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At least 307 records · Page 17Linked to original sources
PubMed2004

The ADPRT V762A genetic variant contributes to prostate cancer susceptibility and deficient enzyme function.

The ADP-ribosyltransferase (ADPRT) gene encodes a zinc-finger DNA-binding protein, poly(ADP-ribose) polymerase-1 (PARP-1), that modifies various nuclear proteins by poly(ADP-ribosyl)ation and functions as a key enzyme in the base excision repair pathway. We have conducted two studies to test whether an amino acid substitution variant, ADPRT V762A (T2444C), is associated with prostate cancer (CaP) risk and decreased enzyme function. The first study used genomic DNA samples from an ongoing, clinic-based case-control study (488 cases and 524 controls) to show that a higher percentage of the CaP cases carried the ADPRT 762 AA genotype than controls (4% versus 2%). In Caucasians, the AA genotype was significantly associated with increased CaP risk [odds ratio (OR), 2.65; 95% confidence interval (CI), 1.08-6.49], and the VA genotype was associated with a slight but not significantly increased CaP risk (OR, 1.18; 95% CI, 0.85-1.64) using VV as the referent group after adjustment for age, benign prostatic hyperplasia, and family history. Furthermore, this association was stronger in younger (<65) men (OR, 4.77; 95% CI, 1.01-22.44) than older (> or =65) men (OR, 1.78; 95% CI, 0.55-5.82). The second study used freshly isolated peripheral lymphocytes from 354 cancer-free subjects to demonstrate that the ADPRT 762 A allele contributed to significantly lower adenosine diphosphate ribosyl transferase (ADPRT)/PARP-1 activities in response to H2O2 in a gene dosage-dependent manner (P < 0.0001, test for linear trend). The PARP-1 activities (mean +/- SD dpm/10(6) cells) were 18,554 +/- 9,070 (n=257), 14,847 +/- 7,082 (n=86), and 12,155 +/- 6,334 (n=11) for VV, VA, and AA genotypes, respectively. This study is the first to provide evidence that the ADPRT V762A-genetic variant contributes to CaP susceptibility and altered ADPRT/PARP-1 enzyme function in response to oxidative damage.

ADP Ribose Transferases↗
PubMed1980

Biochemical and immunological characterization of genetic variants of phosphoglucose isomerase from mouse.

Two electrophoretic variants of phosphoglucose isomerase (PGI) were purified from whole body extracts of DBA/2J and C57BL/6J mice by a substrate-affinity elution from an 8-(6-aminohexyl)amino-ATP-Sepharose column followed by preparative isoelectric focusing. Both PGI variants were shown to be dimers of the same molecular weight, sedimentation coefficient, and Km for fructose-6-phosphate. The isoelectric points were found to be 8.4 and 8.7 for variants from DBA/2J and C57BL/6J mice, respectively. Differential thermal stability was observed for the two variants in 0.1 M tris-HCl buffer, pH 8.0, at 54 C; the half-lives of the purified PGI from DBA/2J and C57BL/6J mice were shown to be 3.4 and 1.8 min, respectively, under those conditions. Similar differences were observed for the enzyme variants in the crude homogenates. Antisera against PGI from DBA/2J mice were raised in rabbits. The variants from DBA/2J and C57BL/6J mice showed no significant differences in their respective inactivation curves by the antisera. Results of amino acid composition analyses and peptide mappings of the two PGI variants indicate that the genetic variation of this enzyme might result from a single charged amino acid substitution.

Animals↗
PubMed2026

Co-regulation of HIV control and cytomegalovirus pp65-specific IL-1&#x3b2; and TNF-&#x3b1; responses by genetic variants in the MHC region.

The spontaneous control of HIV infection in the absence of antiretroviral therapy, termed HIV control, is associated with genetic variation in the Major Histocompatibility Complex (MHC) locus. These variants are known to influence the immune response to HIV itself. However, people living with HIV are often co-infected with other pathogens that can also elicit immune responses, which might also be regulated by these variants. Here, we assessed whether genetic variants associated with HIV control influence cytokine responses to various co-pathogens. HIV-control-associated single nucleotide polymorphisms (SNPs) were enriched among variants regulating TNF-&#x3b1; and IL-1&#x3b2; production upon CMV pp65 peptide pool stimulation. The top enriched SNPs, rs1128175-A and rs2853971-A, were linked to lower odds of HIV control and increased cytokine responses to CMV. These SNPs were in linkage disequilibrium (LD) with classical HLA alleles HLA-B*07:02 and HLA-C*07:02. Intracellular cytokine staining showed CMV serostatus-dependent production of TNF-&#x3b1; by monocytes and CD8 T cells. The rs1128175-A/rs2853971-A/HLA-B*07:02/HLA-C*07:02 haplotype was associated with increased IFN-&#x3b3; production by CD8 T cells upon CMV pp65 peptide pool stimulation, indicating an effect on memory responses. Quantitative trait locus (QTL) mapping showed that rs1128175 and rs2853971 influence HLA-B and HLA-C expression, DNA methylation levels and cell-type-specific cis-effects on chromatin accessibility, as well as CD8 T cell subset abundance. These QTL associations suggest that variants associated with poor HIV control are linked to heightened pro-inflammatory responses to CMV pp65 through effects on antigen presentation, epigenetic modifications, gene expression and immune cell repertoire, potentially negatively affecting HIV control status.

Humans↗
PubMed2000

Allelic frequencies of host genetic variants influencing susceptibility to HIV-1 infection and disease in South African populations.

OBJECTIVES: Limited information is available on the prevalence in African populations of host genetic polymorphisms conferring resistance to HIV-1 infection and disease. The objective of this study was to determine the allelic frequencies in South African populations of the chemokine receptor gene variants CCR5delta32, CCR5m303 and CCR2b-641 and the CXCR4 ligand gene variant SDF1-3'A. METHOD: Cross-sectional study to determine the prevalence of these gene variants in South African subjects of African and European descent. RESULTS: The CCR5delta32 genetic variant is rare in individuals of African origin, having an allelic frequency of 0.1% (n = 1247) compared with 9.8% (n = 144) in Caucasians. The CCR5m303 mutation was not detected in Africans (n = 687), whereas an allelic frequency of 0.9% (n = 145) was identified in Caucasians. The frequency of CCR2b-641 allele was 13.1% (n = 180) in Africans, which was significantly higher that the 7.2% (n = 146) detected in Caucasians. Finally the allelic frequency of the SDF1-3'A gene variant was only 1.0% (n = 198) in Africans compared with 19.8% (n = 145) in Caucasians. CONCLUSIONS: These results indicate that genetic polymorphisms conferring resistance to HIV-1 infection are rare in the South African Black population. Except for the CCR2b-641 gene variant, individuals of African origin also had a much lower prevalence of genetic variants associated with prolonged disease progression.

Alleles↗
PubMed1978

Genetic variants of hemoglobin in canine erythrocytes.

Genetic polymorphism of hemoglobin was found in the erythrocytes of dogs of seven Japanese native breeds by using starch gel electrophoresis. Analysis of parentage records of the dogs revealed that the phenotypic variation of hemoglobin is controlled by one autosomal locus with two codominant alleles, HbA and HbB. the allele HbA occurred only in Japanese native breeds except Shikoku. The frequency of HbA in the Japanese breeds was low and 0.08. All the dogs belonging to 25 European breeds and 5 oriental origin (except Japan) breeds examined in this experimnets had the homozygous genotype constitution HbB/HbB.

Alleles↗
PubMed1999

Luteinizing hormone and different genetic variants, as indicators of frailty in healthy elderly men.

We investigated the possible clinical correlates between the serum LH concentration and characteristics of frailty and determined the presence and concentration of a genetic LH variant in an independently living population of elderly men. After exclusion of subjects with severe mobility problems and signs of dementia, 403 healthy men (aged 73-94 yr) were randomly selected from a population-based sample. Total testosterone (T), sex hormone-binding globulin (SHBG), and leptin were determined by RIA. Non-SHBG-bound T was calculated. LH and the presence of the genetic LH variant were measured using immunofluorometric assays. The characteristics of frailty were leg extensor strength using dynamometry, bone mineral density of total body and proximal femur, and body composition, including lean mass and fat mass, measured by dual energy x-ray absorptiometry. Disability was further assessed by the Modified Health Assessment Questionnaire and by a measure of physical performance. LH significantly increased with age and inversely correlated with T and non-SHBG-bound T. LH was inversely related to muscle strength and lean mass, and both relations were independent of T. LH was positively related to self-reported disability (Modified Health Assessment Questionnaire); 12.5% of the study population was heterozygous for the LH variant allele. T levels and the degree of frailty were not different in the wild-type LH group compared with the heterozygote LH variant group. A significant positive relation between LH and fat mass as well as leptin was only present in the heterozygote LH variant group. In conclusion, serum LH levels increases with age in independently living elderly men and correlates inversely with a variety of indicators of frailty. The observed relation between LH and frailty, independent of T, suggests that LH reflects serum androgen activity in a different way than T, possibly reflecting more closely the combined feedback effect of estrogen and androgen. A difference in biological response between the two LH forms is suggested, as a difference exists in the relation between LH and fat mass, respectively, and leptin in the heterozygote LH variant subjects vs. the wild-type LH subjects.

Aged↗
PubMed2006

A novel XPC pathogenic variant detected in archival material from a patient diagnosed with Xeroderma Pigmentosum: a case report and review of the genetic variants reported in XPC.

The disease Xeroderma Pigmentosum (XP) is genetically heterogeneous and defined by pathogenic variants (formerly termed mutations) in any of eight different genes. Pathogenic variants in the XPC gene are the most commonly observed in US patients. Moreover, pathogenic variants in just four of the genes, XPA, XPC, XPD/ERCC2 and XPV/POLH account for 91% of all XP cases worldwide. In the current study, we describe the clinical, histopathologic, molecular genetic, and pathophysiological features of a 19-year-old female patient clinically diagnosed with XP as an infant. Analysis of archival material reveals a novel variation of a 13 base pair deletion in XPC exon 14 and a previously reported A>C missense pathogenic variant in the proximal splice site for XPC exon 6. Both variations induce frameshifts most likely leading to a truncated XPC protein product. Quantitative RT-PCR also revealed reduced mRNA levels in the archived specimen. Analysis of the XPA, XPD/ERCC2 and XPV/POLH genes in the current specimen failed to reveal pathologic variants. All previously reported pathogenic variants, polymorphisms and known amino acid changes for the XPC gene are compiled and described in the current nomenclature. Given the relative ease of screening for genetic variation and the potential role for such variation in human disease, a proposal for screening appropriate archival materials for alterations in the four most prevalent XP genes is presented.

Adult↗
PubMed2026

RAREsim2: flexible simulation of rare variant genetic data using real haplotypes.

MOTIVATION: Realistic simulated data is critical for advancing methodological development and optimizing study design in genetics research. However, many genetic simulation tools are unable to replicate the distribution of rare variants or incorporate key genetic information, such as functional annotations and linkage disequilibrium. RAREsim, an accurate rare variant simulation algorithm that uses real genetic haplotypes, was developed to address these limitations. Here, we introduce RAREsim2, an update that provides both streamlined software and new functionalities for simulating individual-level differences (e.g., case-control status, technological or batch effects) and variant-level differences to represent a variety of causal models. RESULTS: We demonstrate RAREsim2's utility with three rare variant association methods (Burden, SKAT, and SKAT-O) across several simulation scenarios, including various genetic ancestries, gene sizes, strengths of association, and proportions of risk variants. Type I Error was maintained and the test with the highest power matched previously known patterns. Importantly, real genetic regions can be simulated to include known variant functions and disease associations. Ultimately, RAREsim2 offers additional flexibility and ease in simulating a multitude of realistic genetic scenarios. AVAILABILITY AND IMPLEMENTATION: The RAREsim2 Python package is publicly available on Github (https://github.com/Hendricks-Research-Team/RAREsim2), PyPI (https://pypi.org/project/raresim/), and Zenodo (https://doi.org/10.5281/zenodo.19442523). Code for the example demonstration can be found at https://github.com/JessMurphy/RAREsim2-demo.

Software↗
PubMed2005

Genetic variants of Banana streak virus in Mauritius.

Genetic variations among isolates of Banana streak virus (BSV) were assessed using two sets of primers. The virus, found in banana accessions in Mauritius, was compared to a Nigerian isolate from cultivar Obino l'Ewai (BSOEV). On the basis of the observed size of amplicons, some Mauritius strains were different from l'Ewai BSOEV. Both Southern blot hybridization and the nucleotide sequences of the PCR products confirmed that they were of episomal BSV origin. An isolate of sugarcane bacilliform virus (SCBV) was found to be also very similar to the BSV isolated from banana samples. Nucleotide sequence analysis showed that even the same size PCR products had differing sequences. The dendrogram placed the isolates from Mauritius in a cluster separate from BSV and SCBV from other geographical locations.

Badnavirus↗
PubMed1986

Fractionation of bovine caseins by reverse phase high performance liquid chromatography: identification of a genetic variant.

Samples of reduced whole casein from genetically typed individual cows were quantitatively separated into their main components, alpha s1-, alpha s2-, beta- and kappa-caseins by reverse phase high performance liquid chromatography (RP-HPLC) using a mobile phase of phosphate-buffered aqueous propan-2-ol containing sodium dodecyl sulphate and an octadecylsilyl stationary phase. One casein sample was found to give two peaks of beta-casein of approximately equal areas. RP-HPLC of tryptic digests of the two separated peak fractions gave identical patterns with the exception of one peptide peak with different retention times. Amino acid analyses performed on both fractions showed that they corresponded to peptide 114-169 of beta-casein A1. The atypical beta-casein differed from the typical one by a Pro----Leu substitution in region 114-169.

Amino Acids↗
PubMed1980

Isolation and characterization of genetic variants of the Kunitz soybean trypsin inhibitor.

Three genetically related forms of the Kunitz soybean trypsin inhibitor have been isolated by ion-exchange chromatography. The three variants have different electrophoretic mobilities and have been designated Tia, Tib and Tic. An enzyme assay system was used to determine the association equilibrium constant of each variant for trypsin at pH 8.1 and values of 2 x 10(9) M-1, 2 x 10(7) M-1 and 3 x 10(10) M-1 were found for Tia, Tib and Tic respectively. The hydrolysis equillibrium constant at pH 6.0 for the reactive site peptide bond hydrolysis for each variant was also determined and found to be 4, 9 and 3 for Tia, Tib and Tic, respectively.

Animals↗
PubMed2006

Inter- and intra-variant genetic heterogeneity of human coronavirus OC43 strains in France.

Human coronavirus OC43 (HCoV-OC43) causes acute, self-limited respiratory infections. A close relationship between bovine coronaviruses (BCoVs) and HCoV-OC43 has recently been demonstrated. This study includes seven clinical, non-cell culture-adapted, contemporary HCoV-OC43 strains detected in France in 2003. By using RT-PCR and clonal sequencing of the S1 gene of HCoV-OC43, the inter-variant heterogeneity of the HCoV-OC43 circulating strains was studied and the intra-variant diversity was assessed by investigation of a quasispecies cloud. This paper brings to the forefront a high genetic diversity of circulating HCoV-OC43 variants. Genetically different groups are defined among the variants described in this study. One of these variants holds characteristics of an outlier and presents a deletion of 12 nt, also found in BCoV strains. Moreover, the presence of HCoV-OC43 as a quasispecies cloud in vivo during an acute respiratory-tract illness was discovered. It has also been revealed that quasispecies-cloud sizes are similar for the two viral populations tested.

Child, Preschool↗
PubMed2000

The BRCA2 genetic variant IVS7 + 2T-->G is a mutation.

Biochemical and genetic characterizations that support the conclusion that the variant BRCA2 IVS7 + 2T --> G represents a deleterious mutation are presented. RNA analysis from a breast cancer patient with BRCA2 IVS7 + 2T --> G showed that the productive message was produced from only one chromosome. A haplotype analysis confirmed that the intronic variant resides on the chromosome that does not produce the normal mRNA. Additionally, an RNA splicing product that deletes exon 7 was produced by the chromosome that carries BRCA2 IVS7 + 2T --> G. The deletion of exon 7 from the RNA alters the open reading frame by removing residues 249-287 and incorporating 18 abnormal amino acids before terminating with an opal stop codon. The experimental approach presented produces strong evidence of the presence of a deleterious mutation, because the contribution by both chromosomes to each RNA species analyzed was tracked using a coding region polymorphism as a marker. Furthermore, a single nucleotide polymorphism (SNP) haplotype analysis that confirms the location of the intronic variant and an associated family history that shows a high incidence of cancer supported these biochemical data.

5' Untranslated Regions↗
PubMed1995

In vivo and in vitro binding of fatty acids to genetic variants of human serum albumin.

The effect of genetic variation on the fatty-acid binding properties of human serum albumin was studied by two methods involving the use of sequenced albumin variants isolated from bisalbuminaemic persons. First, the amount of total fatty acid and of several individuals fatty acids bound to eighteen different variants and to their normal counterpart (Alb A) were determined by a gas-chromatographic micromethod. Pronounced effects on total fatty acid binding were found for the glycosylated variants Alb Redhill (modified in domain II) and Alb Casebrook (domain III) in which cases a 1.7- and 8.6-fold increment, respectively, was found. By contrast, Alb Malm0 (glycosylated in domain I) carried the same amount of fatty acid as Alb A. The fatty acid loads on three chain-termination variants were normal. Finally, eight albumins with single amino-acid substitutions bound normal amounts of fatty acid, whereas one bound increased (1.7-fold) and three albumins bound diminished amounts (0.5-0.6-fold). Information on nineteen individual fatty acids was also obtained. It was possible, based on the type of changes in their relative amounts, to group the fatty acids as follows: (a) = C6:0 - C14:0, (b) = C15:0 - C18:0, (c) = C16:1 - C18:1, and (d) a group composed of essential and conditionally essential fatty acids. For nine variants, in most cases modified in domain III, large changes in one or more of these groups were observed. The changes were not related to any changes in total fatty acid load. Second, the binding of laurate, as a representative of the group (a) fatty acids, to delipidated albumin preparations was studied at pH 7.4 by a kinetic dialysis technique. The first stoichiometric association constant for binding to Alb Redhill (0.7-fold) and Alb Casebrook (0.6-fold) was diminished as compared with binding to their corresponding Alb A, whereas binding to one chain-termination variant and three single amino-acid substitutions were all unaffected by the mutation.

Chromatography, Gas↗
PubMed1985

Ross River virus genetic variants in Australia and the Pacific Islands.

HaeIII and TaqI restriction digest profiles of cDNA to infected cell RNA or virion RNA were used as a guide to genetic relationships between fourteen isolates of Ross River virus (RRV) obtained from mosquitoes collected in various localities in eastern Australia where the virus is endemic. RRV isolates from Fiji, American Samoa, the Cook Islands and the Wallis Islands where major outbreaks of epidemic polyarthritis took place in 1979-1980 were also examined. Among these RRV isolates we have identified three genetic types (I-III) on the basis of differences between their restriction digest profiles. We estimate that 1.5-5% nucleotide sequence diversity exists between genetic types. Within each genetic type strain differentiation gave rise to small but significant differences in restriction digest profiles. No clear pattern of geographic distribution of RRV genetic types could be established from the limited number of RRV isolates examined. Genetic types I, II and III, respectively, were isolated from three, three and one different mosquito species, indicating there is no strong association between genetic type and the species of mosquito vector. HaeIII restriction digest analysis did not detect any genetic difference between the four Pacific Island isolates, suggesting that a single RRV variant was involved in the epidemics. Genetically, this variant was closely related to isolates of genetic type II. Virtually identical HaeIII restriction digest profiles were observed for isolates obtained at various stages of the Pacific Island epidemics, suggesting that extensive sequence evolution did not accompany Ross River virus spread.

Alphavirus↗
PubMed1996

Association between genetic variants of mast-cell chymase and eczema.

BACKGROUND: Atopy is a common syndrome underlying asthma, rhinitis, and eczema, and is characterised by high immunoglobulin E (IgE) responses to common antigens. IgE and mast-cell chymase (MCC-a serine protease secreted by skin mast cells) have a key role in atopic or allergic inflammation of the skin. The gene for MCC is located within a cluster of genes for cellular proteases on chromosome 14q11.2. We aimed to identify variants of MCC and another gene within this complex, and assess whether there is a genetic association between variants of MCC and atopic disorders-particularly eczema. METHODS: We randomly selected 100 controls and recruited patients-100 in each group-with atopic asthma, non-atopic asthma, atopic rhinitis, and atopic eczema. PCR amplification was used to test genomic DNA for an association between allelic polymorphisms in MCC and a flanking gene (CGL1, for the cathepsin-G-like protein) on chromosome 14q11 and asthma, rhinitis, and eczema. FINDINGS: We found a significant association between a BstXI polymorphism in MCC and eczema (odds ratio 2.17 [95% CI 1.21-3.88], p = 0.009), but no association with atopic asthma, rhinitis, or non-atopic asthma. There was no association between an Mboll polymorphism in CGL1 and any of the atopic disorders. INTERPRETATION: These findings suggest that variants of MCC may be one source of genetic risk for eczema.

Adolescent↗
PubMed1998

Common genetic variants of lipoprotein lipase and apolipoproteins AI-CIII that relate to coronary artery disease: a study in Chinese and European subjects.

The large ethnic differences in prevalence of coronary artery disease between China and Europe may relate to both genetic and environmental differences. To assess possible genetic factors we have therefore studied the frequencies of disease-related variants of genes involved in lipid transport in 69 hypertriglyceridemic Chinese subjects and 74 healthy Chinese controls. The loci studied include lipoprotein lipase (Asp9Asn, Asn291Ser, Ser447Ter, and Thr361Thr); apolipoprotein A1 (restriction sites at MspI, XmnI, and PstI); and apolipoprotein (apo) CIII (G3175C). All these variants have been shown in previous literature publications to relate to either dyslipidemia and/or premature coronary heart disease in Caucasians. Two disease-related genetic variants in Europeans (Asp9Asn and Asn291Ser) were not found in the Chinese sample. The apo CIII G3175C variant was found more frequently in the upper tertile distributions for apolipoprotein CIII, apolipoprotein E, and plasma triglyceride/HDL ratios (P < 0.05). The rare allele of the apo AI MspI restriction site polymorphic variant was also found more frequently in the upper tertiles for apo CIII, apo E, and plasma triglyceride/HDL ratios (P < 0.04). Eleven of the most lipaemic Chinese subjects (with fasting plasma triglycerides >700 mg/dl) were analyzed for DNA sequence variation. One novel mutation was observed C1338A (which is a silent mutation at Thr361) and two others that are also found in European subjects (Ala261Thr and Ser447Ter). We conclude that genetic differences between Chinese and Europeans may have an effect on the prevalence of coronary artery risk factors involved in lipid transport, and further extended study is warranted.

Alleles↗