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PubMed2006

[Genetic polymorphism of penta e locus in four Chinese nationalities].

To study the genetic polymorphism of Penta E locus in four Chinese nationalities using home made reagent kits, DNA samples were obtained from about 400 unrelated peoples of four different Chinese nationalities. As a result, we found 20 alleles in the four nationalities with frequencies ranging from 0.0048 to 0.2396. The genotype frequencies of Penta E locus met Hardy-Weinberg equilibrium. It proved that Penta E locus was a high polymorphic STR genetic marker and was valuable for forensic science.

Asian People↗
PubMed2005

Genetic polymorphisms of ataxia telangiectasia mutated and breast cancer risk.

To evaluate the role of genetic polymorphisms of ataxia telangiectasia mutated (ATM) in the etiology of breast cancer, a hospital-based case-control study was conducted in Korea. Nine-hundred ninety-six histologically confirmed incident breast cancer cases and 1,181 cancer-free controls were recruited in Seoul between 1995 and 2003. Genotypes of the ATM polymorphisms-5144A > T, IVS21 + 1049T > C, IVS33 - 55T > C, IVS34 + 60G > A, and 3393T > G were determined by the 5'-nuclease assay. Individual haplotypes were estimated from genotype data by a Bayesian method. Five ATM alleles were found to be in strong linkage disequilibrium (D' > 0.82; P < 0.001). Haplotype frequencies were significantly different between cases and controls (chi2 test, P < 0.001). The ATM IVS21 + 1049 TC or CC, IVS34 + 60 GA or AA, and 3393 TG or GG genotypes were associated with increased breast cancer risk, particularly in premenopausal women [odds ratios (OR), 1.51; 95% confidence interval (CI), 1.11-2.05; OR, 1.42; 95% CI, 1.08-1.88; and OR, 1.37; 95% CI, 1.04-1.80, respectively]. Compared with diploid of TCCAG:TCCAG, the most common haplotype, the ATTGT:ATTGT was associated with decreased risk of breast cancer with borderline significance (OR, 0.77; 95% CI, 0.58-1.04) and TCCAG:ATCGT and ATTGT:ACCAG were associated with increased breast cancer risk (OR, 2.30; 95% CI, 1.18-4.48 and OR, 2.43; 95% CI, 1.1.07-5.52, respectively) after adjusting for age, education, age at first full-term pregnancy, parity, family history of breast cancer, alcohol consumption, and smoking. As the number of ATTGT haplotype decreased, the risk of breast cancer increased (P for trend < 0.01). Our results thus suggest that genetic polymorphisms of ATM play an important role in the development of breast cancer in Korean women.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2004

Functional genetic polymorphisms in cytokines and metabolic genes as additional genetic markers for susceptibility to develop type 1 diabetes.

Genetic association with type 1 diabetes (T1D) has been established for two chromosomal regions: HLA DQ/DR (IDDM1) and INS VNTR (IDDM2). To identify additional genetic markers, we tested polymorphisms in regulatory regions of several cytokine and important metabolic genes. These polymorphisms exhibit functional consequences for expression and function. Functional genetic polymorphisms of proinflammatory (T-helper-1: IL-2, IL-12 and IFN-gamma), anti-inflammatory (T-helper-2: IL-4, IL-6 and IL-10) and metabolic (IGF-I, VDR and INS) genes were determined in 206 Dutch simplex families with juvenile onset T1D and the results were analysed using the transmission disequilibrium test. Significantly increased transmission to T1D probands was observed for the loci IDDM1, IDDM2 and the vitamin D receptor. Although none of the other individual polymorphisms was associated with disease individually, the combination of T-helper-2 and metabolic/growth alleles IL-10(*)R2, IL-4(*)C, VDR(*)C and IGF-I(*)wt was found to be transmitted more frequently than expected (67%, P(c)=0.015). We conclude that additional genetic predisposition to T1D is defined by combinations of markers (eg Th2 and metabolic) rather than by a single marker. The consequences of the increased transmission of a low Th2 expressing genotypes together with a normal Th1 profile may result in a net proinflammatory cytokine expression pattern.

Adolescent↗
PubMed2006

[Analysis of DC-SIGN and DC-SIGNR genetic polymorphism in Chinese Han population].

OBJECTIVE: To understand the genetic polymorphism of DC-SIGN's and DC-SIGNR's neck regions in normal Chinese Han population, and to obtain the genetic data of the two loci in Chinese Han population. METHODS: The genotypes and alleles of repeat sequences of DC-SIGN and DC-SIGNR neck region were typed by PCR, agarose gel electrophoresis and sequencing. Polymorphism information content (PIC) of DC-SIGNR was calculated. RESULTS: DC-SIGN genetic polymorphism was rare. Allele 7 was most and its frequency was 0.9808. 4-, 5-, 6- and 8- alleles were also found, although their frequencies were very low. Caucasians had only 6- and 8- allele mutants; DC-SIGNR genetic polymorphism was high, its PIC was 0.5312, 4-,5-,6-,7-,8-,9- alleles and 16 genotypes were found in normal Chinese Han population. The differences of 6/5,7/4,7/5,7/6,7/7,9/5,9/7,9/9 genotypes distribution and 5-,6-,7-,9- alleles frequency between normal Chinese Han population and Caucasian population were all extremely distinct (P<0.01). The inserted mutation seemed more in Chinese Hans than Caucasian population. CONCLUSION: DC-SIGN and DC-SIGNR genotypes and alleles distribution in Chinese Han population are significantly different from Caucasian population and with Chinese own population genetic characteristics, compared with Caucasians.

Adolescent↗
PubMedDate not supplied

[Statistical analysis of genetic polymorphisms in epidemiological studies].

Analysis of genetic polymorphisms allows the genes that confer susceptibility to diseases to be analyzed. This paper presents the nomenclature used in genetic epidemiology literature and a basic strategy for statistical analysis of epidemiological studies that use genetic markers. First, a descriptive analysis of a single nucleotide polymorphism is presented, with assessment of Hardy-Weinberg equilibrium. Next, methods to assess the association with disease are presented. To do this, logistic regression models are used and alternative models of inheritance are explored. Finally, methods for the simultaneous analysis of multiple polymorphisms are presented: haplotype frequency estimation and analysis of disease association.

Algorithms↗
PubMed1986

Genetic polymorphism and fertility parameters in the Aymara of Chile and Bolivia.

To determine whether increased fitness in natural populations is associated with heterozygosity, several studies have attempted to correlate heterozygosity at one or a few genetic loci with fitness-related quantitative traits. The results have been equivocal at best. Furthermore, data on fertility-related parameters and the extent of genetic polymorphism at a large number of loci in man are quite scanty. This report examines the association of four fertility-related parameters (number of pregnancies, number of livebirths, number of children surviving at least one year and number of children alive at the time of the survey) with heterozygosity at 17 polymorphic immunological and biochemical systems in the Aymara of Chile and Bolivia. Women 45 years of age and above, on whom complete fertility histories and phenotype data are available, were included in the study (n = 190). None of the fertility parameters seem to be correlated with heterozygosity, as measured by the proportion of polymorphic loci. For some individual loci, however, an association between heterozygous state and fertility parameters exists. Even in these cases, heterozygosity did not always confer higher fertility. To see whether these negative results are due to heterogeneity in the data, the total sample was divided according to altitude of residence and ethnicity. The conclusions remained the same, indicating that the lack of association of these fertility parameters with genetic polymorphism is not due to population heterogeneity alone. Reproductive fitness differentials, therefore, were not detectable in the Aymara by heterozygosity determined by the polymorphic genetic systems scored by serological and electrophoretic techniques.

Adolescent↗
PubMed1997

Genetic polymorphism of cytochrome P450 as a biomarker of susceptibility to environmental toxicity.

Cytochrome P450 (CYP) enzymes are responsible for the metabolism of numerous xenobiotics and endogenous compounds, including the metabolic activation of most environmental toxic chemicals and carcinogens. Both metabolic and genetic polymorphisms have been identified for human CYP enzymes. The association of CYP genetic polymorphism and human cancer risk, and susceptibility to environmental hazards, have received increasing attention. This article briefly reviews the approaches and methods currently used in CYP genetic polymorphism studies. In addition, the current status and perspectives of using CYP genetic polymorphism as a biomarker of individual susceptibility to cancer and environmental toxicity are discussed.

Biomarkers↗
PubMed1994

Analysis of cytochrome P450 2E1 genetic polymorphisms in relation to human lung cancer.

Human cancer risk assessment using molecular genetic techniques is a rapidly emerging field. Many studies suggest that both inherited and acquired genetic predispositions play an important role in carcinogenesis. Cytochrome P450 (CYP) 2E1 is involved in the metabolic activation of N-nitrosamines and other low molecular weight compounds. A recently described genetic polymorphism of CYP2E1 [DraI restriction fragment length polymorphism (RFLP)] has been associated with an increased risk of lung cancer in Japanese. We have assessed the allelic frequency of three RFLPs (PstI, RsaI, and DraI) in African-Americans (n = 109), Caucasian Americans (n = 153), and octogenarian Japanese (n = 42), and also in a United States case-control study of lung cancer (histologically confirmed lung cancer, n = 58; controls, n = 56; total, n = 114). The relationship of the CYP2E1 DraI polymorphism to other CYP2E1 polymorphisms (PstI and RsaI RFLP) was examined. The allelic frequency of the DraI C minor allele for all subjects was 0.09 in Caucasians, 0.09 in African-Americans, and 0.31 in Japanese. In the case-control study of lung cancer, no association of the CYP2E1 DraI genotype with lung cancer was found (odds ratio, 1.57; 95% confidence interval, 0.59-4.18). Comparison after discordant CYP2E1 genotypes suggests the presence of different haplotypes in Americans and Japanese. These results indicate that the CYP2E1 DraI RFLP is probably not a cancer risk factor in United States Caucasian or African-Americans, although statistical power is limited given the low frequency of the CYP2E1 DraI C minor alleles.

Aged↗
PubMed2001

Sample size considerations in genetic polymorphism studies.

OBJECTIVES: Molecular studies for genetic polymorphisms are being carried out for a number of different applications, such as genetic disorders in different populations, pharmacogenomics, genetic identification of ethnic groups for forensic and legal applications, genetic identification of breed/stock in animals and plants for commercial applications and conservation of germ plasm. In this paper, for a random sampling scheme, we address two questions: (A) What should be the minimum size of the sample so that, with a prespecified probability, all alleles at a given locus (or haplotypes at a given set of loci) are detected? (B) What should be the sample size so that the allele frequency distribution at a given locus (or haplotype frequency distribution at a given set of loci) is estimated reliably within permissible error limits? METHODS: We have used combinatorial probabilistic arguments and Monte Carlo simulations to answer these questions. RESULTS: We found that the minimum sample size required in case A depends mainly on the prespecified probability of detecting all alleles, while in case B, it varies greatly depending on the permissible error in estimation (which will vary with the application). We have obtained the minimum sample sizes for different degrees of polymorphism at a locus under high stringency, as well as a relaxed level of permissible error. We present a detailed sampling procedure for estimating allele frequencies at a given locus, which will be of use in practical applications. CONCLUSION: Since the sample size required for reliable estimation of allele frequency distribution increases with the number of alleles at the locus, there is a strong case for using biallelic markers (like single nucleotide polymorphisms) when the available sample size is about 800 or less.

Gene Frequency↗
PubMed2004

[Interluekin-1 beta genetic polymorphism influences the impact of cytochrome P 2C19 genotype on the cure rate of H. pylori eradication therapy].

Genetic polymorphism of interleukin(IL)-1 beta is associated with differences in gastric acid suppression in response to H. pylori infection. Thus, the polymorphism might affect H. pylori eradication therapy since antibiotics used in treatment regimens may be acid-sensitive. We examined the impact of IL-1 beta genetic polymorphism on the cure rate of triple therapy for H. pylori in relation to cytochrome P(CYP)2C19 genotype. In the normal acid-secretion IL-1 beta genotype group, the cure rate among CYP2C19 poor metabolizers was significantly higher than among those in the CYP2C19 extensive metabolizer groups. IL-1 beta genetic polymorphism, although not an independent factor in treatment outcome, influences the impact of the CYP2C19 genotype on the cure rate of H. pylori eradication therapy.

Amoxicillin↗
PubMed2003

Relationship between genetic polymorphism of cytochrome P450IIE1 and fatty liver.

AIM: To study the correlation between genetic polymorphism of cytochrome P450IIE1 (CYPIIE1) and fatty liver. METHODS: Peripheral blood mononuclear cells were collected in 56 patients with fatty liver, 26 patients without fatty liver and 20 normal controls. Then PCR-RFLP was used to analyze genetic polymorphism of CYPIIE1 in monocytes on the region of Pst I and Rsa I. RESULTS: The frequency of homozygotic C1 gene in patients with alcoholic fatty liver (28.6%), obese fatty liver (38.5%), or diabetic fatty liver (33.3%) was significantly lower than that of the corresponding patients without fatty liver (100%, 100% and 80% respectively), while the frequency of C2 genes, including C1/C2 and C2/C2, was significantly higher (71.4%/0%, 61.5%/0%, and 66.7%/20%) (P<0.01). The frequency distribution of the above genes of non-fatty liver patients (100%/0, 100%/0, and 80%/20%) was not significantly different from that of the normal controls (85%/15%) (P>0.05). CONCLUSION: The genetic polymorphism of CYPIIE1 on the position of Pst I and Rsa I is related to the susceptibility of fatty liver. Besides, C2 gene may play a key role in the pathogenesis of fatty liver.

Cytochrome P-450 CYP2E1↗
PubMed2005

Geographical distribution of genetic polymorphism of the pathogen Histoplasma capsulatum isolated from infected bats, captured in a central zone of Mexico.

Fourteen Histoplasma capsulatum isolates recovered from infected bats captured in Mexican caves and two human H. capsulatum reference strains were analyzed using random amplification of polymorphic DNA PCR-based and partial DNA sequences of four genes. Cluster analysis of random amplification of polymorphic DNA-patterns revealed differences for two H. capsulatum isolates of one migratory bat Tadarida brasiliensis. Three groups were identified by distance and maximum-parsimony analyses of arf, H-anti, ole, and tub1 H. capsulatum genes. Group I included most isolates from infected bats and one clinical strain from central Mexico; group II included the two isolates from T. brasiliensis; the human G-217B reference strain from USA formed an independent group III. Isolates from group II showed diversity in relation to groups I and III, suggesting a different H. capsulatum population.

Animals↗
PubMed2000

Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation.

Interleukin 6 (IL6) plays key roles in hematopoiesis, immune, and acute phase responses. Dysregulated IL6 expression is implicated in diseases such as atherosclerosis and arthritis. We have examined the functional effect of four polymorphisms in the IL6 promoter (-597G-->A, -572G-->C, -373A(n)T(n), -174G-->C) by identifying the naturally occurring haplotypes and comparing their effects on reporter gene expression. The results indicate different transcriptional regulation in the ECV304 cell line compared with the HeLa cell line, suggesting cell type-specific regulation of IL6 expression. The haplotypes showed functional differences in the ECV304 cell line; transcription was higher from the GG9/11G haplotype and lower from the AG8/12G allele. The differences suggest that more than one of the polymorphic sites is functional; the base differences at distinct polymorphic sites do not act independently of one another, and one polymorphism influences the functional effect of variation at other polymorphic sites. These results show that genetic polymorphisms in the promoter influence IL6 transcription not by a simple additive mechanism but rather through complex interactions determined by the haplotype.

Exons↗
PubMed2001

Genetic polymorphism in exon 4 of cytochrome P450 CYP2C9 may be associated with warfarin sensitivity in Chinese patients.

CYP2C9 polymorphisms reported in Caucasians (Arg144Cys in exon 3 and Ile359Leu in exon 7) are extremely uncommon in Chinese persons. The genotype of CYP2C9 in this population was characterized to investigate its relation with the interindividual variation in warfarin dosages. Eighty-nine Chinese patients receiving warfarin were recruited. Target sequences in CYP2C9 in exons 1, 4, and 5 were amplified by polymerase chain reaction, followed by direct sequencing. Polymorphisms at 4 positions were demonstrated in exon 4. Heterozygosities for 608TTG>GTG (Leu208Val), 561CAG>CCG (Gln192Pro), 537CAT>CCT (His184Pro), and 527ATT>CTT (Ile181Leu) existed at frequencies 0.75, 0.20, 0.10, and 0.09, respectively. Seventeen patients (frequency, 0.19) were homozygous for Val208. The common genotypic combinations at these loci are Ile181/His184/Gln192/Leu208Val (n = 50), Ile181/His184/Gln192/Val208 (n = 15), Ile181/His184/Gln192/Leu208 (n = 4), Ile181/His184/Gln192Pro/Leu208Val (n = 6), Ile181/His184Pro/Gln192Pro/Leu208Val (n = 4), and Ile181Leu/His184/Gln192Pro/ Leu208Val (n = 4). At codon 208, heterozygous Leu208Val and homozygous Val208 appeared to have a lower warfarin dose requirement than the homozygous Leu208. Patients who are heterozygous for Ile181Leu had a higher warfarin dose requirement than the homozygous Ile181. Amplified sequences in exons 1 and 5 did not exhibit polymorphism. In conclusion, Chinese patients showed genetic polymorphisms of CYP2C9 in exon 4 and at codon 208; most were heterozygous Leu208Val and homozygous Val208. Homozygous Leu208, a common allele in Caucasians, is uncommon in this cohort. The significance of these CYP2C9 polymorphic alleles remains to be determined.

Alleles↗
PubMed2003

Genetic polymorphism by RAPD-PCR and phenotypic characteristics of isolated thermotolerant Bacillus strains from hot spring sources.

The polymerase chain reaction (PCR) based random amplified polymorphic DNA (RAPD) assay, morphological, physiological, biochemical and antimicrobial susceptibility test methods have been evaluated for use in the taxonomy of isolated thermotolerant Bacillus from Jordanian hot springs, with specific reference to strains Geobacillus stearothermophilus (ATCC 12980), Bacillus circulans (ATCC 4513) and Bacillus sphaericus (ATCC 14577). A RAPD assay has been optimized and is able to discriminate between numerous thermotolerant Bacillus strains. RAPD-PCR was found to give reproducible thermotolerant Bacillus strains classification of DNA fingerprints for 14 strains including 3 reference strains. A study of 14 isolates and 3 reference strains, analyzing 53 phenotypic characters, resulted in their allocation to five major clusters at 60% similarity. Whereas at 80% similarity, twelve taxonomically distinct groups were evident.

Bacillus↗
PubMed2005

CYP2C9, CYP2C19, ABCB1 (MDR1) genetic polymorphisms and phenytoin metabolism in a Black Beninese population.

The genetically polymorphic cytochrome P450 2C9 (CYP2C9) metabolizes many important drugs. Among them, phenytoin has been used as a probe to determine CYP2C9 phenotype by measuring the urinary excretion of its major metabolite, S-enantiomer of 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH). Phenytoin pharmacokinetic is also dependent on the activity of CYP2C19 and p-glycoprotein (ABCB1). To determine the influence of CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms on phenytoin metabolism in a Black population, 109 healthy Beninese subjects received a single 300 mg oral dose of phenytoin. Blood was drawn 4 h after drug intake and urine was collected during the first 8 h. Plasma phenytoin and urine S- and R-enantiomers of p-HPPH were determined by high-performance liquid chromatography. Urinary excretion of (S)-p-HPPH [defined as urinary volumex(S)-p-HPPH urinary concentration] and PMR (defined as the ratio of p-HPPH in urine to 4 h phenytoin plasma concentration), both markers of CYP2C9 activity, were used to determine the functional relevance of new variants of CYP2C9 (*5, *6, *8, *9 and *11) in this population. Plasma phenytoin concentration was significantly associated with ABCB1 haplotype/genotype (P=0.05, Kruskal-Wallis test) and levels increased significantly in the genotype order: wild-type, T3421A and Block-2 genotypes (P=0.015, Jonckheere-Terpstra test). Urinary excretion of (S)-p-HPPH and PMR were significantly associated with the CYP2C9 genotype (P=0.001, analysis of variance (ANOVA) and P<0.0001, Kruskal-Wallis test, respectively) and decreased in the order: CYP2C9*1/*1, CYP2C9*1/*9, CYP2C9*9/*9, CYP2C9*1/*8, CYP2C9*8/*9, CYP2C9*9/*11, CYP2C9*1/*5, CYP2C9*6/*9, CYP2C9*1/*6, CYP2C9*8/*11, CYP2C9*5/*8 and CYP2C9*5/*6 (P<0.001, Jonckheere-Terpstra test). A combined analysis of CYP2C9, 2C19 and ABCB1 revealed that only ABCB1 predicted phenytoin concentration at 4 h and explained 8% of the variability (r=0.08, P=0.04). On the other hand, only CYP2C9 was predictive for the urinary excretion of (S)-p-HPPH and PMR (r=0.21, P=0.001 and r=0.25, P<0.001, respectively). Furthermore, significant relation was found between urinary excretion of (R)-p-HPPH and CYP2C9 genotype (P=0.035) and levels significantly increased in the genotype order: CYP2C9*1/*9, CYP2C9*1/*1, CYP2C9*9/*11, CYP2C9*1/*8 and CYP2C9*1/*5 (P<0.001, Jonckheere-Terpstra test). In summary, the present study demonstrates that, in a Black population, CYP2C9*5, *6, *8 and *11 variants, but not CYP2C9*9, are associated with a decreased phenytoin metabolism. The data also confirm the limited contribution of MDR1 gene to inter-individual phenytoin pharmacokinetic variation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Genetic polymorphisms in the tumour necrosis factor locus in childhood acute lymphoblastic leukaemia.

Genetic polymorphisms in the tumour necrosis factor (TNF) locus influence the outcome of non-Hodgkin's lymphoma (NHL). We investigated whether these polymorphisms might contribute to the clinical course of childhood acute lymphoblastic leukaemia (ALL). Genomic DNA from 214 childhood ALL patients was analysed. Patients with a high-risk haplotype were older than patients with low-risk haplotype (P = 0.024). No statistically significant associations were found between TNF haplotype and sex, WBC counts, central nervous system involvement, immunophenotype, response to chemotherapy, and event-free survival. These data suggest that genetic polymorphisms in the TNF locus have a limited effect on the outcome of childhood ALL.

Age Factors↗