Different Effects of Polymorphic Flavin-Containing Monooxygenase 3 and Cytochrome P450 2A6 Activities on an Index of Arteriosclerosis as a Lifestyle-Related Disease in a General Population in Japan

2020 ◽  
Vol 21 (14) ◽  
pp. 1161-1164
Author(s):  
Mirai Uraoka ◽  
Makiko Shimizu ◽  
Yoshiki Kuwajima ◽  
Ami Mizugaki ◽  
Haruka Yokoyama ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
General Population ◽  
Odds Ratio ◽  
Dietary Habits ◽  
Risk Index ◽  
Wild Type Allele ◽  
Wild Type ◽  
Type Allele ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme

Background: The relationships between lifestyle-related diseases and polymorphic drug-metabolizing enzyme activities in the general population in Japan remain unclear. Objective: In this study, the relationships between an index of arteriosclerosis and the phenotypic activities of flavin-containing monooxygenase 3 (FMO3) and cytochrome P450 (P450) 2A6 were analysed. Methods: Subjects in a general population in Japan (age range 35-97 years, 640 men and 795 women, 12% were current smokers) who took part in a health check program were recruited. Results: Subjects were divided into two groups using the median ankle-brachial pressure index (ABI) score. Subjects harbouring P450 2A6 wild-type allele had a significant age-adjusted odds ratio of 1.3 (95% CI, 1.0-1.6) of having a lower than median ABI score compared with subjects for mutant P450 2A6. For subjects with wild-type FMO3, the odds ratio of 0.89 was not significant. The proportions of P450 2A6 extensive metabolizers varied significantly across the inter-quartile ranges of the ABI scores (p = 0.008). Furthermore, the proportion of subjects with low ABI scores was also dependent on the phenotypic P450 2A6 activity (p = 0.025) as estimated from the P450 2A6 genotype. These results suggest that in a general population in Japan, the ABI score, as a risk index for arteriosclerosis, is associated with the predicted P450 2A6 phenotype but is not associated with FMO3 function. Conclusion : The P450 2A6 wild-type allele may be a possible candidate biomarker for arteriosclerosis in a general population in Japan with a variety of dietary habits.

scholarly journals CYP2C19 Polymorphisms in Indonesia: Comparison among Ethnicities and the Association with Clinical Outcomes

Biology ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 300
Author(s):  
Muhammad Miftahussurur ◽  
Dalla Doohan ◽  
Ari Fahrial Syam ◽  
Iswan Abbas Nusi ◽  
Phawinee Subsomwong ◽  
...  
Keyword(s):  
Proton Pump Inhibitor ◽  
Clinical Outcomes ◽  
Proton Pump ◽  
Poor Metabolizers ◽  
Wild Type Allele ◽  
Wild Type ◽  
Type Allele ◽  
Sydney System ◽  
Intermediate Metabolizers ◽  
Cyp2c19 Polymorphisms

CYP2C19 polymorphisms are important factors for proton pump inhibitor-based therapy. We examined the CYP2C19 genotypes and analyzed the distribution among ethnicities and clinical outcomes in Indonesia. We employed the polymerase chain reaction-restriction fragment length polymorphism method to determine the CYP2C19 genotypes and evaluated inflammation severity with the updated Sydney system. For CYP2C19*2, 46.4% were the homozygous wild-type allele, 14.5% were the homozygous mutated allele, and 39.2% were the heterozygous allele. For CYP2C19*3, 88.6% were the homozygous wild-type allele, 2.4% were the homozygous mutated allele, and 9.0% were the heterozygous allele. Overall, the prevalence of rapid, intermediate, and poor metabolizers in Indonesia was 38.5, 41.6, and 19.9%, respectively. In the poor metabolizer group, the frequency of allele *2 (78.8%) was higher than the frequency of allele *3 (21.2%). The Papuan had a significantly higher likelihood of possessing poor metabolizers than the Balinese (OR 11.0; P = 0.002). The prevalence of poor metabolizers was lower compared with the rapid and intermediate metabolizers among patients with gastritis and gastroesophageal reflux disease. Intermediate metabolizers had the highest prevalence, followed by rapid metabolizers and poor metabolizers. Dosage adjustment should therefore be considered when administering proton pump inhibitor-based therapy in Indonesia.

scholarly journals Estimation of polymorphisms in the drug-metabolizing enzyme, cytochrome P450 2C19 gene in six major ethnicities of Pakistan

Bioengineered ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 4442-4451
Author(s):  
Sagheer Ahmed ◽  
Saima Gul ◽  
Muhammad Akhlaq ◽  
Abrar Hussain ◽  
Sidrah Tariq Khan ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolizing Enzyme ◽  
Cytochrome P450 2C19 ◽  
Metabolizing Enzyme

scholarly journals Functional Assessment of 12 Rare Allelic CYP2C9 Variants Identified in a Population of 4773 Japanese Individuals

2021 ◽  
Vol 11 (2) ◽  
pp. 94
Author(s):  
Masaki Kumondai ◽  
Akio Ito ◽  
Evelyn Marie Gutiérrez Rico ◽  
Eiji Hishinuma ◽  
Akiko Ueda ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Three Dimensional ◽  
Warfarin Dose ◽  
Catalytic Efficiency ◽  
Therapeutic Window ◽  
Wild Type ◽  
Drug Metabolizing Enzyme ◽  
Novel Variants ◽  
Metabolizing Enzyme ◽  
Almost All

Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by CYP2C9 genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These CYP2C9 variants were heterologously expressed in 293FT cells, and the kinetic parameters (Km, kcat, Vmax, catalytic efficiency, and CLint) of (S)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (S)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype–phenotype associations based on the novel CYP2C9 rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appropriate warfarin dose.

Monoallelic Expression of Pax5: A Paradigm for the Haploinsufficiency of Mammalian Pax Genes?

1999 ◽  
Vol 380 (6) ◽  
Author(s):  
S.L. Nutt ◽  
M. Busslinger
Keyword(s):  
Human Disease ◽  
Mouse Genome ◽  
Monoallelic Expression ◽  
Wild Type Allele ◽  
Loss Of Function ◽  
Wild Type ◽  
Type Allele ◽  
Pax Genes ◽  
Default State ◽  
Mammalian Genes

AbstractIt is generally assumed that most mammalian genes are transcribed from both alleles. Hence, the diploid state of the genome offers the advantage that a loss-of-function mutation in one allele can be compensated for by the remaining wild-type allele of the same gene. Indeed, the vast majority of human disease syndromes and engineered mutations in the mouse genome are recessive, indicating that recessiveness is the ‘default’ state. However, a minority of genes are semi-dominant, as heterozygous loss-of-function mutation in these genes leads to phenotypic abnormalities. This condition, known as haploinsufficiency, has been described for five of the nine mammalian

Multiple Congenital Ocular Anomalies in a silver coat Missouri Fox Trotter stallion

2021 ◽  
Vol 49 (05) ◽  
pp. 350-354
Author(s):  
Verena Maria Herb ◽  
Verena Zehetner ◽  
Klaas-Ole Blohm
Keyword(s):  
Missense Mutation ◽  
Coat Color ◽  
Incidental Finding ◽  
Unknown Origin ◽  
Allelic Frequency ◽  
Cystic Lesions ◽  
Wild Type Allele ◽  
Wild Type ◽  
Type Allele ◽  
Phenotype Characterization

AbstractThis is the first description of Multiple Congenital Ocular Anomalies (MCOA) in a silver coat Missouri Fox Trotter determined to be heterozygous for the Silver PMEL17 missense mutation associated with MCOA and a silver coat in other breeds. The stallion was treated for meningoencephalitis and bilateral uveitis of unknown origin. A complete ophthalmic examination and ocular ultrasonography were performed. As an incidental finding, the patient exhibited bilateral cystic lesions restricted to the temporal anterior uvea consistent with the Cyst phenotype and was genotyped heterozygous for the Silver mutation. Additionally, 4 other non-silver colored Missouri Fox Trotters were genotyped homozygous for the wild-type allele. Screening for PMEL17 mutation in Missouri Fox Trotters accompanied by ophthalmic phenotype characterization is recommended to determine the allelic frequency and facilitate informed breeding decisions since the silver coat color is particularly popular.

scholarly journals GENETIC ANALYSIS OF THREE DOMINANT FEMALE-STERILE MUTATIONS LOCATED ON THE X CHROMOSOME OF DROSOPHILA MELANOGASTER

Genetics ◽  
1983 ◽  
Vol 105 (2) ◽  
pp. 309-325
Author(s):  
D Busson ◽  
M Gans ◽  
K Komitopoulou ◽  
M Masson
Keyword(s):  
X Chromosome ◽  
Germ Line ◽  
Female Sterility ◽  
Recessive Mutation ◽  
Wild Type Allele ◽  
Wild Type ◽  
Allelic Series ◽  
Type Allele ◽  
Dominant Female ◽  
Female Germ Line

ABSTRACT Three dominant female-sterile mutations were isolated following ethyl methanesulfonate (EMS) mutagenesis. Females heterozygous for two of these mutations show atrophy of the ovaries and produce no eggs (ovoD  1) or few eggs (ovoD  2); females heterozygous for the third mutation, ovoD  3, lay flaccid eggs. All three mutations are germ line-dependent and map to the cytological region 4D-E on the X chromosome; they represent a single allelic series. Two doses of the wild-type allele restore fertility to females carrying ovoD  3 and ovoD  2, but females carrying ovoD  1 and three doses of the wild-type allele remain sterile. The three mutations are stable in males but are capable of reversion in females; reversion of the dominant mutations is accompanied by the appearance, in the same region, of a recessive mutation causing female sterility. We discuss the utility of these mutations as markers of clones induced in the female germ line by mitotic recombination as well as the nature of the mutations.

scholarly journals Short and sweet: foreleg abnormalities in Havanese and the role of the FGF4 retrogene

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Kim K. L. Bellamy ◽  
Frode Lingaas
Keyword(s):  
Mutant Allele ◽  
Large Degree ◽  
Population Increase ◽  
Wild Type Allele ◽  
Wild Type ◽  
Gradual Decline ◽  
Type Allele ◽  
Population Frequency ◽  
Welfare Implications

Abstract Background Cases of foreleg deformities, characterized by varying degrees of shortened and bowed forelegs, have been reported in the Havanese breed. Because the health and welfare implications are severe in some of the affected dogs, further efforts should be made to investigate the genetic background of the trait. A FGF4-retrogene on CFA18 is known to cause chondrodystrophy in dogs. In most breeds, either the wild type allele or the mutant allele is fixed. However, the large degree of genetic diversity reported in Havanese, could entail that both the wild type and the mutant allele segregate in this breed. We hypothesize that the shortened and bowed forelegs seen in some Havanese could be a consequence of FGF4RG-associated chondrodystrophy. Here we study the population prevalence of the wild type and mutant allele, as well as effect on phenotype. We also investigate how the prevalence of the allele associated with chondrodystrophy have changed over time. We hypothesize that recent selection, may have led to a gradual decline in the population frequency of the lower-risk, wild type allele. Results We studied the FGF4-retrogene on CFA18 in 355 Havanese and found variation in the presence/absence of the retrogene. The prevalence of the non-chondrodystrophic wild type is low, with allele frequencies of 0.025 and 0.975 for the wild type and mutant allele, respectively (linked marker). We found that carriers of the beneficial wild type allele were significantly taller at the shoulder than mutant allele homozygotes, with average heights of 31.3 cm and 26.4 cm, respectively. We further found that wild type carriers were born on average 4.7 years earlier than mutant allele homozygotes and that there has been a gradual decline in the population frequency of the wild type allele during the past two decades. Conclusions Our results indicate that FGF4RG-associated chondrodystrophy may contribute to the shortened forelegs found in some Havanese and that both the wild type and mutant allele segregate in the breed. The population frequency of the wild type allele is low and appear to be decreasing. Efforts should be made to preserve the healthier wild type in the population, increase the prevalence of a more moderate phenotype and possibly reduce the risk of foreleg pathology.

scholarly journals Intragenic deletion of CDH1 as the inactivating mechanism of the wild-type allele in an HDGC tumour

Oncogene ◽  
2003 ◽  
Vol 23 (12) ◽  
pp. 2236-2240 ◽  
Author(s):  
Carla Oliveira ◽  
Joyce de Bruin ◽  
Sérgio Nabais ◽  
Marjolijn Ligtenberg ◽  
Cátia Moutinho ◽  
...  
Keyword(s):  
Wild Type Allele ◽  
Wild Type ◽  
Type Allele ◽  
Intragenic Deletion

scholarly journals A Gene-Targeting Approach Identifies a Function for the First Intron in Expression of the α1(I) Collagen Gene

1998 ◽  
Vol 18 (6) ◽  
pp. 3368-3375 ◽  
Author(s):  
Sheriar G. Hormuzdi ◽  
Risto Penttinen ◽  
Rudolf Jaenisch ◽  
Paul Bornstein
Keyword(s):  
Gene Targeting ◽  
Cultured Cells ◽  
Silent Mutation ◽  
Type I ◽  
Wild Type Allele ◽  
Normal Allele ◽  
Wild Type ◽  
Rnase Protection ◽  
Type Allele ◽  
First Intron

ABSTRACT The role of the first intron of the Col1A1 gene in the regulation of type I collagen synthesis remains uncertain and controversial despite numerous studies that have made use of transgenic and transfection experiments. To examine the importance of the first intron in regulation of the gene, we have used the double-replacement method of gene targeting to introduce, by homologous recombination in embryonic stem (ES) cells, a mutated Col1A1 allele (Col-IntΔ). The Col-IntΔ allele contains a 1.3-kb deletion within intron I and is also marked by the introduction of a silent mutation that created an XhoI restriction site in exon 7. Targeted mice were generated from two independently derived ES cell clones. Mice carrying two copies of the mutated gene were born in the expected Mendelian ratio, developed normally, and showed no apparent abnormalities. We used heterozygous mice to determine whether expression of the mutated allele differs from that of the normal allele. For this purpose, we developed a reverse transcription-PCR assay which takes advantage of the XhoI polymorphism in exon 7. Our results indicate that in the skin, and in cultured cells derived from the skin, the intron plays little or no role in constitutive expression of collagen I. However, in the lungs of young mice, the mutated allele was expressed at about 75% of the level of the normal allele, and in the adult lung expression was decreased to less than 50%. These results were confirmed by RNase protection assays which demonstrated a two- to threefold decrease in Col1A1mRNA in lungs of homozygous mutant mice. Surprisingly, in cultured cells derived from the lung, the mutated allele was expressed at a level similar to that of the wild-type allele. Our results also indicated an age-dependent requirement for the intact intron in expression of the Col1A1 gene in muscle. Since the intron is spliced normally, and since the mutant allele is expressed as well as the wild-type allele in the skin, reduced mRNA stability is unlikely to contribute to the reduction in transcript levels. We conclude that the first intron of the Col1A1 gene plays a tissue-specific and developmentally regulated role in transcriptional regulation of the gene. Our experiments demonstrate the utility of gene-targeting techniques that produce subtle mutations for studies ofcis-acting elements in gene regulation.

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