroism, UV change, intrinsic fluorescence quenching), suggesting that the bound ligand has chiral conformation that would largely overlap with other ligands inside the protein cavity. Binding parameters of Ka=1.7(+/-0.2)x10(6)M(-1) and n=0.94 could be determined for the binding on the F1-S variant at 37 degrees . Imatinib binding on the A variant is weaker and less specific. The binding affinity of imatinib to human serum albumin (nKa approximately 3 x 10(4)M(-1)) is low. Pharmacologically relevant binding interactions with other drugs can be expected on the F1-S variant of AGP.

Acridine Orange↗

PubMed1997

Capillary electrophoretic analysis of genetic variants of milk proteins from different species.

Polymorphism of bovine, ovine and caprine milk proteins was studied by CE. Identification of some rare bovine variants was carried out by isoelectric focussing (IEF) using PhastSystem. Genetic variants A and D of bovine alpha s2-casein, beta-casein variants A1, A2, A3, B and C and alpha s1-casein variants B and C were determined by CE. In addition, the different casein fractions including some genetic variants of ovine and caprine milk were identified by CE. In order to carry out this identification, collected fractions from a cation-exchange FPLC separation were injected by CE.

Animals↗

PubMed2002

Differences in denaturation of genetic variants of soy glycinin.

In heat denaturation studies conducted in the past the genetic variants of glycinin have been considered as a homogeneous group of proteins. In this work the validity of this assumption was tested. It was found by calorimetric studies that glycinin denatures heterogeneously at pH 7.6. When the temperature of isothermal treatment is increased from 70 to 82 degrees C the proportion of glycinin remaining native progressively decreases from 95% to 5% while the denaturation temperature of the glycinin remaining native increases from 88.5 to 95 degrees C. Similar trends were found for pH 3.8. Fractionation and subsequent analysis (MALDI-TOF and CE) of isothermally treated samples demonstrated that at pH 7.6 the heterogeneous denaturation is caused by differences in thermal stability of the genetic variants of glycinin. The stability increases in the order G2/G3/G1< A(4)< G5 < G4.

Calorimetry↗

PubMed1988

[Genetic variants of human albumin: structural characterization of allotypes used as references for electrophoretic classification].

Eight different types of genetic variants of albumin are observed in the French population. The analysis of electrophoretic patterns of sera containing these variants, performed a three different pHs (8.6, 5.0 and 6.9) after addition of a reference protein (transferrin), allows the identification each variant by a quantitative estimation of its relative mobilities. The accuracy and reproducibility of the technique make it a useful reference method, commonly employed for studying European variants. The samples used as references for five genetic variant types, proalbumins Christchurch and Lille, albumins Vanves, B and Reading, were subjected to sequence analysis to determine the nature and localization of their structural change. Together with the mutations of albumins Gent and Roma previously described, the data presented here make available seven reference specimens for which the structural changes are characterized out of the eight variants known to exist in France.

Amino Acid Sequence↗

PubMed1988

Genetic variants of influenza A/Taiwan/1/86 cocirculating in Canada during the winter of 1986 to 1987.

The first isolate of influenza virus in Canada during the winter of 1986 to 1987 was a genetic variant of A/Taiwan/1/86. This genetic variant type was the predominant strain obtained from several of the western provinces. The variant strains were antigenically indistinguishable from A/Taiwan/1/86 but were remarkably distinct by T1 oligonucleotide mapping. T1 mapping of individual genome segments indicated that the variants evolved from an A/Taiwan/1/86-like virus through the accumulation of point mutation or deletion or insertion events and probably do not contain foreign genes. The relative distribution of genetic variation was approximately equal among the individual genes, with the possible exception of segments 1 or 2 that were analyzed in combination and thus could not be individually associated with the observed variation.

Canada↗

PubMed1999

Genetic variants in the tumor necrosis factor receptor 1 gene in patients with MS.

We scanned for all genetic variants in functionally important regions of the tumor necrosis factor receptor 1 gene (TNF-R1) in 100 to 111 MS patients from Olmsted County, MN, and analyzed selected variants for an association with disease course and severity. Ten genetic variants were uncovered. Only one variant, a silent substitution, was found in coding sequence. One intronic variant may generate a novel splice-junction sequence. We did not find an association between either this intronic variant or another common promoter variant and the course or severity of MS.

Chromosome Mapping↗

PubMed2001

Role of biantennary glycans and genetic variants of human alpha1-acid glycoprotein in enantioselective binding of basic drugs as studied by high performance frontal analysis/capillary electrophoresis.

PURPOSE: To establish a clear understanding of the role of biantennary branching glycans and genetic variants of alpha1-acid glycoprotein (AGP) in enantioselective bindings of basic drug. METHODS: Human native AGP was separated using concanavalin A affinity chromatography into two subfractions, the unretained fraction (UR-AGP, defect of biantennary glycan) and the retained fraction (R-AGP, possessing biantennary glycan(s)). Imminodiacetate-copper (II) affinity chromatography was used to separate human native AGP into A variant and a mixture of F1 and S variants (F1*S variants). The mixed solutions of the (R)- or (S)-isomer of the model drugs (15 microM disopyramide (DP) or 30 microM verapamil (VER)) and 40 microM of respective AGP species were subjected to high-performance frontal analysis/capillary electrophoresis (HPFA/CE) to determine the unbound drug concentrations. RESULTS: The unbound concentrations (Cu) of DP in UR-AGP solutions were lower than those in R-AGP solutions, whereas there was no significant difference in the enantiomeric ratios (Cu(R)/Cu(S)) of DP between UR- and R-AGP solutions. In case of genetic variant, the Cu(R)/Cu(S) values of DP in F1*S and A solutions were 1.07 and 2.37, respectively. On the other hand, the enantiomeric ratio of VER in F1*S and A variant solutions were 0.900 and 0.871, respectively. CONCLUSIONS: The biantennary glycan structures are related to binding affinity of DP to AGP, but not responsible for the enantioselectivity. Genetic variants give significant effect on the enantioselectivity in DP binding, but not in VER binding.

Anti-Arrhythmia Agents↗

PubMed1998

Study of the expression of the genetic variants of human alpha1-acid glycoprotein in healthy subjects using isoelectric focusing and immunoblotting.

Human alpha1-acid glycoprotein (AAG) exists as an heterogeneous population of two or three genetic variants (ORM1 F1 and/or S and ORM2 A) in the plasma of most individuals. The ORM1 and ORM2 variants have a separate genetic origin. AAG belongs to the acute-phase proteins, which, under conditions of inflammation, increase several-fold in concentration. Additionally, there is evidence to suggest that it is not only the concentration but also the distribution of the two gene products of AAG (ORM1 and ORM2) that alter in such conditions. Variations of the relative concentrations of the AAG variants in certain diseases, such as cancer, can only be shown by reference to data collected in healthy people. In this study, we have investigated a group of 74 healthy subjects (42 men and 32 women) for AAG concentrations, AAG phenotypes and relative proportions of genetic variants in plasma. The specific assay of AAG was carried out by an immunonephelometric method and the phenotyping was performed, after desialylation of AAG, by analytical isoelectric focusing. Detection of the AAG variants was made by immunoblotting and their relative proportions were determined by laser densitometry analysis. The AAG plasma concentrations in the healthy group ranged between 0.28 and 0.92 g/l (mean value 0.50+/-0.14 g/l). The relative proportions of the variants derived from the two genes of AAG were variable, depending on the individual, but the amount of ORM1 variants almost always exceeded that of the ORM2 variant. No sex-related differences were observed in respect either in the total AAG level nor the relative proportions of the ORM1 and ORM2 variants. The data collected in this study may serve as a reference towards the investigation of possible changes in the expression of the genetic variants of AAG in chronic inflammatory diseases.

Adult↗

PubMed2026

Genetic Variants at the NAT2 and HLA-DOA are Associated With Anti-Tuberculosis Drug-Induced Liver Injury Susceptibility and Clinical Manifestations in Western Chinese Populations.

BACKGROUND: Anti-tuberculosis drug-induced liver injury (ATDILI) is one of the most prevalent and serious adverse reactions during anti-tuberculosis treatment and can potentially lead to liver failure or mortality. This study aims to investigate whether genetic variants in the N-acetyltransferase 2 gene (NAT2) and the HLA-DOA gene (HLA-DOA) are associated with ATDILI susceptibility and clinical manifestations in a Western Chinese population. METHODS: A total of 1358 participants with active tuberculosis were enrolled and genotyped for four NAT2 polymorphisms and five HLA-DOA loci. Associations between candidate genetic variants and ATDILI were evaluated using logistic regression analyses, with multiple comparisons adjusted by Bonferroni correction. RESULTS: The overall incidence of ATDILI was 28.4% (385/1358) in this cohort. Under a recessive model, NAT2 rs1799930 was found to increase the risk of ATDILI (odds ratio [OR] = 1.88, 95% confidence interval [CI]: 1.20-2.95, p = 0.006), which remained significant after Bonferroni correction (adjusted p = 0.048). Meanwhile, while HLA-DOA rs1367731 (OR = 0.41, 95% CI: 0.18-0.93, p = 0.033), rs6913008 (OR = 0.39, 95% CI: 0.17-0.89, p = 0.024), and rs9276975 (OR = 0.47, 95% CI: 0.23-0.98, p = 0.045) demonstrated a promising protective genomic characteristic that may mitigate the development of ATDILI. However, none of the reported HLA-DOA associations remained statistically significant after applying Bonferroni corrections. Regarding clinical manifestations, NAT2 rs1799930 and rs1799931 have been linked to poor ATDILI clinical presentations, whereas certain HLA-DOA variants (rs1367731, rs6913008, and rs9276975) were possibly linked to milder ATDILI severity. CONCLUSION: Our findings preliminarily suggest that the NAT2 and HLA-DOA genetic variants may play a role in ATDILI susceptibility and clinical outcomes. NAT2 rs1799930 represents a potential genetic risk marker, while HLA-DOA variants may serve as protective factors warranting further validation. These findings may contribute to the precision management of ATDILI and the prevention of anti-TB drug-associated liver injury.

Adult↗

PubMed1982

Genetic analysis of human lymphocyte proteins by two-dimensional gel electrophoresis: 3. Frequent occurrence of genetic variants in some abundant polypeptides of PHA-stimulated peripheral blood lymphocytes.

The 100 or so most intensely Coomassie blue-stained polypeptides from PHA-stimulated peripheral blood lymphocytes were analyzed by two-dimensional electrophoresis in combination with family and population studies. Besides polymorphic lymphocyte cytosol 64k polypeptide reported previously, genetic variants were frequently observed in three polypeptides with molecular weights of 100,000, 49,000, and 40,000. All of them occur in the cytosol. These variant polypeptides are charge variants, because they are separated in the isoelectric focusing dimension. It is indicated by family and population studies and cell distribution analysis that the polypeptide with a molecular weight of 100,000 shows a genetic polymorphism determined by two alleles at a new autosomal locus, as described in the following paper. Family and population studies also suggest that a genetic polymorphism defined by alleles at an autosomal locus is present in each of the polypeptides with molecular weights of 49,000 and 40,000. In contrast to the previous reports of the extremely restricted genetic variability of the 100 or so most abundant fibroblast polypeptides, the present data indicate that common genetic variants are present at least in four of the 100 or so most intensely Coomassie blue-stained lymphocyte polypeptides. The result also shows that careful side-by-side comparison of two-dimensional electrophoresis patterns among both parents and their children is an effective method to detect genetic variant polypeptides.

Blood Protein Electrophoresis↗

PubMed2003

Genetic variants of TNF-[FC12]a, IL-1beta, IL-4 receptor [FC12]a-chain, IL-6 and IL-10 genes are not risk factors for sepsis in low-birth-weight infants.

The amount of inflammatory cytokines is a major determinant for the development of sepsis in very-low-birth-weight (VLBW) neonates. We investigated whether variants of tumor necrosis factor-alpha, interleukin (IL)-1 beta, IL-4 receptor alpha-chain, IL-6 and IL-10 genes, associated with altered cytokine production, might influence the risk and complications of sepsis in VLBW infants. We determined the presence of these genetic variants in dried blood samples of 33 septic, 35 infected and 35 healthy VLBW neonates by PCR and RFLP methods and analyzed their association with the risk and complications of sepsis. The frequencies of genetic variants did not differ in uninfected and in infected infants with or without sepsis. Moreover, none of the studied complications was associated with carrier state of any of genetic variants. Four of the 5 septic neonates with disseminated intravascular coagulation, however, carried simultaneously the variants of IL-1 beta and IL-10 genes. We concluded that these genetic polymorphisms do not influence the risk and course of sepsis in VLBW neonates.

Alleles↗

PubMed2003

Rheological properties of concentrated skim milk: influence of heat treatment and genetic variants on the changes in viscosity during storage.

Heat treatment during manufacturing of milk powder is one of the most important tools for manipulation of its functional properties, and it is the basis of the classification of these proteins into low-, medium-, and high-heat types. Slight differences in the sequences of the major proteins in milk (genetic variants) seem to have also a significant effect in milk powder processing (U.S. patent). Therefore, the effects of high-temperature storage and heat treatment on skim milk of defined genetic variants of beta-lactoglobulin (beta-LG) were measured. The samples had 45% total solids, the temperature of aging was 50 degrees C, and the heat treatment was 90 degrees C for 10 min prior to evaporation. Measurements on shear rate and on apparent viscosity were determined for each sample. During storage of the concentrated milk, the apparent viscosity and yield values increased markedly, and the age-dependent increase in viscosity in heat-treated concentrated skim milks was much more pronounced than in those prepared from unheated skim milks. The increase in apparent viscosity and yield value with storage time was notably different for milks containing different genetic variants. Unheated concentrated milks containing the B variant of beta-LG showed the most rapid increase in apparent viscosity with storage time, whereas the viscosity increase was slowest in the concentrate containing the A variant. In contrast, heat-treated concentrated milks containing the A variant of beta-LG showed the most rapid increase in viscosity with storage time, whereas the viscosity increase was slowest in the concentrate containing the AB variant. The changes in apparent viscosity of concentrated milk were largely reversible under high shear during the early stages of storage, but samples stored for a long time showed irreversible changes in apparent viscosity. Particle size analysis confirmed irreversible aggregation and fusion of casein particles during storage.

Animals↗

PubMed2004

Brain-derived neurotrophic factor, apolipoprotein E genetic variants and cognitive performance in Alzheimer's disease.

Since greater attention has been paid to the direct link of genetic variation to cognition and memory performance, apolipoprotein E (ApoE) and brain-derived neurotrophic factor (BDNF) have been the two most frequently studied genes. To investigate the effect of BDNF and ApoE polymorphisms on the cognitive profile of mild-moderate Alzheimer's disease (AD) cases, AD patients, genotyped for ApoE and BDNF polymorphisms, underwent extensive neuropsychological investigation. The effect of either ApoE epsilon4 allele and BDNF genetic variant on the neuropsychological pattern of mental impairment was examined both in terms of group differences in performance on the neuropsychological tests between carriers and non-carriers of each variant and by selecting the best predictor of cognitive performance among demographic and genetic factors by means of a multiple regression analysis. Our data confirm a specific effect caused by the presence and amount of ApoE epsilon4 allele, while they suggest that BDNF genetic variants are not a susceptibility factor to AD.

Aged↗

PubMed2001

Crystal structures of bovine beta-lactoglobulin in the orthorhombic space group C222(1). Structural differences between genetic variants A and B and features of the Tanford transition.

The crystal structures of beta-lactoglobulin genetic variants A and B have been determined in the orthorhombic space group C222(1) (lattice Y) by X-ray diffraction at 2.0 A and 1.95 A resolution, respectively. The structural comparison shows that both variants exhibit the open conformation of the EF loop at the pH of crystallization (pH 7.9), in contrast to what has been reported for the same genetic variants at pH 7.1 in the trigonal space group P3221 (lattice Z) [Qin, B.Y., Bewley, M.C., Creamer, L.K., Baker, E.N. & Jameson, G.B. (1999) Protein Sci. 8, 75-83]. Furthermore, it was found that the stereochemical environment of Tyr42 changes significantly with pH variation between pH 7 and pH 8. This may provide a structural explanation for an as yet unexplained feature of the Tanford transition, namely the increase in exposure of a tyrosine residue.

Animals↗

PubMed2002

Synthesis, purification and structural and functional characterization of recombinant form of a common genetic variant of human luteinizing hormone.

A common genetic variant (V) of luteinizing hormone (LH), with two mutations (Trp(8)Arg and Ile(15)Thr) and an extra glycosylation consensus site (Asn(13)-Ala-Thr), is associated with abnormalities of reproductive function. To address the molecular basis of the functional differences between V- and wild-type (WT)-LH, recombinant (rec) forms of WT- and V-LH were synthesized in human embryonic kidney (HEK 293) cells. The rec hormones synthesized were rigorously purified employing affinity, immunoaffinity and ion exchange chromatographies (final purity approximately 12 000 IU/mg, 180-fold purification, 28% recovery). Functional properties of the hormone preparations were compared in vitro and in vivo. The molecular size of both rec LHs was 31 kDa, as determined by SDS-PAGE. Although the mutations in V-LHbeta did not significantly affect the affinity of LH receptor (LHR) binding (Kd approximately 0.4 nmol/L), V-LH had higher in vitro biopotency than WT-LH, in terms of mLTC-1 mouse Leydig tumor cell cAMP and progesterone (P) production, and steroidogenic acute regulatory protein (StAR) expression. In addition, in HEK 293 cells expressing the human LHR, V-LH demonstrated 1.8-fold higher response of inositol trisphosphate (IP(3)) production than WT-LH. Furthermore, HEK 293 cells expressing the ElK1 trans-reporting plasmids displayed 2.7-fold greater luciferase response to V-LH than WT-LH, documenting stimulation of the mitogen-activated protein kinase (MAPK) pathway. The in vivo half-life of V-LH was clearly faster (5-9 min) than that of WT-LH (12-22 min) and human chorionic gonadotropin (hCG; 50-70 min), when injected into rat circulation. It is worth noting that analysis by matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) demonstrated clear differences in structures of carbohydrate side chains attached to the two forms of rec LHs, including incomplete processing of high mannose glycans (Man(5,8,9)) in V-LH, suggesting different pathways in its intracellular trafficking. Collectively, the present findings provide the molecular basis for the qualitative and quantitative differences in LH action that are observed in carriers of the V-LHbeta allele.

Carbohydrate Conformation↗

PubMed1990

A comparison of the structure and properties of normal human transferrin and a genetic variant of human transferrin.

1. A rare genetic variant of human serum transferrin (TfBSHAW) is reported. 2. The variant and normal transferrins have been purified. 3. The two proteins have been shown to be identical with respect to their molecular weights, heat stability, iron uptake and absorbance spectra. 4. The amino acid substitution is thought to be isoleucine replaced by asparagine at either position 378 or position 381. 5. The ferric iron bound to the C-site of TfBSHAW is unstable in the presence of protons or 6 M urea.

Amino Acids↗

PubMedDate not supplied

[The geographical distribution of genetic variants of the tick-borne encephalitis virus].

Geographic distribution of 185 tick-borne encephalitis (TBE) virus strains isolated in 8 physico-geographic areas and classified into six genetic variants was analysed. The strains of genetic variant I homologous to the Sophyin prototype strain were found to occur predominantly in the Far East and also frequently found in Western and North-Western parts of the East European plain. The vast territories from lake Baikal in the East to Ukraine in the West harbor mostly the strains significantly different from the Far-Eastern Sophyin strain. Hybridization experiments with oligonucleotide probes specific for the Neudorffle strain showed that the strains genetically similar to the virus of central European encephalitis occurred also in Eastern Europe and Western Siberia. It is concluded that a relationship exists between genetic types of TBE virus and their geographic origin.

Animals↗