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At least 199 records · Page 11Linked to original sources
PubMed2004

Interactions between common genetic polymorphisms in ABCG5/G8 and CYP7A1 on LDL cholesterol-lowering response to atorvastatin.

Cholesterol excretion by ATP binding cassette transporters G5 and G8 (ABCG5/G8) and bile acid biosynthesis by cholesterol 7alpha-hydroxylase (CYP7A1) are major pathways for the removal of cholesterol into bile. To investigate the interactions between common polymorphisms in ABCG5/G8 and CYP7A1 and statin response, we examined the relationships between five non-synonymous polymorphisms in ABCG5/G8 (Q604E, D19H, Y54C, T400K, and A632V) and a promoter variant in CYP7A1 (A-204C) in 337 hypercholesterolemic patients treated with atorvastatin 10mg. The ABCG8 H19 allele was significantly associated with a greater LDL cholesterol reduction relative to the wild type D19 allele (39.6% versus 36.6%, P = 0.043). This difference was enhanced in non-carriers of the CYP7A1 promoter polymorphism (42.7% versus 38.2%, P = 0.048), and was diminished in accordance with the number of CYP7A1 variant alleles (1.8% in heterozygotes and 0.2% in homozygotes). Combination analysis of these polymorphisms explained a greater percentage of LDL cholesterol response variation (8.5% difference across subgroups) than did single polymorphism analysis (4.2% in CYP7A1 and 3.0% in ABCG8 D19H). The other ABCG5/G8 polymorphisms did not show any significant interactions with the CYP7A1 polymorphism. We conclude that the ABCG8 H19 and CYP7A1 C-204 alleles appear to interact in a dose-dependent manner on atorvastatin response.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMedDate not supplied

Evidence for balancing selection at the major histocompatibility complex in a free-living ruminant.

Evidence for selective maintenance of genetic diversity at the major histocompatibility complex (MHC) was investigated in an unmanaged population of Soay sheep on the island of Hirta, St. Kilda, Scotland. Animals were sampled as newborn lambs and between 887 and 1209 individuals were typed at each of five microsatellite markers located either within or flanking the ovine MHC. Markers located within the MHC showed high levels of linkage disequilibrium with each other but not with flanking markers. Hardy-Weinberg proportions were found for all loci; however, two of the three markers within the MHC showed relatively even allele frequency distributions that were unlikely to have resulted from neutrality and suggest the action of recent balancing selection. Sequence polymorphism was examined within DRB, a class II gene immediately adjacent to one of the microsatellite markers, and high correlation of sequence polymorphism with microsatellite length variation was found. An excess of nonsynonymous substitution compared to synonymous substitution was found, indicating the action of balancing selection favoring novel MHC variants and hence increased diversity over a longer time period.

Alleles↗
PubMed2005

Description of a new HLA-DRB1*1104, DRB1*110403.

We report here the exon 2 sequence of the novel HLA-DRB1*110403 which differs from DRB1*110401 by a single synonymous nucleotide substitution at codon 78, where TAC is substituted by TAT. The variant originally identified in a Caucasoid individual was confirmed by cloning and sequencing.

Alleles↗
PubMed2005

Compound heterozygosity for two non-synonymous polymorphisms in NPC1L1 in a non-responder to ezetimibe.

Ezetimibe reduces plasma low-density lipoprotein (LDL) cholesterol by blocking sterol absorption in enterocytes. The NPC1L1 gene product was recently identified as the molecular target for ezetimibe, although functional details are incomplete. We used the non-response phenotype of plasma LDL cholesterol to ezetimibe treatment to ascertain individuals who might have variant NPC1L1. We found that one non-responder to ezetimibe was a compound heterozygote for two rare non-synonymous polymorphisms in NPC1L1 that were absent in normal control subjects. We also characterized other NPC1L1 polymorphisms. While there are many explanations for non-response to medications, our data suggest a possible relationship between NPC1L1 variation and ezetimibe response and further indicate that a non-response phenotype might ascertain subjects with genomic DNA variants that could help define metabolic pathways.

Adult↗
PubMed2025

FuNTB: a functional network clustering tool for the analysis of genome-wide genetic variants in Mycobacterium tuberculosis.

MOTIVATION: Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), still claims around 1.25 million lives each year. The growing threat of drug resistance-often driven by single‑nucleotide polymorphisms (SNPs) in Mtb genomes underscores the need for high‑quality genomic data and powerful bioinformatics tools. We present FuNTB, a python‑based pipeline that detects non‑synonymous SNPs in Mtb and builds functional network clusters to reveal genotype-phenotype relationships. RESULTS: FuNTB profiles non‑synonymous SNPs at the gene level across user‑defined phenotypes, pinpointing both shared and unique mutations. It ingests annotated Variant Call Format (VCF) files or MTBseq outputs and merges them with clinical metadata to produce network‑XML files compatible with Cytoscape and Gephi. When applied to the CRyPTIC Mtb collection, FuNTB rapidly recovered established resistance genes and surfaced novel candidates, validating its utility for mapping genotype-phenotype associations. AVAILABILITY AND IMPLEMENTATION: FuNTB is implemented in Python 3.8+ and is freely available under the MIT license at https://doi.org/10.5281/zenodo.15399917.

Mycobacterium tuberculosis↗
PubMedDate not supplied

[The genetic variability of the protease-encoding region in HIV-1 A isolates and in CRF03_AB recombinants as observed in the CIS territory].

Protease-encoding nucleotide sequences of 27 HIV-1 variants isolated in Russia and other CIS countries from seropositive intravenous drug-users were analyzed. None of the above persons did ever take antiretroviral drugs. The nucleotide sequences were shown to belong to subtypes A and to be have a high degree of genetic homogeneity (0.00-3.23; mean--1.38 +/- 0.79). No isolates contained any primary mutations of resistance to protease inhibitors. At the same time, above one half of the isolates bore the V771 substitution, which, according to published data, is the secondary mutation of resistance that conditions a higher resistance to Nelfinavir. Moreover, the substitution was associated with 2 synonymous mutations in triplets 31 and 78, which denotes a single origin for all V771 variants.

Adolescent↗
PubMed2005

Identification of HLA-A*0111N: a synonymous substitution, introducing an alternative splice site in exon 3, silenced the expression of an HLA-A allele.

A new variant of the HLA-A*010101 allele designated as HLA-A*0111N, previously known as HLA-A*010101var, was identified in a patient requiring a stem-cell transplantation. The patient was typed by serologic methods as HLA-A2 homozygous and by sequence-based typing (SBT) as A*010101,020601. Flow-cytometric (FCM) analysis with 11 human monoclonal antibodies (mAbs) for the A1 molecule confirmed lack of any cell membrane expression of the A*0111N allele. One-dimensional isoelectric focusing (1D-IEF) of total cell lysate from the patient's cells revealed no cell surface and cytoplasmic A1 protein expression, whereas the HLA-A2 molecule was identified by both FCM analysis and 1D-IEF. DNA sequence analysis showed the presence of a synonymous substitution from G to T at position 597 in codon 175. RNA SBT revealed a deletion of 24 bp in exon 3, position 596 through 619, encoding codons 175 through 182 of the HLA-A*0111N allele. The synonymous substitution introduced a new splice site, resulting in an efficient splicing, because no classical A1 protein could be detected in the patient. This alternative splicing prevented the translation into a correct and stable class I molecule expression on the cell surface.

Alleles↗
PubMed2003

Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor.

Although changes in nucleotide sequence affecting the composition and the structure of proteins are well known, functional changes resulting from nucleotide substitutions cannot always be inferred from simple analysis of DNA sequence. Because a strong synonymous codon usage bias in the human DRD2 gene, suggesting selection on synonymous positions, was revealed by the relative independence of the G+C content of the third codon positions from the isochoric G+C frequencies, we chose to investigate functional effects of the six known naturally occurring synonymous changes (C132T, G423A, T765C, C939T, C957T, and G1101A) in the human DRD2. We report here that some synonymous mutations in the human DRD2 have functional effects and suggest a novel genetic mechanism. 957T, rather than being 'silent', altered the predicted mRNA folding, led to a decrease in mRNA stability and translation, and dramatically changed dopamine-induced up-regulation of DRD2 expression. 1101A did not show an effect by itself but annulled the above effects of 957T in the compound clone 957T/1101A, demonstrating that combinations of synonymous mutations can have functional consequences drastically different from those of each isolated mutation. C957T was found to be in linkage disequilibrium in a European-American population with the -141C Ins/Del and TaqI 'A' variants, which have been reported to be associated with schizophrenia and alcoholism, respectively. These results call into question some assumptions made about synonymous variation in molecular population genetics and gene-mapping studies of diseases with complex inheritance, and indicate that synonymous variation can have effects of potential pathophysiological and pharmacogenetic importance.

Dopamine↗
PubMed2006

T cell line passage can select for pre-existing neutralization-sensitive variants from the quasispecies of primary human immunodeficiency virus type-1 isolates.

Primary human immunodeficiency type 1 viruses (HIV-1) resist antibody neutralization but become sensitive after passage through T cell lines. We and others previously reported an increased neutralization sensitivity of HIV-1 after prolonged culture on primary peripheral blood mononuclear cells (PBMC). Hence we hypothesized that adaptation to growth in T cell lines is in fact selection of a pre-existing neutralization-sensitive HIV-1 variant from the quasispecies in the PBMC culture. Indeed, increased neutralization sensitivity was associated with largely identical synonymous and non-synonymous mutations between progeny of parallel H9 passages from the same split inoculum from 2 of 3 viruses. H9 T cell line adaptation of molecular cloned HIV-1 was less successful and associated with only a few de novo mutations that varied between parallel H9-adapted progeny from the same split inoculum. We conclude that T cell line adaptation of HIV-1 can indeed select for a pre-existing variant but that this most likely depends on the viral diversity in the inoculum.

Adaptation, Physiological↗
PubMed2005

Functional analysis of genetic variants in the human concentrative nucleoside transporter 3 (CNT3; SLC28A3).

The human concentrative nucleoside transporter, CNT3 (SLC28A3), plays an important role in mediating the cellular entry of a broad array of physiological nucleosides and synthetic anticancer nucleoside analog drugs. As a first step toward understanding the genetic basis for interindividual differences in the disposition and response to antileukemic nucleoside analogs, we examined the genetic and functional diversity of CNT3. In all, 56 variable sites in the exons and flanking intronic region of SLC28A3 were identified in a collection of 270 DNA samples from US populations (80 African-Americans, 80 European-Americans, 60 Asian-Americans, and 50 Mexican-Americans). Of the 16 coding region variants, 12 had not been previously reported. Also, 10 resulted in amino-acid changes and three of these had total allele frequencies of >/=1%. Nucleotide diversity (pi) at nonsynonymous and synonymous sites was estimated to be 1.81 x 10(4) and 18.13 x 10(4), respectively, suggesting that SLC28A3 is under negative selection. All nonsynonymous variants, constructed by site-directed mutagenesis and expressed in Xenopus laevis oocytes, transported purine and pyrimidine model substrates, except for c. 1099G>A (p. Gly367Arg). This rare variant alters an evolutionarily conserved site in the putative substrate recognition domain of CNT3. The presence of three additional evolutionarily conserved glycine residues in the vicinity of p. Gly367Arg that are also conserved in human paralogs suggest that these glycine residues are critical in the function of the concentrative nucleoside transporter family. The genetic analysis and functional characterization of CNT3 variants suggest that this transporter does not tolerate nonsynonymous changes and is important for human fitness.

Adenosine↗
PubMed2002

Synonymous nucleotide substitutions in the neonatal Fc receptor.

The neonatal Fc receptor (FcRn) is a key receptor involved in the transcytosis of IgG across the maternal-fetal barrier. The level of IgG varies considerably among newborn infants. Since other Fc gamma receptors show single nucleotide functional variants, we determined whether common variant alleles exist for the FcRn. Direct sequence analysis was performed on PCR-amplified complementary DNA (cDNA) isolated from ten placental mRNAs (20 alleles examined). Two synonymous nucleotide polymorphisms were detected from the same source. A G251T and C707T substitution, reflecting amino acid positions Pro19 and Arg171 of the mature polypeptide, did not alter the amino acid encoded. No other nucleotide substitutions or sequence variations were observed. Thus, the variation in IgG transport is not due to common variant alleles among the human population. Due to the limited number of samples tested (n=20), low-frequency alleles would go undetected by chance alone when q has a frequency < or = 0.14. It is unlikely that low-frequency variant alleles, if present, are responsible for the major variation seen in the transcytosis of IgG.

Histocompatibility Antigens Class I↗
PubMed2000

A single-nucleotide polymorphic variant of the RET proto-oncogene is underrepresented in sporadic Hirschsprung disease.

Hirschsprung disease (HSCR) is an inherited disorder characterised by absence of intrinsic ganglion cells in the distal gastrointestinal tract. Different susceptibility genes, involved in either the Ret-tyrosine kinase or the endothelin signalling pathways, contribute to HSCR phenotype. Interestingly, alterations of these genes are detected in only 30-50% of all HSCR patients, suggesting the involvement of modifier genes and/or additional genetic or environmental risk factors. In complex disorders common polymorphic variants can be associated with the disease phenotype, thus modifying the risk of recurrence. To investigate whether sequence variants of the RET proto-oncogene may be associated with the development of the HSCR phenotype, we analysed 92 Italian patients for the 2508C > T synonymous substitution in exon 14 (S836S) finding that the T allele is clearly less frequent than in control individuals (Fisher exact test P = 0.0002). On the other hand, this RET variant allele is overrepresented in patients affected with medullary thyroid carcinoma. Assuming a direct effect of this single-nucleotide polymorphism in predisposing to RET associated pathologies, we have performed functional tests which excluded any possible involvement of the C and T alleles in DNA-protein binding, transcript stability and RNA splicing and editing.

Alleles↗
PubMed2000

Single nucleotide polymorphism analyses of the human proliferating cell nuclear antigen (pCNA) and flap endonuclease (FEN1) genes.

The products of proliferating cell nuclear antigen (PCNA) and flap endonuclease (FEN1) genes are multifunctional proteins that are involved in DNA replication and damage repair. Yeast models suggest association of mutant forms of PCNA and FEN1 with genomic instability. In our study, we have determined the single nucleotide polymorphisms in human PCNA and FEN1 genes. We sequenced the coding region and adjacent noncoding region of both the PCNA and FEN1 genes in 120 alleles (60 individuals). In the PCNA gene, we detected 9 sequence variants with Hardy-Weinberg allele frequency ranging from 0.008 to 0.088. No polymorphism was detected in the FEN1 gene. The sequence variants in the PCNA gene included 7 intronic single nucleotide polymorphisms (SNP) and 2 synonymous exonic SNPs. All the intronic SNPs were located in introns 1 and 4, which contain several regulatory elements involved in the control of PCNA gene expression. Six of the 7 intronic SNPs showed complete linkage disequilibrium. We confirmed this allelic linkage disequilibrium by allele-specific PCR sequencing. We genotyped 117 additional individuals belonging to 3 population subgroups using the PCR-RFLP method. Finally, to see if the detected polymorphisms are associated with any cancer type, we genotyped cases with melanomas (37 cases), breast cancers (118 cases) and lung cancers (100 cases). We did not find statistical difference in frequency of polymorphism in any cancer type compared with healthy controls, although in breast cancer the frequency was low. Our results suggest that the coding regions of the PCNA and FEN1 genes are highly conserved when compared with other DNA repair genes. The potential of some of the detected intronic polymorphisms to effect regulation of the PCNA gene expression remains to be determined.

Alleles↗
PubMed2003

BUB1 infrequently mutated in human breast carcinomas.

The BUB1 gene is a key player in the mitotic spindle checkpoint machinery that monitors proper segregation of sister chromatides during mitosis. It has been suggested that mutations in BUB1 may disrupt the spindle checkpoint and thereby cause chromosomal instability, which is a hallmark of solid tumors including those from the breast. From a series of breast carcinomas we selected 20 cases with genomic instability, as scored by Comparative Genome Hybridization (CGH), and without somatic TP53 (p53) mutations, and sequenced the entire coding region of the BUB1 gene. Two different constitutional sequence variants were found; a base substitution in exon 5, c.481G>A (CAG>CAA, a synonymous change encoding Gln144) in two samples, and a base substitution 8 bp upstream of exon 10, c.1007-8T>C in two other samples. No somatic mutations were detected. These results indicate that genomic instability scored as copy number alterations by CGH in TP53 wild type breast carcinomas is not caused by somatic mutations in the BUB1 gene.

Breast Neoplasms↗
PubMed2006

Common non-synonymous polymorphisms in the BRCA1 Associated RING Domain (BARD1) gene are associated with breast cancer susceptibility: a case-control analysis.

The BRCA1 Associated RING Domain (BARD1) gene has been identified as a high penetrance gene for breast cancer, whose germline and somatic mutations were reported in both non-BRCA1/2 hereditary site-specific and sporadic breast cancer cases. BARD1 plays a crucial role in tumor repression, along with its heterodimeric partner BRCA1. In the current study, we tested the hypothesis that common non-synonymous polymorphisms in BARD1 are associated with breast cancer susceptibility in a case-control study of 507 patients with incident breast cancer and 539 frequency-matched cancer-free controls in Chinese women. We genotyped all three common (minor allele frequency (MAF)>0.10) non-synonymous polymorphisms (Pro24Ser, Arg378Ser, and Val507Met) in BARD1. We found that the BARD1 Pro24Ser variant genotypes (24Pro/Ser and 24Ser/Ser) and Arg378Ser variant homozygote 378Ser/Ser were associated with a significantly decreased breast cancer risk, compared with their wild-type homozygotes, respectively. Furthermore, a significant locus-locus interaction was evident between Pro24Ser and Arg378Ser (P(int )= 0.032). Among the 378Ser variant allele carriers, the 24Pro/Pro wild-type homozygote was associated with a significantly increased breast cancer risk (adjusted OR=1.81, 95% CI=1.11-2.95), but the subjects having 24Pro/Ser or Ser/Ser variant genotypes had a significantly decreased risk (adjusted OR=0.74, 95% CI=0.56-0.99). In stratified analysis, this locus-locus interaction was more evident among subjects without family cancer history, those with positive estrogen receptor (ER) and individuals with negative progesterone receptor (PR). These findings indicate that the potentially functional polymorphisms Pro24Ser and Arg378Ser in BARD1 may jointly contribute to the susceptibility of breast cancer.

Adult↗
PubMed2003

Low hanging fruit: a subset of human cSNPs is both highly non-uniform and predictable.

We present a point mutation classification method that contrasts SNP databases and has the potential to illuminate the relative mutational load of genes caused by codon bias. We group point variation gleaned from public databases by their wild-type and mutant codons, e.g. codon mutation classes (CMCs, 576 possible such as ACG-->ATG), whose frequencies in a database are assembled into a BLOSUM-style matrix describing the likelihood of observing all possible single base codon changes as tuned by the intertwined effects of mutation rate and selection. The rankings of the CMCs in any database are reshuffled according to the population stratification of the typical genotyping experiment producing that resource's data. Analysis of four independent databases reveals that a considerable fraction of mutation in functional genes can be described by a few CMCs regardless of gene identity or population stratification in the genotyping experiment. For example, the top 5% (29/576) of CMCs account for 27.4% of the observed variants in dbSNP while the bottom 5% account for only 0.02%. For non-synonymous disease-causing mutation, 40.8% are described by the top 5% of all possible non-silent CMCs (22/438). Overall, the most observed polymorphism is a G-->A transition at CpG dinucleotides causing ACG, TCG, GCG, and CCG to frequently undergo silent mutation in any gene due to the putative lack of impact on the protein product. In order to assess how well CMC spectrums estimate the aggregate non-synonymous mutational trends of a single gene, a CMC matrix was applied to seven unrelated genes to compute the most likely point mutations. In excess of 87% of these mutation predictions are historically known to play an important role in a disease state according to published literature. CMC-based mutation prediction may aid design and execution of direct association genotyping studies.

Base Sequence↗
PubMed2005

Molecular analysis of the myocilin gene in Chinese subjects with chronic primary-angle closure glaucoma.

PURPOSE: Mutations in the myocilin (MYOC) gene have been implicated in juvenile as well as late-onset primary open-angle glaucoma (POAG). Overall, MYOC mutations account for 3% to 5% of cases of POAG worldwide, making it the most significant gene identified so far in glaucoma. Although there are some similarities in the phenotype of POAG and in particular chronic primary angle-closure glaucoma (PACG), little is known about the role of MYOC in the causation of PACG. To address this, the MYOC gene was screened in a cohort of 106 patients with chronic PACG. METHODS: Genomic DNA was extracted from leukocytes of the peripheral blood and exons 1 to 3 of the MYOC gene were PCR amplified and subjected to bidirectional sequencing and analysis. RESULTS: One hundred six patients with chronic PACG of Chinese ethnicity were studied. Sequencing of the MYOC gene in these patients revealed eight sequence variants. Of these, one was a nonsense change, three were missense changes, two were synonymous codon changes, and two were changes in noncoding sequences. These included the Arg46Stop and Thr353Ile mutations, which have been reported in individuals with POAG. However, all the sequence alterations identified have been found in normal Chinese subjects. CONCLUSIONS: The results of this study do not support a role for MYOC mutations in the pathogenesis of chronic PACG in the Chinese.

Aged↗
PubMed2006

Genetic mutation screening in an italian cohort of nonsyndromic pheochromocytoma/paraganglioma patients.

To assess the prevalence of genetic mutations in nonsyndromic pheochromocytoma/paraganglioma (PHEO/PGL) patients we have performed a systematic search for mutations in the succinate dehydrogenase (SDH) B, C, and D subunits, von Hippel-Lindau (VHL), and RET genes by direct bidirectional sequencing. Patients were selected from the medical records of hypertension centers. After exclusion of syndromic patients, 45 patients with familial (F+, n=3) and sporadic (F-, n=42) cases of isolated PHEO/PGL were considered. They included 35 patients with PHEO, 7 with PGL, and 3 with head/neck PGL (hnPGL). Three patients with PHEO (2F-, 1F+) presented VHL mutations (P86A, G93C, and R167W), six with PGL (4F-, 2F+) were positive for SDH or VHL mutations (SDHB R230G in two patients, SDHB S8F, R46Q, R90Q, and VHL P81L in one subject each), and one with hnPGL carried the SDHD 348-351delGACT mutation. We have also detected missense (SDHB S163P, SDHD H50R and G12S), synonymous (SDHB A6A, SDHD S68S), and intronic mutations that have been considered nonpathological polymorphic variants. No mutation was found in SDHC or RET genes. Our data indicate that germline mutations of VHL and SDH subunits are not infrequent in familial as well as in sporadic cases of nonsyndromic PHEO/PGL (overall, 12 of 45 probands, 22%). Accordingly, screening for such mutations seems to be justified. However, a more precise characterization of the functional relevance of any observed sequence variant and of other genetic and environmental determinants of neoplastic transformation is essential in order to plan appropriate protocols for family screening and follow-up.

Adrenal Gland Neoplasms↗