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Results for “Genetic polymorphisms”

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At least 613 records · Page 34Linked to original sources
PubMed2006

Combined effects of itraconazole and CYP2D6*10 genetic polymorphism on the pharmacokinetics and pharmacodynamics of haloperidol in healthy subjects.

This study was to evaluate the combined effects of the CYP3A4 inhibitor itraconazole and the CYP2D6*10 genotype on the pharmacokinetics and pharmacodynamics of haloperidol, a substrate of both CYP2D6 and CYP3A4, in healthy subjects. Nineteen healthy volunteers whose CYP2D6 genotypes were predetermined were enrolled (9 for CYP2D6*1/*1 and 10 for CYP2D6*10/*10). Four subjects (1 for CYP2D6*1/*1 and 3 for CYP2D6*10/*10) did not complete the study because of adverse events. The pharmacokinetics of haloperidol and its pharmacodynamic effects measured for QTc prolongation and neurologic side effects were evaluated after a single dose of 5 mg haloperidol following a pretreatment of placebo or itraconazole at 200 mg/d for 10 days in a randomized crossover manner. Itraconazole pretreatment increased the mean area under the time-concentration curves (AUCs) of haloperidol by 55% compared to placebo pretreatment (21.7 +/- 11.3 vs 33.5 +/- 29.3 ng h/mL). The subjects with CYP2D6*10/*10 genotype showed 81% higher AUC compared to that of subjects with CYP2D6*1/*1 genotype (27.6 +/- 22.2 vs 50.2 +/- 47.1 ng h/mL). In the presence of itraconazole, subjects with CYP2D6*10/*10 showed 3-fold higher AUC of haloperidol compared to that of placebo pretreated subjects with CYP2D6*1/*1 genotype (21.7 +/- 11.3 vs 66.7 +/- 62.1 ng h/mL; P < 0.05). The CYP2D6*10 genotype and itraconazole pretreatment decreased the oral clearance of haloperidol by 24% and 25%, respectively, but without a statistical significance. In the subjects with both CYP2D6*10 genotype and itraconazole pretreatment, however, the oral clearance was significantly decreased to 42% of subjects with wild genotype in the placebo pretreatment (4.7 +/- 3.6 vs 2.0 +/- 1.9 L/h/kg; P < 0.05). Barnes Akathisia Rating Scale (BARS) of subjects with CYP2D6*10/*10 in the presence of itraconazole pretreatment was significantly higher than that of subjects with CYP2D6*1/*1 genotype in the period of placebo pretreatment. Except for this, all other pharmacodynamic estimations did not reach to statistical significance although each CYP2D6*10 genotype and itraconazole pretreatment caused higher value of UKU side effect and BARS scores. The moderate effect of CYP2D6*10 genotype on the pharmacokinetics and pharmacodynamics of haloperidol seems to be augmented by the presence of itraconazole pretreatment.

Adult↗
PubMed2003

Genetic polymorphism of NPHS1 modifies the clinical manifestations of Ig A nephropathy.

Nephrin, the molecule responsible for congenital nephrotic syndrome of Finnish type, is crucial in maintaining the glomerular filtration barrier. Recently, its complete gene structure and common gene polymorphisms in its exons have been reported, although the functional and clinical significance of these polymorphisms has not yet been elucidated. We investigated a possible association of the NPHS1 polymorphisms with the development of Ig A nephropathy (IgAN), as well as the clinical and histologic manifestations in IgAN. A total of 464 Japanese subjects, including 267 patients with histologically proven IgAN and 197 healthy controls with normal urinalysis, were genotyped for the NPHS1 G349A, G2289A, and T3315C polymorphisms. The frequencies of the genotypes, alleles, and estimated haplotypes of NPHS1 polymorphisms were no different between patients with IgAN and the controls. Within the IgAN group, patients carrying at least one G allele of G349A tended to present with more proteinuria, lower renal function, and more severe histopathologic injury than those with the AA genotype, although the time from the first urinary abnormality to the renal biopsy was no different between both groups. The logistic regression analysis indicated that even after adjusting for the effect of proteinuria and hypertension the GG genotype of NPHS1 G349A was an independent risk factor for the deteriorated renal function at the time of diagnosis. This study suggests that the NPHS1 G349A polymorphism may be associated with heavy proteinuria and a decline in renal function in patients with IgAN.

Adolescent↗
PubMed2003

Impact of cytochrome p450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients.

BACKGROUND: Tacrolimus pharmacokinetic characteristics vary greatly among individuals. Tacrolimus is a substrate of cytochrome p450 (CYP), of subfamily CYP3A. CYP3A activity is the sum of the activities of the family of CYP3A genes, including CYP3A5. Subjects with the CYP3A5*1/*1 genotype express large amounts of CYP3A5. Heterozygotes (genotype CYP3A5*1/*3) also express the enzyme. We postulated that CYP3A5 polymorphism is associated with tacrolimus pharmacokinetic variations. METHODS: CYP3A5 genotype was evaluated in 80 renal transplant recipients and correlated with the daily tacrolimus dose and concentration-to-dose ratio. RESULTS: The frequency of the homozygous CYP3A5*1 genotype (CYP3A5*1/*1) was 5%, and 11% of subjects were heterozygous (CYP3A5*1/*3). The mean doses required to obtain the targeted concentration-to-dose ratio were significantly lower in patients with the CYP3A5*1/*1 genotype. CONCLUSIONS: Determination of CYP3A5 genotype is predictive of the dose of tacrolimus in renal transplant recipients and may help to determine the initial daily dose needed by individual patients for adequate immunosuppression without excess nephrotoxicity.

Adult↗
PubMed1993

Genetic polymorphisms in prehistoric Pacific islanders determined by analysis of ancient bone DNA.

A previously characterized Asian-specific mitochondrial DNA (mtDNA) length mutation has been detected in DNA isolated from prehistoric human bones from Polynesia, including Hawaii, Chatham Islands and Society Islands. In contrast, the Asian mutation was absent in skeletal samples from the Melanesian archipelagos of New Britain and Vanuatu and in the oldest samples from Fiji, Tonga and Samoa in the central Pacific (2700-1600 years BP) although it was present in a more recent prehistoric sample from Tonga. These results, augmented by informative DNA sequence data from the hypervariable region of mtDNA, fail to support current views that the central Pacific was settled directly by voyagers from island Southeast Asia, the putative ancestors of modern Polynesians. An earlier occupation by peoples from the neighbouring Melanesian archipelagos seems more likely.

Animals↗
PubMed2001

RNA replication kinetics, genetic polymorphism and selection in the case of the hepatitis C virus.

We show in a simple theoretical quasispecies model that the replication dynamics of hepatitis C virus and a related model-system, the bovine viral diarrhoea virus, result in an effective reduction of RNA templates in infected cells. Viral fitness does not translate directly into RNA sequence replication efficiency, and hence the abundance of the viral master sequences diminishes over time. Our results suggest that genes not involved in RNA replication accumulate mutations over time because they do not undergo selection during this phase. The selection of viral RNA occurs not only during replication but also during the ensuing stages of the viral life cycle: (i) envelopment of viral RNA and (ii) successful infection of other cells, which also requires functionality of non-replicative genes. In particular, viral fitness requires the ability of the genome to encode structural proteins which do not encounter selective pressure during RNA replication. We conclude by discussing the potential value of antiviral drugs which inhibit selection on parts of the viral genome.

Hepacivirus↗
PubMed2001

Genetic polymorphism of human herpesvirus-7 among human populations.

The analysis of three human herpesvirus-7 (HHV-7) genes encoding phosphoprotein p100, glycoprotein B and major capsid protein respectively had previously shown the existence of distinct gene alleles, leading to the concept of HHV-7 variants. We have analysed the distribution of HHV-7 variants among 297 distinct subjects who belonged to different human populations from Africa, Asia, Europe and America. Two variants, designated Co1 and Co2, were found in 52% and 20% of studied subjects. Ten other variants, designated Co3-Co12, were less frequent and classified into two groups related to Co1 and Co2 respectively. While the former group was ubiquitous and the most frequent in Africa and Asia, the latter one was predominantly found in European and Mongol populations. Despite the high stability of the HHV-7 genome, a few nucleotide substitutions at precise positions define distinct variants which, to some extent, behave as markers of human populations.

Africa↗
PubMed2006

Genetic polymorphisms of interleukin-1-beta in association with sustained response to anti-viral treatment in chronic hepatitis B in Chinese.

BACKGROUND: Interleukin-1beta is a pro-inflammatory cytokine that may influence host defence against viral infection. AIM: To investigate the impact of interleukin-1beta gene polymorphism on the response to anti-viral treatment. METHOD: Hepatitis B e antigen-positive chronic hepatitis B patients who have completed a randomized study of peginterferon alpha-2b and lamivudine combination vs. lamivudine monotherapy were included. Sustained responders were patients who had persistent hepatitis B e antigen loss and less than two occasions with hepatitis B virus DNA >100 000 copies/mL at any time up to week 76 post-treatment. Polymorphisms at interleukin-1beta-511, -31 and -3954 and interleukin-1 receptor antagonist (RN) were studied. RESULTS: Eighty-eight patients were studied and 18 (20%) patients developed sustained response. Near complete linkage disequilibrium was observed between interleukin-1beta-511 and -31 loci. After adjustment for the potential confounding effects of treatment allocation, hepatitis B virus genotype, pre-treatment alanine aminotransferase and hepatitis B virus DNA levels, genotype C/T at interleukin-1beta-511 was found to be associated with higher sustained response than genotype C/C (adjusted odds ratio 10.4, 95% CI 1.1, 96.9, P = 0.040). The proportion of sustained responders tend to be higher among patients with allele T at interleukin-1beta-511 (83%) than those without (70%) (P = 0.058). CONCLUSION: High interleukin-1beta production genotype at position -511 has a favourable response to anti-viral treatments.

Adult↗
PubMed1977

Genetic polymorphism of eserine resistant esterases in canine plasma.

Six plasma eserine resistant esterase phenotypes were observed in a population of 1438 dogs consisting of 38 breeds. Analysis of parentage records of the dogs examined revealed that the phenotypic variation of eserine resistant esterases was controlled by 3 codominant alleles ESA, ESB and ESC at one autosomal locus. The gene frequency of ESB was high in most of the breeds examined. Allele ESC was only seen in 5 Japanese native breeds, Akita, Shikoku, Hokkaido, Shinshu-Shiba and Mino-Shiba, and in a Spitz dog. Allele ESA has a low frequency in Japanese breeds but a higher frequency in some of the European breeds tested.

Alleles↗
PubMed1980

Genetic polymorphism of erythrocyte esterase-D in pigs.

The erythrocyte esterase-D (Es-D) of four European-American pig breeds, two Taiwan native pigs (Taoyuan and Short ear breeds), Philippine native pig and wild boar populations (Sus scrofa riukiuanus) in Japan was investigated by using starch gel electrophoresis. Analysis of parentage records of the pigs revealed that the phenotypic variation of erythrocyte esterase-D was controlled by two codominant alleles Es-DA and Es-DB. The allele Es-DB was mostly found in three European-American pig breeds, Landrace (0.100), Hampshire (0.135) and Duroc (0.102). All of the wild boar populations were monomorphic for allele Es-DA.

Alleles↗