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Genotype Frequencies (genotype + frequency)
Selected AbstractsPower of Genetic Association Studies with Fixed and Random Genotype FrequenciesANNALS OF HUMAN GENETICS, Issue 5 2010Julia Kozlitina Summary When estimating the power of genetic association studies, the allele and genotype frequencies are often assumed to be known, and the numbers of individuals with each genotype are set equal to their expectations under Hardy-Weinberg equilibrium. In fact, both allele and genotype frequencies are unknown and thus random. It has previously been suggested that ignoring uncertainty in these parameters could lead to inflated power expectations. To overcome the problem, one can average power estimates over the distributions of unknown frequencies. We investigate the power-averaging method and find that, despite the intuitive appeal, it may not improve accuracy in practice, while significantly increasing computational time. For a fixed allele frequency, we show that the amount of overestimation diminishes rapidly with sample size and is completely negligible for N > 200. For an unknown frequency, the result of averaging depends on the genetic model, and may not always provide a more conservative estimate of power. We explore the effect of uncertainty in the factors that determine statistical power of association studies and propose a more economical approach to the power analysis. [source] Genotype Frequencies of Selected Drug Metabolizing Enzymes and ABC Drug Transporters among Breast Cancer Patients on FAC ChemotherapyBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 1 2010Nasir Ali Afsar With some exemptions, single nucleotide polymorphisms in such genes, however, are not known to be susceptibility factors for breast cancer. This study explored genotype profiles for the breast cancer patients on fluorouracil, doxorubicin and cyclophosphamide (FAC) in a Pakistani set of population and their comparison with HapMap data. Sixty-eight female breast cancer patients were included. All received FAC chemotherapy. Relevant genotyping was done either through restriction fragment length polymorphism or pyrosequencing. The variant allele frequencies were: 5.1% for CYP2C9*2 (430C>T), 15.4% for CYP2C9*3 (1075A>C), 27.2% for CYP2C19*2 (681G>A), 33.1% for GSTA1*B (-69C>T, -52G>A), 62.5% for ALDH3A1*2 (985C>G), 58.8% and 4.4% for ABCB1 (2677 G>T/A), 64.7% for ABCB1 3435 C>T, and 15.4%, 33.1% and 39.7% for ABCC2 (,24 C>T, 1249 G>A and 3972 C>T). In comparison with HapMap, this first exploration in Pakistani samples shows higher frequency of (i) CYP2C9*3 carriers (p < 0.05) than in Hispanic, Chinese, Japanese and African samples, (ii) ALDH3A1*2 carriers (p < 0.01) than Caucasian, Hispanic, Chinese, Japanese and African samples. For ABC transporters, a higher frequency of variant allele was observed in (iii) ABCB1 2677 G>T/A (p < 0.01) than Caucasian, Hispanic and African, (iv) ABCB1 3435 C>T (p < 0.05) than Chinese, Japanese and African, (v) ABCC2 1249 G>A (p < 0.01) than Hispanic, Chinese and Japanese samples. In conclusion, cyclophosphamide activation and detoxification of reactive intermediates may be altered in the Pakistani. Though carriers of CYP2C19*2 were higher than in Caucasian and Hispanics, they did not reach statistical significance (p = 0.05). [source] Evaluating bias due to population stratification in case-control association studies of admixed populations,GENETIC EPIDEMIOLOGY, Issue 1 2004Yiting Wang Abstract The potential for bias from population stratification (PS) has raised concerns about case-control studies involving admixed ethnicities. We evaluated the potential bias due to PS in relating a binary outcome with a candidate gene under simulated settings where study populations consist of multiple ethnicities. Disease risks were assigned within the range of prostate cancer rates of African Americans reported in SEER registries assuming k=2, 5, or 10 admixed ethnicities. Genotype frequencies were considered in the range of 5,95%. Under a model assuming no genotype effect on disease (odds ratio (OR)=1), the range of observed OR estimates ignoring ethnicity was 0.64,1.55 for k=2, 0.72,1.33 for k=5, and 0.81,1.22 for k=10. When genotype effect on disease was modeled to be OR=2, the ranges of observed OR estimates were 1.28,3.09, 1.43,2.65, and 1.62,2.42 for k=2, 5, and 10 ethnicities, respectively. Our results indicate that the magnitude of bias is small unless extreme differences exist in genotype frequency. Bias due to PS decreases as the number of admixed ethnicities increases. The biases are bounded by the minimum and maximum of all pairwise baseline disease odds ratios across ethnicities. Therefore, bias due to PS alone may be small when baseline risk differences are small within major categories of admixed ethnicity, such as African Americans. © 2004 Wiley-Liss, Inc. [source] Multidrug resistance 1 gene polymorphism and susceptibility to inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 5 2007S. Ardizzone MD Abstract Background: Several studies have evaluated the role of the multidrug resistance 1 gene (MDR1) polymorphism, which encodes the membrane-bound efflux transporter P-glycoprotein 170, in determining susceptibility to and disease behavior in inflammatory bowel disease (IBD), but with conflicting results. Methods: A total of 211 patients with Crohn's disease (CD), 97 patients with ulcerative colitis (UC), and 212 control subjects were investigated for the presence of MDR1 G2677T/A and C3435T polymorphisms. Genotype frequencies of CD and UC patients were compared to those observed in a control population. Genotype,phenotype correlations with major clinical features were also established and estimated risks (odds ratio [OR] with 95% confidence interval [CI]) for the mutations were calculated by a logistic regression analysis and multiple correspondent analysis. Results: No significant difference was observed for genotype frequencies for both MDR1 G2677T/A and C3435T polymorphisms on overall disease susceptibility for either CD or UC patients compared with control subjects. A significant association was found between the MDR1 C3435T polymorphism and patients with ileo-colonic CD (OR = 3.34; 95% CI: 1.34,8.27). Interestingly, a negative association was found between MDR1 C3435T polymorphism in patients with a positive family history for IBD (OR = 0.44; 95% CI: 0.20,0.95) and articular manifestations (OR = 0.29; 95% CI: 0.13,0.68). Both susceptible and protective effects were identified. No significant association between G2677T/A polymorphism and any specific subphenotypes was found, nor was there any association with subphenotypic categories of UC and both single nucleotide polymorphisms. Conclusions: The results of our study suggest that MDR1 gene polymorphism could have a role in determining susceptibility to IBD. The variability of this possible effect in the several studies reported so far may be the indirect expression of the complex role played by the MDR1 gene and its product, P-glycoprotein 170, in the regulation of host,bacteria interactions and in the pathogenesis of IBD. (Inflamm Bowel Dis 2007) [source] A search for cyclophilin-A gene (PPIA) variation and its contribution to the risk of atherosclerosis and myocardial infarctionINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 2 2008M. Palacín Summary Cyclophilin A is secreted by vascular smooth muscle cells in response to inflammatory stimuli, and could thus contribute to atherosclerosis. We hypothesized that the genetic variation at the cyclophilin A gene (PPIA) could affect the risk for developing atherosclerosis and myocardial infarction. This study included 250 myocardial infarction patients (all male and < 60 years; 95% are smokers). All these cases had at least one atherosclerotic diseased coronary vessel. DNA was obtained from patients and from 250 healthy controls. The variation at the PPIA gene was determined in the patients through single-strand conformation analysis and direct sequencing of seven polymerase chain reaction fragments. Allele and genotype frequencies were compared between patients and controls. The effect of a promoter polymorphism (,11 G/C) on gene expression was in vitro analysed with luciferase-reporter assays. We found two common polymorphisms in the PPIA promoter (,11 G/C) and the 5, non-translated (+36 G/A) regions. Cells transfected with luciferase-plasmids containing the ,11 G had significantly higher luciferase activity. Genotype frequencies for these polymorphisms did not differ between patients and controls. In conclusion, we reported a functional variant in the PPIA promoter. However, the PPIA variation did not significantly contribute to the risk of suffering from myocardial infarction among patients with atherosclerotic diseased vessels. [source] Mimicry and the evolution of premating isolation in Heliconius melpomene LinnaeusJOURNAL OF EVOLUTIONARY BIOLOGY, Issue 3 2004C. D. Jiggins Abstract Ecological divergence can cause speciation if adaptive traits have pleiotropic effects on mate choice. In Heliconius butterflies, mimetic patterns play a role in mate detection between sister species, as well as signalling to predators. Here we show that male butterflies from four recently diverged parapatric populations of Heliconius melpomene are more likely to approach and court their own colour patterns as compared with those of other races. A few exceptions, where males were more attracted to patterns other than their own, suggest that some mimetic patterns are sub-optimal in mate choice. Genotype frequencies in hybrid zones between races of H. melpomene suggest that mating is random, so reinforcement is unlikely to have played a role in intra-specific divergence. In summary, co-evolved divergence of colour pattern and mate preference occurs rapidly and is likely the first step in Heliconius speciation. [source] Genetic profiling of the Azores Islands (Portugal): Data from 10 X-chromosome STRsAMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 2 2010Francisca Silva The populations from the Azores islands have been the target of several genetic studies, using data derived from monoparental and recombining genetic systems. These studies have provided a complex picture of the genetic landscape of the three groups of Azorean islands, and further data are required to assess its genetic profile. We present a study of the polymorphism in 10 X-chromosome STR loci (DSXS8378, DXS9898, DXS7133, GATA31E08, GATA172D05, DXS7423, DXS6809, DXS7132, DXS9902, DXS6789) conducted on a total of 304 chromosomes (97 females and 110 males) of unrelated individuals with Azorean ancestry. Average gene diversity was 74.47%, ranging from 66.21% (DXS7133) to 81.19% (GATA172D05). No shared haplotypes were found. Genotype frequencies among females displayed conformity with Hardy-Weinberg expectations for all loci. Pairwise linkage disequilibrium tests did not reveal evidences of association between the studied markers. Significant differences in allelic frequencies between the Western and the Eastern group of islands are in agreement with previous results from mitochondrial DNA and Y chromosome studies, providing further evidence that the Azores cannot be considered an homogeneous population. Moreover, differences between the Western group and the North of Portugal are also reported, supporting the pertinence of a specific database for the Azores populations, on what concerns the genetic markers analyzed. Am. J. Hum. Biol., 2010. © 2009 Wiley-Liss, Inc. [source] Genetic analysis of CC16, OGG1 and GCLC polymorphisms and susceptibility to COPDRESPIROLOGY, Issue 1 2007Shengming LIU Background and objectives: The importance of genetic susceptibility in COPD has not been determined. The aim of this study was to investigate the association between susceptibility to COPD and polymorphisms in the Clara cell 16 kDa secretory protein (CC16), 8-hydroxy-guanine glycosylase (OGG1) and glutamatecysteine ligase catalytic subunit (GCLC) genes in a southern Chinese population of Han nationality. Methods: A case-control study was performed on 166 paired subjects with or without COPD, who were randomly selected from a pool of 310 paired subjects. These subjects were selected from epidemiological survey participants, with matched-pairs being strictly localized in the Guangzhou urban and Shaoguan rural areas. The following polymorphisms were genotyped by PCR-single strand conformation polymorphism analysis: 38 A/G in exon 1 of the CC16 gene, 1245C/G in exon 7 of the OGG1 gene and ,129C/T in the GCLC gene. Genotype frequencies and allelic frequencies were analysed. Results: There were no significant differences in the distribution of genotype frequencies for CC16 38 A/G, OGG1 1245C/G or GCLC ,129C/T between the COPD and non-COPD subjects. The distribution of the allelic frequencies of these three genes also showed no significant difference between the two groups. Conclusions: The genetic polymorphisms in CC16 38 A/G, OGG1 1245C/G and GCLC ,129C/T are not associated with susceptibility to COPD in a southern Chinese population of Han nationality. [source] Genotype frequencies and linkage disequilibrium in the CEPH human diversity panel for variants in folate pathway genes MTHFR, MTHFD, MTRR, RFC1, and GCP2BIRTH DEFECTS RESEARCH, Issue 8 2003Min Shi BACKGROUND Genetic variation in enzymes involved in vitamin metabolism is a candidate for analysis in studies of how nutritional covariates may impact a disease state. The role of folate pathway genes in birth defects and cardiovascular disease in humans has been widely studied. Since incidence rates for these disorders vary by geographic origins, it is useful to know which variants are the best candidates for studies based on genotype and allele frequency, as well as linkage disequilibrium (LD) in founder populations. METHODS Six polymorphisms in five folate metabolism-related genes (MTHFR, MTHFD, MTRR, GCP2, and RFC1) were genotyped on a collection of 1064 DNA samples from populations around the world, which were made available by the Centre d'Étude du Polymorphisme Humain (CEPH) consortium for analysis. RESULTS In this study we report the genotype frequencies for variants in the MTHFR, MTHFD, MTRR, GCP2, and RFC1 genes, and the LD for two variants (C677T and A1298C) in MTHFR. CONCLUSIONS The rare allele frequency for each of the five genes studied varied widely. LD is strongest in Pakistani and Brazilian populations (D, = 1.0) and weakest in Mexican populations (D, = 0.45). These findings will allow the selection of variants that will provide the most power in studies of folate pathway genes involving different ancestral populations, and contribute to our knowledge of the population distribution of selected nutritional gene variants. Birth Defects Research (Part A), 2003. © 2003 Wiley-Liss, Inc. [source] Apolipoprotein E and apolipoprotein B genotypes and risk for spina bifidaBIRTH DEFECTS RESEARCH, Issue 5 2002Kelly A. Volcik Background Altered cholesterol metabolism and defects in cholesterol biosynthesis may influence abnormal central nervous system (CNS) development. During early stages of embryonic development, high levels of cholesterol are needed by rapidly proliferating cells that utilize cholesterol as a key cell membrane component. Alterations in cholesterol levels are influenced by variations in the apolipoprotein E (apoE) and apolipoprotein B (apoB) genes. The purpose of our study was to explore the possible association between infant genetic variations in the apoE and apoB genes and spina bifida (SB) risk. Methods Genomic DNA was extracted from newborn screening blood spots obtained from 26 infants with SB and 73 non-malformed control infants. ApoE and apoB genotypes were determined by restriction enzyme digestion of PCR amplification products. Results Genotype frequencies for the apoE and apoB polymorphisms were not statistically different between case and control infants. For each apoB polymorphism, however, the frequency of the wild-type allele was higher in SB infants as compared to controls. Additionally, the apoE genotype E2/E3 was observed more frequently in the controls than in SB infants [15% in controls compared to 4% in cases; OR = 0.2 (0,1.6)]. Conclusions Results from this study suggest that genetic variations in the apoE and apoB genes, known to regulate cholesterol metabolism, do not substantially contribute to the risk of SB in infants. Teratology 66:257,259, 2002. © 2002 Wiley-Liss, Inc. [source] Caucasian patients with type 2 diabetes mellitus have elevated levels of monocyte chemoattractant protein-1 that are not influenced by the ,2518 A,G promoter polymorphismDIABETES OBESITY & METABOLISM, Issue 5 2005B. Zietz Aim:, To investigate the association of serum levels and the ,2518 A,G promoter polymorphism of the gene for chemokine monocyte chemoattractant protein-1 (MCP-1), a major chemoattractant of monocytes and activated lymphocytes, with metabolic parameters as well as insulin, leptin and the cytokines tumour necrosis factor-, (TNF-,) and interleukin-6 (IL-6) in 534 Caucasian patients with type 2 diabetes mellitus. Methods:, MCP-1 concentrations were measured by enzyme-linked immunosorbent assay. MCP-1 genotyping was performed by RFLP analysis in a subset of 426 patients. Results:, Two hundred and thirty-one (54.2%) patients were homozygous for the wildtype allele (AA), 156 (36.6%) were heterozygous (AG) and 39 (9.2%) were homozygous for the mutated allele (GG). Allelic frequency was similar to non-diabetic populations (wildtype allele A: 0.73; mutated allele G: 0.27). MCP-1 mean concentrations and percentiles were substantially higher in non-diabetic populations but were not influenced by the genotype (AA: 662.0 ± 323.0 pg/ml; AG: 730.6 ± 491.4 pg/ml; GG: 641.2 ± 323.8 pg/ml). MCP-1 serum levels and genotypes were only marginally related to hormones (insulin and leptin) and cytokines (TNF-, and IL-6). Conclusions:, This is the first study providing MCP-1 levels, percentiles and genotype frequency in a large and representative cohort of patients with type 2 diabetes mellitus. Compared to the literature, MCP-1 levels were found to be substantially higher in patients with type 2 diabetes mellitus. In contrast, genotype frequencies were similar compared to those in non-diabetic patients and were not related to MCP-1 levels. The mechanisms behind these elevated MCP-1 serum levels in type 2 diabetes are not to be explained by simple associations with hormones, cytokines or genotypes. [source] Genetic indicators of herbicide stress in the pacific oyster Crassostrea gigas under experimental conditionsENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2000Dario Moraga Abstract This study examined use of the oyster Crassostrea gigas as a bioindicator of experimental pollution caused by two concentrations of five pesticides (atrazine, isoproturon, alachlore, metolachlore, and diuron) used in agricultural and urban activities. The effect of these pesticides on the genetic structure of the marine bivalve was studied as part of an environmental biomonitoring project. This research was performed on two natural estuarine populations sampled along the French Atlantic coast as part of an ongoing monitoring program to survey the ecosystem of Brittany using two approaches: identifying the genetic markers based on the alleles and genotypes associated with pollution effects, and searching for a correlation between these markers and the sensitivity or tolerance of individuals under stress conditions. Results indicate a differential survival of individuals subjected to the various pollutants examined. The sensitivity of alleles and genotypes to environmental stress can be assessed based on the significant differences in allele and genotype frequencies observed between resistant and sensitive individuals when subjected to the pesticides. This genetic study included examination of five enzyme systems (Ak, Pgi, Cap, Pgm, and Mdh) involved in physiologic processes. A total of six alleles and five genotypes at three loci (Ak, Pgi, and Pgm) were identified as being markers of resistance or sensitivity. It is hypothesized that these markers could be used as potential genetic markers in estuarine ecosystem monitoring. [source] DRD3 Ser9Gly variant is not associated with essential tremor in a series of Italian patientsEUROPEAN JOURNAL OF NEUROLOGY, Issue 9 2008C. Vitale Background: Essential tremor (ET) is the most common movement disorder worldwide. Three susceptibility loci on chromosomes 3q13, 2p24.1, and 6p23 have been reported, but no causative genes were found. The Ser9Gly variant of dopamine D3 receptor (DRD3) receptor was found associated to ET in a French and US population. Methods: A case,control study to evaluate the association between the Ser9Gly variant and ET was performed in a cohort of 116 Italian patients with familial ET and in 158 normal controls. Results: No significant difference in allele and genotype frequencies was found between the two groups. Conclusions: These results do not support an association between DRD3 Ser9Gly and susceptibility to ET in Italian patients. [source] PAX9 polymorphisms and susceptibility to sporadic tooth agenesis: a case,control study in southeast ChinaEUROPEAN JOURNAL OF ORAL SCIENCES, Issue 2 2008Yongchu Pan Tooth agenesis is one of the most common developmental disorders in humans. The PAX9 gene, which plays an important role in odontogenesis, is associated with familial and sporadic tooth agenesis. A case,control study was performed in 102 subjects with tooth agenesis (cases) and 116 healthy controls. We genotyped four PAX9 gene polymorphisms using a polymerase chain reaction,restriction fragment length polymorphism (PCR-RFLP) assay. The allele and genotype frequencies of the four polymorphisms were not significantly different between the controls and the subjects with tooth agenesis. Similar results were observed in a subgroup analysis of test subjects only with mandibular incisor agenesis. Further analysis showed no significant difference in the haplotype distribution between the controls and the subjects with tooth agenesis or mandibular incisor agenesis. However, we found that the AGGC haplotype was associated with a decreased risk of tooth agenesis, compared with the most common haplotype, AGCC (odds ratio, 0.14; 95% confidence interval: 0.00,0.95). These results suggest that the four PAX9 polymorphisms alone have a non-significant main effect on the risk of tooth agenesis but that the AGGC haplotype may have a protective effect associated with a decreased risk of tooth agenesis. [source] A FORMAL ASSESSMENT OF GENE FLOW AND SELECTION IN THE FIRE ANT SOLENOPSIS INVICTAEVOLUTION, Issue 2 2000Michael A. D. Goodisman Abstract., Recent studies of the introduced fire ant Solenopsis invicta suggest that introduced polygyne (with multiple queens per nest) populations are strongly influenced by male-mediated gene flow from neighboring monogyne (single queen per nest) populations and selection acting on a single locus, general protein-9 (Gp-9). This investigation formally tests this hypothesis and determines if these processes can account for the genotypic structure of polygyne S. invicta. To increase the statistical power of this test, we considered the genotypes of polygyne queens and workers at both Gp-9 and the closely linked, selectively neutral locus Pgm-3. We then constructed and analyzed a novel mathematical model to delimit the effects of monogyne male gene flow and selection on the joint genotypes at the Pgm-3/Gp-9 superlocus. Using this framework, a hierarchical maximum-likelihood method was developed to estimate the best-fitting gene flow and selection parameters based on the fit of our model to data from both the current study and an earlier one of the same population. In each case, selection on polygyne queens and workers alone, with no monogyne male gene flow, provides the most parsimonious explanation for the observed genotype frequencies. The apparent discrepancy between this result and the empirical evidence for monogyne male gene flow indicates that undocumented factors, such as other forms of selection in polygyne males or workers, are operating in introduced polygyne S. invicta. [source] The guanine nucleotide binding protein , polypeptide 3 gene C825T polymorphism is associated with elite endurance athletesEXPERIMENTAL PHYSIOLOGY, Issue 3 2009Nir Eynon A functional C825T polymorphism in the human guanine nucleotide binding protein , polypeptide 3 (GNB3) gene has been associated with enhanced G protein activation. Since reports regarding the interaction between physical activity and the GNB3 C825T polymorphism are limited and inconsistent, the aim of this study was to determine the frequency of C825T alleles among 155 elite Israeli athletes (endurance athletes and sprinters) and 234 healthy control subjects. Genotyping for GNB3 C825T was performed using polymerase chain reaction on DNA from leucocytes. Results showed that there was a significant difference in GNB3 C825T polymorphism genotype frequencies between endurance athletes and sprinters (P= 0.045) as well as between endurance athletes and control subjects (P= 0.046). We also observed a significantly higher proportion of the GNB3 TT genotype in the group of endurance athletes (19%) compared with the sprinters (5%, P= 0.014) and the control subjects (8.5%, P= 0.026). In the group of athletes, the odds ratio of GNB3 TT genotype being an endurance athlete was 4.49 (95% confidence interval 1.4,14.3) and of GNB3 CC genotype was 0.91 (95% confidence interval 0.47,1.77). These results were even more pronounced when we compared between the subgroups of 20 top-level endurance athletes and 24 top-level sprinters. We conclude that in Israeli athletes the GNB3 TT genotype is higher in elite endurance athletes than it is in sprinters, and within the endurance group it is higher in top-level athletes, suggesting a positive association between the TT genotype and the likelihood of being an elite endurance athlete. [source] Population genetic structure of three freshwater mussel (Unionidae) species within a small stream system: significant variation at local spatial scalesFRESHWATER BIOLOGY, Issue 8 2007DAVID J. BERG Summary 1. Unionid mussels are highly threatened, but little is known about genetic structure in populations of these organisms. We used allozyme electrophoresis to examine partitioning of genetic variation in three locally abundant and widely distributed species of mussels from a catchment in Ohio. 2. Within-population variation was similar to that previously reported for freshwater mussels, but genotype frequencies exhibited heterozygote deficiencies in many instances. All three species exhibited significant among-population variation. Evidence of isolation-by-distance was found in Elliptio dilatata and Ptychobranchus fasciolaris, while Lampsilis siliquoidea showed no geographical pattern of among-population variation. 3. Our results suggest that the isolating effects of genetic drift were greater in L. siliquoidea than in the other species. Differentiation of populations occurred at a much smaller spatial scale than has previously been found in freshwater mussels. Differences among species may reflect differences in the dispersal abilities of fishes that serve as hosts for the glochidia larvae of mussels. 4. Based on our results, we hypothesise that species of mussels that are common to large rivers exhibit relatively large amounts of within-population genetic variation and little differentiation over large geographical distances. Conversely, species typical of small streams show lower within-population genetic variation and populations will be more isolated. If this hypothesis can be supported, it may prove useful in the design of conservation strategies that maintain the genetic structure of target species. [source] CYP2C9 and CYP2C19 genetic polymorphisms: frequencies in the south Indian populationFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2005Rosemary Jose Abstract The aim of the study was to establish the frequencies of CYP2C9*1, *2, *3 and CYP2C19*1, *2 and *3 in the south Indian population and to compare them with the inter-racial distribution of the CYP2C9 and CYP2C19 genetic polymorphisms. Genotyping analyses of CYP2C9 and CYP2C19 were conducted in unrelated, healthy volunteers from the three south Indian states of Andhra Pradesh, Karnataka and Kerala, by the polymerase chain reaction,restriction fragment-length polymorphism (PCR,RFLP). The allele frequencies of the populations of these three states were then pooled with our previous genotyping data of Tamilians (also in south India), to arrive at the distribution of CYP2C9 and CYP2C19 alleles in the south Indian population. Frequencies of CYP2C9 and CYP2C19 alleles and genotypes among various populations were compared using the two-tailed Fisher's exact test. The frequencies of CYP2C9*1, *2 and *3 in the south Indian population were 0.88 (95% CI 0.85,0.91), 0.04 (95% CI 0.02,0.06) and 0.08 (95% CI 0.06,0.11), respectively. The frequencies of CYP2C9 genotypes *1/*1, *1/*2, *1/*3, *2/*2, *2/*3 and *3/*3 were 0.78 (95% CI 0.74,0.82), 0.05 (95% CI 0.03,0.07), 0.15 (95% CI 0.12,0.18), 0.01 (95% CI 0.0,0.02), 0.01 (95% CI 0.0,0.02) and 0.0, respectively. CYP2C19*1, *2 and *3 frequencies were 0.64 (95% CI 0.60,0.68), 0.35 (95% CI 0.31,0.39) and 0.01 (95% CI 0.0,0.03), respectively. As a result of a significant heterogeneity, the data on CYP2C19 genotype frequencies were not pooled. The frequency of CYP2C9*2 mutant alleles in south Indians was higher than in Chinese and Caucasians, while CYP2C9*3 was similar to Caucasians. CYP2C19*2 was higher than in other major populations reported so far. The relatively high CYP2C19 poor-metabolizer genotype frequency of 12.6% indicates that over 28 million south Indians are poor metabolizers of CYP2C19 substrates. [source] A prevalence-based association test for case-control studiesGENETIC EPIDEMIOLOGY, Issue 7 2008Kelli K. Ryckman Abstract Genetic association is often determined in case-control studies by the differential distribution of alleles or genotypes. Recent work has demonstrated that association can also be assessed by deviations from the expected distributions of alleles or genotypes. Specifically, multiple methods motivated by the principles of Hardy-Weinberg equilibrium (HWE) have been developed. However, these methods do not take into account many of the assumptions of HWE. Therefore, we have developed a prevalence-based association test (PRAT) as an alternative method for detecting association in case-control studies. This method, also motivated by the principles of HWE, uses an estimated population allele frequency to generate expected genotype frequencies instead of using the case and control frequencies separately. Our method often has greater power, under a wide variety of genetic models, to detect association than genotypic, allelic or Cochran-Armitage trend association tests. Therefore, we propose PRAT as a powerful alternative method of testing for association. Genet. Epidemiol. 2008. © 2008 Wiley-Liss, Inc. [source] Interleukin-6 (G-174C) and tumour necrosis factor-alpha (G-308A) gene polymorphisms in geriatric patients with chronic periodontitisGERODONTOLOGY, Issue 1 2010A. M. Costa doi:10.1111/j.1741-2358.2009.00291.x Interleukin-6 (G-174C) and tumour necrosis factor-alpha (G-308A) gene polymorphisms in geriatric patients with chronic periodontitis Background and objective:, Periodontitis is a chronic inflammatory disease, and genetic factors may have an important role in its severity. Polymorphisms in the promoter regions of the interleukin-6 (IL-6) and tumour necrosis factor-, (TNF-,) genes have been reported to cause changes in the production of these cytokines. The aim of this study was to evaluate the possible role of IL-6 (G,174C) and tumour necrosis factor (G,308A) polymorphisms, in the severity of chronic periodontitis in an elderly population. Materials and methods:, In this study, a group of 65 elderly women, comprising 17 patients with moderate chronic periodontitis, 21 with severe chronic periodontitis and 27 healthy patients were selected. DNA was isolated from all subjects, and polymerase chain reaction was used to study the IL-6 and TNF-, gene polymorphisms. Results:, The results of this study showed a significant difference in the allele and genotype frequencies of IL-6 gene polymorphism between patients with periodontal disease and controls. Subjects carrying the G/G genotype of IL-6 were most severely affected by periodontitis. The TNF-, gene polymorphism showed no association with chronic periodontitis between patients and controls. Conclusion:, The results suggest that the IL-6 gene polymorphism may be associated with chronic periodontitis, and that TNF-, gene polymorphism may not be involved in the progression of chronic periodontitis in the population of elderly Brazilian women. [source] The extensive polymorphism of KIR genesIMMUNOLOGY, Issue 1 2010Derek Middleton Summary The functions of human natural killer (NK) cells are controlled by diverse families of antigen receptors. Prominent among these are the killer cell immunoglobulin-like receptors (KIR), a family of genes clustered in one of the most variable regions of the human genome. Within this review we discuss the vast polymorphism of the KIR gene complex which rivals that of the human leucocyte antigen (HLA) complex. There are several aspects to this polymorphism. Initially there is presence/absence of individual KIR genes, with four of these genes, termed framework genes, being present in all individuals tested to date, except on those very occasional instances when the gene has been deleted. Within each gene, alleles are present at different frequencies. We provide details of a new website that enables convenient searching for data on KIR gene, allele and genotype frequencies in different populations and show how these frequencies vary in different worldwide populations and the high probability of individuals differing in their KIR repertoire when both gene and allele polymorphism is considered. The KIR genes present in an individual may be classified into A and/or B haplotypes, which respectively have a more inhibitory role or a more activating role on the function of the NK cell. Family studies have been used to ascertain the make-up of these haplotypes, inclusion of allele typing enabling determination of whether one or two copies of a particular gene is present. In addition to genetic diversification the KIR gene complex shows differences at the functional level with different alleles having different protein expression levels and different avidity with their HLA ligand. [source] Multidrug resistance 1 gene polymorphism and susceptibility to inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 5 2007S. Ardizzone MD Abstract Background: Several studies have evaluated the role of the multidrug resistance 1 gene (MDR1) polymorphism, which encodes the membrane-bound efflux transporter P-glycoprotein 170, in determining susceptibility to and disease behavior in inflammatory bowel disease (IBD), but with conflicting results. Methods: A total of 211 patients with Crohn's disease (CD), 97 patients with ulcerative colitis (UC), and 212 control subjects were investigated for the presence of MDR1 G2677T/A and C3435T polymorphisms. Genotype frequencies of CD and UC patients were compared to those observed in a control population. Genotype,phenotype correlations with major clinical features were also established and estimated risks (odds ratio [OR] with 95% confidence interval [CI]) for the mutations were calculated by a logistic regression analysis and multiple correspondent analysis. Results: No significant difference was observed for genotype frequencies for both MDR1 G2677T/A and C3435T polymorphisms on overall disease susceptibility for either CD or UC patients compared with control subjects. A significant association was found between the MDR1 C3435T polymorphism and patients with ileo-colonic CD (OR = 3.34; 95% CI: 1.34,8.27). Interestingly, a negative association was found between MDR1 C3435T polymorphism in patients with a positive family history for IBD (OR = 0.44; 95% CI: 0.20,0.95) and articular manifestations (OR = 0.29; 95% CI: 0.13,0.68). Both susceptible and protective effects were identified. No significant association between G2677T/A polymorphism and any specific subphenotypes was found, nor was there any association with subphenotypic categories of UC and both single nucleotide polymorphisms. Conclusions: The results of our study suggest that MDR1 gene polymorphism could have a role in determining susceptibility to IBD. The variability of this possible effect in the several studies reported so far may be the indirect expression of the complex role played by the MDR1 gene and its product, P-glycoprotein 170, in the regulation of host,bacteria interactions and in the pathogenesis of IBD. (Inflamm Bowel Dis 2007) [source] Association between IL-18 gene promoter polymorphisms and inflammatory bowel disease in a Japanese populationINFLAMMATORY BOWEL DISEASES, Issue 12 2005T Takagawa MD Abstract Background: Interleukin-18 (IL-18) is a pleiotropic cytokine that induces the production of interferon (IFN)-, and also to regulate Th2 cytokines. Recently, association studies between IL-18 gene promoter polymorphisms and several Th1- or Th2-mediated inflammatory diseases were reported. In inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), recent evidence suggests that IL-18 is involved in the pathogenesis. Methods: Using DNA direct sequencing, we investigated IL-18 gene promoter polymorphisms at ,607C/A and ,137G/C. Allele, genotype, and haplotype frequencies were determined in 210 Japanese patients with UC, 205 patients with CD, and 212 controls. Results: In UC, the ,137C allele frequency was significantly higher in the proctitis-type patients than in controls (Pc = 0.0068). The ,137 genotype frequency was also significantly different in the proctitis-type patients than in controls (Pc = 0.032). No other allele and genotype frequencies were significantly associated with UC after Bonferroni correction. Furthermore, the frequency of haplotype 2 (,607A, ,137C), which had a lower promoter activity and IFN-, mRNA level than the other haplotypes as previously reported, was significantly higher in the proctitis-type patients than in controls (Pc = 0.01). In CD, we could not find any significant differences. Conclusions: IL-18 gene promoter polymorphisms may not be associated with disease susceptibility but related to the extent of disease in UC. [source] Susceptibility to refractory ulcerative colitis is associated with polymorphism in the hMLH1 mismatch repair geneINFLAMMATORY BOWEL DISEASES, Issue 6 2004Siro Bagnoli MD Abstract The hMLH1 gene lies in the linkage susceptibility region to inflammatory bowel disease (IBD) on 3p21. A single nucleotide polymorphism, 655A>G, in exon 8 of the gene causes an I219V change in the MLH1 protein. To test whether hMLH1 may confer susceptibility to ulcerative colitis (UC), we investigated an association between the 655A>G polymorphism and the disease. DNA-based technologies were used to analyze the 655A>G polymorphism in 201 UC patients and 126 healthy ethnically matched controls. The comparison of the allelic frequencies of the 655A>G polymorphism in UC patients and healthy controls did not show significant differences. However, genotype frequencies at the hMLH1 655 position were found to be significantly different when patients with and without refractory UC were compared. This was mainly attributable to a higher level of homozygosity for the G allele in refractory UC patients. Almost 5 times as many (4.9 times) refractory UC patients carried the GG genotype compared with nonrefractory patients (P < 0.0001). The present study provides evidence that the hMLH1 gene is involved in genetic susceptibility to refractory UC. If confirmed by other studies, the GG genotype at position 655 of the hMLH1 gene may represent a useful predictive factor for the clinical management of UC patients. [source] Evidence for extensive genetic differentiation among populations of the malaria vector Anopheles arabiensis in Eastern AfricaINSECT MOLECULAR BIOLOGY, Issue 4 2000M. J. Donnelly Abstract We describe the geographical population structure of the malaria vector Anopheles arabiensis in Eastern Africa. Allelic variation at eight microsatellite loci was scored in samples from nine localities along a 4500 km transect from Sudan to Mozambique. Highly significant differences in genotype frequencies were found between all populations separated by more than 200 km. Populations within Malawi separated by 191 km were indistinguishable, as were those within Sudan separated by 134 km. FST and ,ST gave significant estimates of isolation by distance. These data, lead us to conclude that there are extensive barriers to gene flow in this region. The high estimates of Nm (9.4 from FST and 5.2 from ,ST) indicate recent range expansion in this species rather than extensive contemporary gene flow. [source] Glutathione S -transferase M3 (A/A) genotype as a risk factor for oral cancer and leukoplakia among Indian tobacco smokersINTERNATIONAL JOURNAL OF CANCER, Issue 1 2004Nilabja Sikdar Abstract Polymorphism in glutathione S -transferase (GST) genes, causing variations in enzyme activities, may influence susceptibility to oral cancer and leukoplakia in smokers and/or smokeless tobacco users. In this case-control study consisting of 109 leukoplakia and 256 oral cancer patients and 259 controls, genotype frequencies at GSTM1, GSTT1, GSTM3 and GSTP1 loci were determined by polymerase chain reaction-restriction fragment length polymorphism methods and analyzed by multiple logistic regression to determine the risks of the diseases. There were no significant differences in the distributions of GSTM1, GSTM3 and GSTT1 genotypes in patients and controls when all individuals were compared. In contrast, frequencies of ile/ile genotype at codon 105 and variant val-ala haplotype of GSTP1 was significantly higher (OR = 1.5; 95% CI = 1.0,2.0) and lower (OR = 1.4; 95% CI = 1.0,1.9) in oral cancer patients compare to controls, respectively. The impacts of all genotypes on risks of oral cancer and leukoplakia were also analyzed in patients with different tobacco habits and doses. Increased risks of cancer and leukoplakia were observed in tobacco smokers with GSTM3 (A/A) genotype (OR = 2.0, 95% CI = 1.0,4.0; OR = 2.0, 95% CI = 1.0,4.4, respectively). So, GSTM3 (A/A) genotype could become one of the markers to know which of the leukoplakia would be transformed into cancer. Heavy tobacco chewing (> 124 chewing-year) increased the risk of cancer in individuals with GSTT1 homozygous null genotype (OR = 3.0; 95% CI = 1.0,9.8). Furthermore, increased lifetime exposure to tobacco smoking (> 11.5 pack-year) increased the risk of leukoplakia in individuals with GSTM1 homozygous null genotype (OR = 2.4; 95% CI = 1.0,5.7). It may be suggested that polymorphisms in GSTP1, GSTM1, GSTM3 and GSTT1 genes regulate risk of cancer and leukoplakia differentially among different tobacco habituals. © 2003 Wiley-Liss, Inc. [source] A search for cyclophilin-A gene (PPIA) variation and its contribution to the risk of atherosclerosis and myocardial infarctionINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 2 2008M. Palacín Summary Cyclophilin A is secreted by vascular smooth muscle cells in response to inflammatory stimuli, and could thus contribute to atherosclerosis. We hypothesized that the genetic variation at the cyclophilin A gene (PPIA) could affect the risk for developing atherosclerosis and myocardial infarction. This study included 250 myocardial infarction patients (all male and < 60 years; 95% are smokers). All these cases had at least one atherosclerotic diseased coronary vessel. DNA was obtained from patients and from 250 healthy controls. The variation at the PPIA gene was determined in the patients through single-strand conformation analysis and direct sequencing of seven polymerase chain reaction fragments. Allele and genotype frequencies were compared between patients and controls. The effect of a promoter polymorphism (,11 G/C) on gene expression was in vitro analysed with luciferase-reporter assays. We found two common polymorphisms in the PPIA promoter (,11 G/C) and the 5, non-translated (+36 G/A) regions. Cells transfected with luciferase-plasmids containing the ,11 G had significantly higher luciferase activity. Genotype frequencies for these polymorphisms did not differ between patients and controls. In conclusion, we reported a functional variant in the PPIA promoter. However, the PPIA variation did not significantly contribute to the risk of suffering from myocardial infarction among patients with atherosclerotic diseased vessels. [source] Single nucleotide polymorphisms of cytokine genes in the healthy Slovak populationINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 4 2007J. Javor Summary Cytokines are molecules that control and modulate the activities of numerous target cells via binding to specific receptors. The observed differences in the cytokine production among individuals can be, at least partially, explained by gene polymorphisms. Several cytokine gene polymorphisms have been identified to play a role in susceptibility to various diseases, including autoimmune, infectious, allergic or cardiovascular diseases. The aim of the current study was to determine allele and genotype frequencies of 22 polymorphisms in 13 cytokine genes in the healthy Slovak population and to compare them with data available from six populations from Central and Southern Europe. A polymerase chain reaction with sequence-specific primers was used to genotype polymorphisms within genes encoding IL-1,, IL-1,, IL-1R, IL-1RA, IL-4R,, IL-12, IFN-,, TGF-,, TNF-,, IL-2, IL-4, IL-6 and IL-10 in a sample of 140 unrelated Slovak subjects. The allelic distribution of all polymorphisms in the Slovak population was very close to that in the geographically and historically closest populations in Central Europe , the Czech and the Polish. However, several differences were found between the Slovak and four populations from Southern Europe. The obtained data represent a basis for further studies on association of cytokine gene polymorphisms with some diseases. [source] Genotyping for cytokine polymorphisms: allele frequencies in the Italian populationINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 1 2003M. Uboldi de Capei Summary It has been demonstrated that many cytokine genes [e.g. tumour necrosis factor , (TNF-,) and interleukin 10 (IL-10)] show polymorphisms which may affect gene transcription, causing individual variations in cytokine production. The majority of polymorphisms described are single nucleotide polymorphisms (SNPs). In 140 healthy Italian subjects, the allelic and genotype frequencies were determined for the cytokine genes IL-1, (T/C ,889), IL-1, (C/T ,511, T/C +3962), IL-12 (C/A ,1188), interferon (IFN)-, (A/T UTR 5644), transforming growth factor (TGF)-, (C/T codon 10, G/C codon 25), TNF-, (G/A ,308, G/A ,238), IL-2 (T/G ,330, G/T +166), IL-4 (T/G ,1098, T/C ,590, T/C ,33), IL-6 (G/C ,174, G/A nt565), IL-10 (G/A ,1082, C/T ,819, C/A ,592), IL-1R (C/T pst11970), IL-1RA (T/C mspa111100) and IL-4RA (G/A +1902). All typings were performed with PCR-SSP assays. Allele and genotype frequencies and linkage disequilibria were calculated and compared with those of other populations. [source] Further support for the association of CCR5 allelic variants with asthma susceptibilityINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 6 2002R. McGinnis Summary English and German nuclear families containing multiple asthmatic children and asthmatic parents were analysed to retest a recently reported association between resistance to asthma and the ,32 allele of chemokine receptor 5 (CCR5). Analysis of the families by the transmission-disequilibrium test (TDT) revealed a non-significant trend in the English families that provided marginal confirmation of the association (P < 0.125), but no similar trend was observed in the German families. Case,control comparison of ,32 allele and genotype frequencies in asthmatic vs. non-asthmatic parents revealed a significantly lower frequency of ,32 in asthmatic English parents (P < 0.009) and a similar but non-significant trend in German parents (P < 0.265). Taken together, the pattern of results provides confirmation for the previously observed ,32,asthma association and indicates that susceptibility to asthma may be influenced by CCR5 or another gene in chromosomal region 3p21. 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