Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Genetic polymorphisms”

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.

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

At least 595 records · Page 33Linked to original sources
PubMed1992

Genetic polymorphism of cytochromes P450: interethnic differences and relationship to incidence of lung cancer.

The cytochromes P450 participate in the metabolic activation of precarcinogens. Recent results reveal that many P450 genes are polymorphically distributed. Different investigators have tried to link polymorphic variants of the CYP1A1, CYP2D6 and CYP2E1 genes to the incidence of cancer, particularly lung cancer, in Asian and Caucasian populations. In the current overview we briefly summarize this research. It appears that interesting functionally linked interindividual differences in the CYP1A1 gene have been found and could be of importance in understanding differences in susceptibility to lung cancer. On the other hand, the data presented regarding CYP2D6 and CYP2E1 are less promising. We also describe interethnic differences in the P450 gene structures as a major obstacle for extrapolation of results between different ethnic groups.

Cytochrome P-450 CYP1A1↗
PubMed1999

The effect of genetic polymorphisms in CYP2C9 on sulphamethoxazole N-hydroxylation.

Sulphamethoxazole undergoes CYP2C9-mediated bioactivation to a hydroxylamine. In this study, we investigated the effect of the CYP2C9Arg144 to Cys (CYP2C9*2) and CYP2C9Ile359 to Leu (CYP2C9*3) polymorphisms on sulphamethoxazole N-hydroxylation. Human livers were genotyped using polymerase chain reaction amplification and restriction fragment length polymorphism analysis. Formation of sulphamethoxazole hydroxylamine and methylhydroxy tolbutamide in microsomes prepared from cell lines and the genotyped human livers was determined by high-pressure liquid chromatography. Microsomes prepared from the cell line expressing the allelic variants CYP2C9-Cys144 and CYP2C9-Leu359 displayed a threefold and 20-fold decrease in intrinsic clearance (Cl(int)) for sulphamethoxazole, respectively, when compared with the wild-type, CYP2C9-Arg144. A significant decrease (P < 0.05) in Cl(int) was also observed with tolbutamide for both mutations. Of the 26 human livers genotyped, 61.5% were homozygous wild-type, 26.9% were heterozygotes for CYP2C9*2 and 15.4% were heterozygotes for CYP2C9*3. No homozygous mutant livers were detected. There was a good correlation between sulphamethoxazole N-hydroxylation and tolbutamide methyl hydroxylation (r = 0.825). However, there was no difference in the kinetic parameters for either sulphamethoxazole N-hydroxylation or tolbutamide methyl hydroxylation between the wild type livers (n = 6) and either the livers heterozygous for the CYP2C9*2 (n = 5) or the livers heterozygous for the CYP2C9*3 mutation (n = 3). The CYP2C9*2 and CYP2C9*3 polymorphisms may have some influence on the bioactivation of sulphamethoxazole, particularly in individuals who are homozygous mutants, and this could act as a protective factor against sulphamethoxazole hypersensitivity. However, given the rarity of homozygous mutants, it is likely that other metabolic and immunological risk factors will dominate individual susceptibility.

Aryl Hydrocarbon Hydroxylases↗
PubMed2000

Alcohol consumption, glutathione S-transferase M1 and T1 genetic polymorphisms and breast cancer risk.

To evaluate the potential association between GSTM1 and GSTT1 genotypes and development of breast cancer, a hospital based case-control study was conducted in a South Korean study population consisting of 189 histologically confirmed incident breast cancer cases and their 189 age-matched control subjects with no present or previous history of cancer. A multiplex polymerase chain reaction method was used for the genotyping analyses and statistical evaluations were performed by unconditional logistic regression model. The GSTM1 null genotype was significantly associated with breast cancer risk in premenopausal women [odds ratio (OR) = 2.0, 95% confidence interval (CI) = 1-3.7], but not in the postmenopausal women (OR = 0.9, 95% CI = 0.5-1.9), nor in all women grouped together (OR = 1.3, 95% CI = 0.8-1.1). The GSTT1 null genotype posed a similar risk of breast cancer with an OR of 1.6 (95% CI = 1.0-2.5) for the total breast cancer group, OR of 1.7 (95% CI = 0.9-3.2) for pre-menopausal women, and OR of 1.3 (95% CI = 0.6-2.8) for post-menopausal women. The breast cancer risk associated with concurrent lack of both GSTM1 and GSTT1 genes was 2.2 (95% CI = 1.1-4.5), and the risk increased as the number of null genotype increased (P for trend = 0.03). When the data were stratified by the known risk factors of breast cancer, a significant interaction was observed between the GSTM1 genotypes and alcohol consumption (P for interaction = 0.03). An especially remarkable risk of breast cancer was observed for alcohol-consuming premenopausal women lacking both the GSTM1 and GSTT1 genes (OR = 5.3, 95% CI = 1.0-27.8) compared to those with both of the genes. Our findings thus suggest a novel gene-environment interaction which plays an important role in the individual susceptibility to breast cancer. p6

Adult↗
PubMed2000

Characterization of human CYP2G genes: widespread loss-of-function mutations and genetic polymorphism.

CYP2G1 is an abundant, olfactory mucosa-specific cytochrome P450 enzyme active in the metabolism of sex steroids and xenobiotic substrates in mammalian animals. Two different human CYP2G genes, CYP2GP1 and CYP2GP2, were characterized in the present study. Polymorphisms in these genes were also studied. CYP2GP1 contained a single nucleotide deletion in exon 2 (deltaC) and a 2.4-kb deletion between exons 3 and 7 (deltaE4-6), whereas CYP2GP2 contained a nonsense mutation in exon 1 and another in exon 3. The coding region sequences in exons 1-3 and 7-9 of the two genes were 96.7% identical. Both genes were localized to human chromosome 19, and Southern blot analysis of human genomic DNA did not detect any additional copies of the CYP2G gene. The occurrence of these loss-of-function mutations was analysed by polymerase chain reaction-based genotyping in more than 200 individuals. The deltaE4-6 deletion in CYP2GP1 was detected in 94% of subjects (either homozygous or heterozygous), and an allele which does not contain this deletion was detected in 11.6% of individuals. The nonsense mutation in CYP2GP2 exon 3 was detected in 86% of individuals (either homozygous or heterozygous); however, a potentially functional CYP2GP2 allele based on the absence of the nonsense mutation in exon 3 was also detected in 31% of individuals. These results indicate that a functional CYP2G allele is rare in humans. Analysis of the allelic distribution in different ethnic groups suggested that a functional CYP2G allele, if present, is more likely to be found in Black and Hispanic subjects.

Alleles↗
PubMed2002

A comparative analysis of translated dihydropyrimidine dehydrogenase cDNA; conservation of functional domains and relevance to genetic polymorphisms.

A pharmacogenetic syndrome caused by molecular defects in the dihydropyrimidine dehydrogenase gene (DPYD ) results in partial to complete loss of dihydropyrimidine dehydrogenase (DPD) enzyme activity with patients exhibiting life-threatening toxicity following administration of routine doses of 5-fluorouracil. To date, more than 19 reported mutations have been putatively associated with DPD deficiency with 16 occurring within the open reading frame of the cDNA. The purpose of this study was to examine the conservation of functional domains (including the uracil, flavine adenine dinucleotide and NADPH binding sites) across three phyla (Chordata, Arthropoda and Nematoda) and the conservation of regions corresponding to the previously reported mutations. Comparative analysis of the uracil and NADPH binding sites in mammals and invertebrates demonstrated 100% amino acid identity between mammals and Drosophila melanogaster. Caenorhabditis elegans demonstrated 89% and 88% identity in these domains, respectively. The mammalian sequences demonstrated 100% identity in two iron sulphur motifs (amino acids 953-964 and 986-997) with significant conservation in D. melanogaster (92% and 92% identity, respectively) and C. elegans (100% and 92% identity, respectively). Comparative amino acid analysis revealed non-conservation in the loci of four DPYD mutations [DPYD*12 (R21Q), DPYD*5 (I543V), DPYD*6 (V732I), DPYD*9A (C29R)]. Seven mutations occurred in highly conserved regions [M166V, DPYD*8 (R235W), DPYD*11 (V335l), DPYD*4 (S534N), DPYD*9B (R886H), D949V, DPYD*10 (V995F)]. In summary, this comparative analysis identified conserved regions which may be critical to enzyme structure and/or function. The conservation of loci where DPYD mutations occur was also examined to evaluate their functional significance on DPD enzyme activity. These data should prove useful in the evaluation of newly discovered mutations in the DPYD gene.

Amino Acid Sequence↗