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PubMed1993

Genetic polymorphism of histone H1.z in duck erythrocytes.

Three different phenotypes of erythrocyte histone H1.z were detected in several lines of duck by using two-dimensional PAGE. Electrophoresis and inheritance data have shown that two co-dominant alleles, z1 and z2, encode two proteins which differ slightly in their apparent molecular masses. Allele z1 was very abundant and was found at a frequency at least 0.94, while allele z2 was very rare and was present at a frequency of less than 0.06. Limited chemical and enzymic cleavages appeared to indicate that the allelic forms of histone H1.z differed in the C-terminal regions of their molecules.

Alleles↗
PubMed2001

The human complement C9 gene: structural analysis of the 5' gene region and genetic polymorphism studies.

C9 is the last of the human complement components creating the membrane attack complex. The single chain serum protein is encoded by a gene located on chromosome 5p13 that is composed of 11 exons. With the aid of inverse PCR, the hitherto unknown regions flanking exon 1 and the 3' part of exon 11 (3'UTR) have been sequenced. A computer-based analysis of the 300-bp region located just upstream of the AUG start codon showed homologies to known DNA modules which affect the transcriptional regulation of certain genes. The most striking of these is a sequence that may substitute the missing TATA box in initiating C9 transcription. In the 3'UTR, three successive polyadenylation signals were found. Although the C9 protein is invariant, four different single nucleotide polymorphisms (SNPs) have been observed at the DNA level by exon-specific PCR and direct sequencing. None of them changes the amino acid composition of the mature protein. Due to a C --> T transition in exon 1 at cDNA position 17, the fifth amino acid of the leader peptide may be either an arginine or a tryptophane. Using either PCR/ RFLP analysis (exons 1 and 11) or allele-specific PCR (intron 1 and exon 4), each polymorphism can be characterized without sequencing. All of the exon 1, intron 1 and exon 11 variants could be detected in small population samples of European, Thai or South American Indian origin. In contrast, the exon 4 C variant was observed only once in a European. The first three SNPs can be combined to designate eight different 'C9 alleles'. Of these, six have actually be found. These data provide strong evidence that several mutation and recombination events occurred in the course of C9 gene evolution.

3' Untranslated Regions↗
PubMed2001

cDNA cloning and genetic polymorphism of the swine major histocompatibility complex (SLA) class II DMA gene.

cDNA clones corresponding to the swine histocompatibility complex (SLA: swine leucocyte antigen)-DM alpha chain were isolated using the polymerase chain reaction (PCR) products from the third exon in the human HLA-DMA gene as a probe. Amino acid comparative analysis revealed that these clones were more closely related to the bovine and human DMA genes than to the other swine class II genes alpha chain genes, DRA, DQA and DOA. These results suggest that the SLA-DMA gene is expressed and may function, like HLA-DM, as an important modulator in class II restricted antigen processing in swine. Furthermore, based on the sequences and PCR-restriction fragment length polymorphism (PCR-RFLP) patterns in the SLA-DMA gene, no allelic variation was recognized in the second exon, but five allelic variations were recognized in the third exon in five different breeds of swine. These DMA alleles were defined by variation at four nucleotide positions. Two of these alleles resulted in an amino acid substitution. These results suggest that SLA-DMA has little polymorphism as observed in HLA-DMA and mouse H2-Ma.

Alleles↗
PubMed1996

The influence of the sparteine/debrisoquine genetic polymorphism on the disposition of dexfenfluramine.

1. To determine whether dexfenfluramine is a substrate of cytochrome P450 2D6 (CYP2D6), its disposition has been studied in nine extensive (EM) and eight poor metabolizers (PM) of debrisoquine. 2. Following a 30 mg dose of dexfenfluramine hydrochloride, urine was collected in all subjects for 96 h post-dose and plasma samples were collected in 11 subjects (six EMs and five PMs). Dexfenfluramine and nordexfenfluramine were measured in urine by h.p.l.c. and in plasma by g.c. 3. Urinary recovery of dexfenfluramine was greater in PMs than EMs (4136 +/- 1509 micrograms vs 1986 +/- 792 micrograms; 95% CI of difference 926-3374; P < 0.05) whereas that of nordexfenfluramine was similar in both phenotypes (PM: 1753 +/- 411 micrograms vs 1626 +/- 444 micrograms). 4. Dexfenfluramine AUC was higher in PMs (677 +/- 348 micrograms l-1 h) than EMs 359 +/- 250 micrograms l-1 h). The apparent oral clearance of dexfenfluramine was greater in EMs than PMs (93.6 +/- 42.4 l h-1 vs 45.6 +/- 19.5 l h-1; 95% CI of difference 1.2-94.7; P < 0.05). The renal clearance was similar in both phenotypes (EMs: 5.88 +/- 2.83 l h-1; PMs 6.60 +/- 2.01 l h-1), indicating that the higher urinary recovery of dexfenfluramine in PMs reflects higher plasma concentrations, rather than phenotype differences in the renal handling, of dexfenfluramine. 5. The apparent nonrenal clearance of dexfenfluramine was substantially lower (P < 0.05; 95% CI of difference 3.0-94.1) in PMs (39.0 +/- 19.5 l h-1) than EMs (87.6 +/- 41.2 l h-1). 6. There was a significant inverse correlation (rs = 0.776 95% CI-0.31-0.94; n = 11; p = 0.005) between the debrisoquine metabolic ratio and the apparent nonrenal clearance of dexfenfluramine. 7. PMs had a higher incidence of adverse effects (nausea and vomiting) than EMs. 8. In conclusion, the metabolism of dexfenfluramine is impaired in PMs. Thus CYP2D6, the isoenzyme deficient in poor metabolizers of debrisoquine, must catalyse at least one pathway of dexfenfluramine biotransformation.

Adult↗
PubMed1999

Genetic polymorphism of (S)-mephenytoin 4'-hydroxylation in populations of African descent.

AIMS: The frequency of CYP2C19 poor metabolizers (PMs) in populations of African descent has been reported to range from 1.0% to 35.4%. In order to determine with greater certainty the frequency of CYP2C19 PMs in such black populations we have performed a meta-analysis of the studies. METHODS: Relevant data on the frequency of both the PM phenotype of probe drugs (mephenytoin, omeprazole, and proguanil), and the distribution frequencies of CYP2C19 alleles and genotypes in black populations were summarized and reanalysed using a meta-analytical approach. RESULTS: Of nine reported studies two were excluded because of significant heterogeneity (chi2=115, P<0.0001). The combined data from the remaining seven studies showed that the frequency of the PM phenotype in 922 healthy unrelated black Africans and black Americans ranged from 1.0% to 7.5% (n=7 for combined data) with an overall frequency being 3.9% (36 of 922; 95%CI: 2.7%-5.2%). The frequency of the PM genotypes in blacks was 3.7% (36 of 966; 95%CI: 2.5%-4.9%), in agreement with the frequency of the PM phenotype. In the extensive metabolizers (EMs) 29% (271 of 930) were heterozygotes (wt/m ). The observed frequencies of the three Mendelian genotypes were 0.68 for wt/wt, 0.28 for wt/m, and 0.04 for m/m. The allelic distribution was appropriate at 82.3% (95%CI: 80.5%-83.9%) for CYP2C19*1, 17.3% (95%CI:15.7%-19.0%) for CYP2C19*2 (m1 ), and 0.4% (95%CI: 0.1%-0.7%) for CYP2C19*3 (m2 ) in these populations. CONCLUSIONS: We conclude that subjects of African ancestry have a low frequency of the CYP2C19 PM phenotype and genotype; that the defective CYP2C19 alleles are uncommon, and that a small proportion of heterozygotes exists in the EM subpopulation.

Africa↗
PubMed2002

Genetic polymorphisms in human CYP2A6 gene causing impaired nicotine metabolism.

AIMS: Previously, we determined the phenotyping of in vivo nicotine metabolism and the genotyping of the CYP2A6 gene (CYP2A6*1 A, CYP2A6*1B, CYP2A6*2, CYP2A6*3, CYP2A6*4 and CYP2A6*5 ) in 92 Japanese and 209 Koreans. In the study, we found one Korean and four Japanese subjects genotyped as CYP2A6*1B/CYP2A6*4 who revealed impaired nicotine metabolism, although other many heterozygotes of CYP2A6*4 demonstrated normal nicotine metabolism (CYP2A6*4 is a whole deletion type). After our previous report, several CYP2A6 alleles, CYP2A6*6 (R128Q), CYP2A6*7 (I471T), and CYP2A6*8 (R485L), have been reported. The purpose of the present study was to clarify whether the impaired nicotine metabolism can be ascribed to these CYP2A6 alleles. Furthermore, we also determined whether the subjects possessing CYP2A6*1x2 (duplication) reveal higher nicotine metabolism. METHODS: Genotyping of CYP2A6 alleles, CYP2A6*6, CYP2A6*7, CYP2A6*8, and CYP2A6*1x2 was determined by PCR. RESULTS: The five poor metabolizers were re-genotyped as CYP2A6*7/CYP2A6*4, suggesting that a single nucleotide polymorphism (SNP) causing I471T decreases nicotine metabolism in vivo. Furthermore, we found that two subjects out of five with a lower potency of nicotine metabolism possessed SNPs of CYP2A6*7 and CYP2A6*8 simultaneously. The novel allele was termed CYP2A6*10. In the 92 Japanese and 209 Koreans, the CYP2A6*6 allele was not found. The allele frequencies of CYP2A6*7, CYP2A6*8, and CYP2A6*10 were 6.5%, 2.2%, and 1.1%, respectively, in Japanese, and 3.6%, 1.4%, and 0.5%, respectively, in Koreans. The CYP2A6*1x2 allele was found in only one Korean subject (0.5%) whose nicotine metabolic potency was not very high. CONCLUSIONS: It was clarified that the impaired in vivo nicotine metabolism was caused by CYP2A6*7 and CYP2A6*10 alleles.

Aryl Hydrocarbon Hydroxylases↗
PubMed2003

Pharmacokinetics of diclofenac and inhibition of cyclooxygenases 1 and 2: no relationship to the CYP2C9 genetic polymorphism in humans.

AIMS: The cytochrome P450 enzyme CYP2C9 catalyses the 4'-hydroxylation of the nonsteroidal analgesic drug diclofenac in humans. We studied the influences of the known amino acid variants, CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu), on diclofenac pharmacokinetics after a 50-mg oral dose of diclofenac in healthy volunteers. As a surrogate marker of diclofenac activity, the ex vivo formation of prostaglandin E2 and thromboxane B2, which reflects COX-2 and COX-1 activity, was measured. METHODS: Genotyping was performed in 516 healthy volunteers to obtain 20 participants with all allelic combinations of the two CYP2C9 variants Arg144Cys (*2) and Ile359Leu (*3). Diclofenac and 4'-hydroxydiclofenac were quantified in plasma by reversed phase h.p.l.c. after oral intake of 50 mg diclofenac. Concentrations of thromboxane B2 (TxB2) and prostaglandin E2 (PGE2) were measured by immunoassays. RESULTS: There was no evidence of impaired metabolism of oral diclofenac in heterozygous and homozygous carriers of the CYP2C9 alleles *2 and *3 compared with the wild type (mean CL/F (95% CI) 20.5 (11, 30) l h-1 for *1/*1, 29.9 (19, 40) l h-1 for *1/*2, 30.0 (4, 56) l h-1 for *2/*2, 22.6 (12, 33) l h-1 for *1/*3, 23.5 (11, 37) l h-1 for *3/*3 and 37.3 (-15, 89) l h-1 in *2/*3). Furthermore, plasma concentrations of the metabolite 4'-hydroxydiclofenac were not lower in carriers of the CYP2C9 low-activity alleles *2 and *3 compared with carriers of the CYP2C9*1/*1 genotype. Marked diclofenac mediated inhibition of COX-1- and COX-2 activity was detected in all individuals independent of CYP2C9 genotype. CONCLUSIONS: Polymorphisms of the CYP2C9 gene had no discernible effect on the pharmacokinetics and pharmacodynamics of diclofenac. The question of whether enzymes other than CYP2C9 play a major role in diclofenac 4'-hydroxylation in vivo or whether 4'-hydroxylation is not a rate-limiting step in diclofenac elimination in vivo, or whether the effect of the CYP2C9 polymorphisms is substrate-dependent, needs further investigation.

Adult↗
PubMed2003

Genetic polymorphisms of CYP2C9 and CYP2C19 in the Beninese and Belgian populations.

AIMS: To investigate the distribution of cytochrome P450 2C9 (CYP2C9) and 2C19 (CYP2C19) genotype frequencies in the Beninese and Belgian Caucasian populations. METHODS: Beninese (n = 111) and Belgian (n = 121) were genotyped for CYP2C9*2, *3, *4, *5, and *11 as well as for CYP2C19*2 and*3. RESULTS: The distribution of alleles was: CYP2C9*1: 95.5 vs. 82.2% (P < 0.001); CYP2C9*2: 0 vs. 10% (P < 0.001); CYP2C9*3: 0 vs. 7.4% (P < 0.01); CYP2C9*4: both 0%; CYP2C9*5: 1.8 vs. 0% (P = 0.05); and CYP2C9*11: 2.7 vs. 0.4% (P < 0.05). The frequencies of the CYP2C19*2 allele were 13 vs. 9.1%, respectively. CYP2C19*3 was not detected in either population. The 95% confidence intervals for the differences of frequencies of CYP2C9*1, CYP2C9*2, CYP2C9*3, CYP2C9*4, CYP2C9*5, CYP2C9*11, CYP2C19*1, CYP2C19*2 and CYP2C19*3 between Belgian and Beninese were 7%, 19%; - 14%, - 6%; - 11%, - 4%; - 1%, 1%; 0%, 4%; 0%, 5%; - 10%, 2%; - 2%, 10%; - 1%; respectively. The distributions of CYP2C9 genotypes in the Beninese and Belgian individuals were: CYP2C9*1/*1: 91 vs. 67% (P < 0.00001); CYP2C9*1/*2: 0 vs. 18.2% (P < 0.0001); CYP2C9*1/*3: 0 vs. 11.6% (P < 0.001); CYP2C9*1/*5: 3.6 vs. 0% (P = 0.05); CYP2C9*1/*11: 5.4 vs. 0.8% (P = 0.05); CYP2C9*2/*3: 0 vs. 1.6% (NS); CYP2C9*3/*3: 0 vs. 0.8% (NS). The distributions of CYP2C19 genotypes between these ethnic groups were: CYP2C19*1/*1: 73.9 vs. 83.5% (NS); CYP2C19*1/*2: 26.1 vs. 14.9% (P < 0.05); CYP2C9*2/*2: 0 vs. 1.6% (NS). CONCLUSIONS: Differences of allele frequencies between Beninese and Belgian populations were statistically significant for CYP2C9*2, *3, *5 and *11, but not for CYP2C9*4 or for CYP2C19*2 and *3.

Adult↗
PubMed1998

Ultraviolet B induced suppression of induction of contact sensitivity in human skin is not associated with tumour necrosis factor-alpha-308 or interleukin-10 genetic polymorphisms.

Low doses of ultraviolet B (UVB) can induce localized immunosuppression in skin. This effect may be important in the induction of skin cancers and is thought to be mediated by tumour necrosis factor (TNF) alpha and interleukin (IL) 10 in conjunction with other factors. In humans a transition polymorphism in the TNF-alpha gene may affect TNF-alpha secretion and the promoter region of the IL-10 gene contains a CA repeat polymorphism which may affect gene function. We have therefore investigated the association of these polymorphisms with UVB-induced immunosuppression in humans. Volunteers (n = 42) were irradiated with UVB then sensitized on irradiated skin with diphenylcyclopropanone (DPCP) and subsequently antigen challenged with DPCP. DNA was extracted from blood samples and volunteers genotyped for the TNF-alpha polymorphism by polymerase chain reaction (PCR) and restriction digestion. The CA repeat polymorphism was amplified by PCR and sized by gel electrophoresis. Twenty-four volunteers were susceptible to UVB-induced immunosuppression and 18 were resistant. The association of allele frequencies and phenotype was statistically tested using a chi2-test. For both the TNF-alpha and IL-10 polymorphisms, there was no statistically significant association between allele types and response to UVB. These results indicate that variation in the immune response to UVB in humans is not associated with the TNF-alpha-308 transition or IL-10 CA repeat polymorphisms, although other as yet undetected DNA sequence variants of these genes may be involved.

Alleles↗
PubMed2003

Clinical relevance of genetic polymorphisms in the human CYP2C9 gene.

Cytochrome p450 (CYP) 2C9 hydroxylates about 16% of drugs in current clinical use. Of special interest are those with a narrow therapeutic index, such as S-warfarin, tolbutamide and phenytoin, where impairment in CYP2C9 metabolic activity might cause difficulties in dose adjustment as well as toxicity. Single-nucleotide polymorphisms (SNP) in the CYP2C9 gene have increasingly been recognized as determinants of the metabolic phenotype that underlies interindividual and ethnic differences. Apart from the wild-type protein CYP2C9*1 at least five allelic variants produce allozymes with reduced or deficient metabolic activity. Among white populations only CYP2C9*2 and CYP2C9*3 variants are of significance, with allelic frequencies of 0.08-0.14 and 0.04-0.16, respectively. In contrast, in Africans (African-Americans and Ethiopians) and Asians both variants are much less frequent (0.005-0.04), and CYP2C9*2 has not yet been detected in Asians. CYP2C9*4 has been exclusively identified in Japanese patients, and CYP2C9*5 and *6 were only found among African-Americans with a low allelic frequency of 0.017 and 0.006, respectively. Furthermore in Japanese a CYP2C9 promotor variant of four linked SNPs was correlated with reduced intrinsic clearance of phenytoin in vitro. Subjects who are carriers of one or more variant alleles may be at risk for adverse drug reactions/toxicities when prescribed drugs extensively metabolized by CYP2C9.

Anticoagulants↗
PubMed2003

Genetic polymorphism of CYP2D6 in Chinese subjects in Malaysia.

BACKGROUND: Although Malaysian Chinese share an origin with the mainland Chinese, their evolution has been influenced by intermarriages. With a gene such as CYP2D6, which is highly polymorphic, it is expected that the Malaysian Chinese would exhibit a polymorphism profile different from those of the Chinese populations in other geographical locations. OBJECTIVE: To study the genotype distribution of CYP2D6 among the Chinese people in Malaysia. METHOD: We obtained DNA from 236 Chinese individuals in Malaysia and used PCR-based methods to identify any common CYP2D6 alleles. RESULTS: A total of 236 subjects were enrolled and were successfully genotyped. Malaysian Chinese were relatively heterogeneous in terms of their CYP2D6 genotypes with nine genotypes recorded. CYP2D6*4, *5, *9, *10 and *17 were detected with the most common genotype being *1/*10. No subject had genotypes that predicted poor metabolic activity. However, 40% showed genotypes (e.g. CYP2D6*10/*10, *17, *4 and *9 and *9/*9) that predicted an intermediate metabolizer phenotype. Another subject carried the defective CYP2D6*17 allele and six carried the defective CYP2D6*9 allele. Both these alleles have not been reported in other earlier Chinese studies. CONCLUSION: This study revealed that, in terms of CYP2D6 polymorphism, Malaysian Chinese were a heterogeneous group of people. Although sharing some similarities with other Orientals, they also seemed to have some notable differences. The alleles CYP2D6*4, *5, *9, *10 and *17 were all detected. CYP2D6*3 was however absent.

Adolescent↗
PubMed1999

Malaria infection and morbidity in infants in relation to genetic polymorphisms in Tanzania.

To investigate the effects of host polymorphisms on malaria morbidity and infection, the frequency distributions of TNF alpha promotor gene and sickle cell trait were studied in infants in an area highly endemic for Plasmodium falciparum transmission in Tanzania. Differences in parasite prevalence, density, febrile episodes with and without parasitaemia, PCV levels and the frequencies of different MSP-2 parasite infections were assessed by genotype. The frequency of the TNF alpha promotor allele 2 was 0.09, and the trait was in Hardy-Weinberg equilibrium. There were no differences in malariametric indices between infants with the normal TNF alpha promoter gene and those who were heterozygous for this trait. Infants heterozygous for the TNF alpha promotor gene appeared to have fewer febrile episodes when they were free of parasites. The two infants homozygous for the TNF alpha promoter allele 2 had both a much higher incidence of fever, independently of parasitaemia, than the average for the other genotypes. The frequency of the sickle cell allele S was 0.06 and the trait was also in Hardy-Weinberg equilibrium. Infants heterozygous for the sickle cell trait had significantly lower parasite densities, but similar prevalence, and MSP-2 infections compared to infants with normal haemoglobin. PCV levels, and the incidence of febrile episodes both with and without parasitaemia were also similar. In contrast to the sickle cell trait, the TNF alpha promotor polymorphism appeared not to have any protective effect on malaria in this study, and its importance in other unspecified fever-causing diseases in this population needs further investigation.

Alleles↗
PubMed2003

Plasmodium falciparum: correlation of in vivo resistance to chloroquine and antifolates with genetic polymorphisms in isolates from the south of Lao PDR.

Levels of drug resistance of Plasmodium falciparum strains against antimalarials have increased in Laos. In several studies, chloroquine (CQ) resistance has been associated with point mutations in the Pfcrt and pfmdr genes, and sulphadoxine/pyrimethamine (S/P) resistance with point mutations in the genes of dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS). We combined a study of these molecular markers with an in vivo antimalarial drug sensitivity study in Attapeu province in the south of Lao PDR. We treated 100 patients with either CQ, S/P or a combination of both. In the CQ group, Pfcrt mutations showed a very high sensitivity (100%) but a low specificity (12.5%) to predict resistance. The combination of mutations in the Pfcrt and pfmdr genes was highly specific and had a positive predictive value of 100%. Mutations in the DHPS gene showed a high correlation with the development of resistance. The prevalence of mutations in the DHFR gene, especially codon 108 Asn, was predictive with high sensitivity (100%) but low specificity. Isolates derived from patients treated with a combination of both drugs showed a high correlation between the mutation in codon 437 of DHPS gene and in vivo-resistance (odds ratio 16.00, CI). The study provides evidence for the existence of antimalarial drug resistance in the south of Lao PDR, and offers a molecular method to predict resistance.

Adolescent↗
PubMed2000

Genetic polymorphism in Xanthomonas albilineans strains originating from 11 geographical locations, revealed by two DNA probes.

Two DNA fragments from Xanthomonas albilineans were used as probes to study the molecular diversity among strains of this pathogen. Two serologically distinct groups, serovars I and II, could be differentiated by hybridization to the probes. These probes, designated 830 and 838, were cloned after subtractive DNA hybridization of common sequences of Xanthomonas campestris pv. vasculorum from a serovar I strain of X. albilineans. They did not hybridize to the DNA of several other xanthomonads or to sugarcane DNA under the conditions of hybridization used. Faint bands were observed upon hybridization of probe 830 with one strain of X. campestris pv. phaseoli. The same banding patterns were obtained with a strain of X. albilineans from Burkina Faso and the serovar II strains of Mauritius. The serovar I strains from Mauritius and two other strains each from Reunion and South Africa had similar pattern.

Africa↗