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PubMed2004

No associations between Parkinson's disease and polymorphisms of the quinone oxidoreductase (NQO1, NQO2) genes.

Reactive oxygen species derived from dopamine metabolism can induce oxidative stress and thus may contribute to Parkinson's disease (PD) pathogenesis. The quinone oxidoreductases, nicotinamide adenine dinucleotide (phosphate) (NAD[P]H): quinone oxidoreductase 1 (NQO1) and dihydronicotinamide riboside (NRH): quinone oxidoreductase 2 (NQO2) detoxify quinones and quinonoid compounds. We investigated associations of genetic polymorphisms of NQO1 (C609T) and NQO2 (I/D, 29 base pairs) with PD in a population-based case-control study of 190 idiopathic PD cases and 305 unrelated controls matched on age and sex. No associations were detected for either gene variant or for any allele combinations.

Aged↗
PubMed2002

Microsomal epoxide hydrolase and glutathione S-transferase polymorphisms in relation to laryngeal carcinoma risk.

Two polymorphic sites of the microsomal epoxide hydrolase gene (EPHX1, 113Tyr-->113His, 139His-->139Arg) and four glutathione S-transferase genes (GSTM1, GSTM3, GSTP1, GSTT1) were genotyped in a group of patients with larynx cancer (N=204) and in a group of healthy controls (N=203), all Spanish caucasians. After adjusting for gender, age, and tobacco smoking, none of the polymorphisms alone were found to be associated with larynx cancer risk. The analysis of EPHX1/GST combinations, however, showed a significant over-representation of patients with a combination of 113Tyr/113Tyr EPHX1 and 105Ile/105Ile GSTP1 (adjusted odds ratio (OR): 1.95; 95% confidence interval (CI): 1.02-3.78). The calculation of the predicted epoxide hydrolase (EH) activity also showed an increased risk for the individuals with both predicted high activity EH and 105Ile/105Ile GSTP1 (OR: 2.90; 95% CI: 1.10-7.67). These results on larynx cancer tend to confirm a former study on lung cancer (Cancer Lett. 173 (2001) 155) suggesting the existence of an interaction between variants of EH and GSTpi, both enzymes being involved in the metabolism of aromatic hydrocarbons, that may increase susceptibility to tobacco-related cancers.

Adult↗
PubMed1999

Reactive airways dysfunction syndrome (RADS): guidelines for diagnosis and treatment and insight into likely prognosis.

Reactive airways dysfunction syndrome (RADS) is defined as the sudden onset of asthma following a high level exposure to a corrosive gas, vapor, or fume. This variant of occupational asthma continues to generate controversy regarding the criteria for its diagnosis. There is also some disagreement as to the likely prognosis with this disorder. Currently, the diagnosis requires the assumption of normal premorbid pulmonary physiology and absence of bronchial hyperreactivity. Criteria for the diagnosis of RADS are discussed with a proposal for both major and minor criteria to increase the confidence of an accurate diagnosis. The pathology of RADS involves a primarily lymphocytic inflammatory response with some evidence of subepithelial thickening and fibrosis. Most patients with this condition who survive the short-term exposure to a toxicant recover completely without significant clinical or physiologic sequelae. The issue of low-level RADs remains controversial and problematic as a tenable diagnosis, and will require further careful investigation to evaluate the premise that chronic, low-level toxicants are capable of leading to such a condition. More likely, most of the cases which have been reported represent preexisting asthma and/or expressions of an atopic predisposition.

Asthma↗
PubMed2005

COMT polymorphisms and anxiety-related personality traits.

High neuroticism and low extraversion are characteristic of anxiety-prone individuals. A functional variant in the catechol-O-methyltransferase (COMT) gene, the Val158Met ('val/met') polymorphism, has been associated in some prior studies with several phenotypes, including neuroticism. We tested the hypothesis that the val158met polymorphism would be associated with both high neuroticism and low extraversion, making it a plausible candidate locus for anxiety susceptibility. To determine whether val158met is responsible for these effects, we also evaluated the association with haplotypes that included two other SNPs within the COMT gene. We collected a sample of 497 undergraduate college students who were phenotyped on a personality inventory (the NEO-Personality Inventory-Raised (NEO-PI-R)). Subjects were genotyped for three COMT polymorphisms: the well-studied nonsynonymous SNP rs4680 that generates a valine-to-methionine substitution (val158met), rs737865 (near exon #1), and rs165599 (also functional, near the 3'-UTR). Together, these three SNPs define a haplotype that is associated with reduced COMT expression in human brain. Logistic regression analyses were used to examine the effects of individual SNPs on extraversion and neuroticism scores. Score tests for association between these traits (quantitatively and dichotomously considered) and haplotypes were also conducted. We evaluated potential for population stratification artifact by genotyping a set of 36 unlinked highly polymorphic markers previously demonstrated to distinguish sufficiently ancestry of major American populations. Two of the SNPs (rs4680 ('val/met') and rs737865) were significantly associated with (low) extraversion and, less consistently, with (high) neuroticism, with effects confined to women. A significant association between COMT haplotype and (low) extraversion and (high) neuroticism was also observed. Formal testing showed that population structure did not explain the findings. These data suggest that involvement of the COMT locus in susceptibility to anxiety-related traits (ie low extraversion and high neuroticism) is unlikely to be wholly accounted for by the well-studied rs4680 ('val/met') polymorphism. Other functional variants may exist that contribute to this relationship. Possible sex-specific effects remain to be further studied and explained.

Adolescent↗
PubMed1997

Dandy-Walker malformation diagnosed before 21 weeks of gestation: associated malformations and chromosomal abnormalities.

This study examined rates of concomitant structural and chromosomal abnormalities in 14 fetuses with a diagnosis of Dandy-Walker malformation or Dandy-Walker variant before 21 weeks' gestational age, compared to 14 fetuses with a diagnosis of Dandy-Walker malformation or variant between 21 weeks' gestation and delivery. A total of 24 fetuses had Dandy-Walker malformation and four had Dandy-Walker variant. Eight of the fetuses with the malformation had ventriculomegaly: one of the fetuses with early diagnosis and seven with later diagnosis (p = 0.027). None of the fetuses with Dandy-Walker variant had ventriculomegaly. The overall prevalence of concomitant structural abnormalities was 13/28; 8/14 for fetuses with early prenatal diagnosis and 5/14 for fetuses with late prenatal diagnosis of the malformation or the variant. Chromosomal abnormality rates were significantly higher among fetuses with early prenatal diagnosis (7/14) than among those with later prenatal diagnosis (1/14; p = 0.032). Abnormal karyotypes were more prevalent among fetuses without ventriculomegaly (7/20), compared to fetuses with ventriculomegaly (1/8). We conclude that fetuses with an antenatal diagnosis of Dandy-Walker malformation or Dandy-Walker variant before 21 weeks' gestational age have worse prognosis than fetuses with a later prenatal diagnosis of the same defect.

Adult↗
PubMed2001

Prothrombin 20210 G: a mutation and Factor V Leiden mutation in women with a history of severe preeclampsia and (H)ELLP syndrome.

OBJECTIVE: The 20210 G-A prothrombin gene variant and the Factor V Leiden mutation are mutations associated with venous thrombotic risk. The aim of our study was to assess the prevalence of these specific mutations in women with a history of preeclampsia or hemolysis elevated liver enzymes, and low platelet count [(H)ELLP] syndrome and their influence on perinatal outcome. In addition, the association with venous thromboembolism was assessed. METHODS: One hundred fourteen (114) women with a history of preeclampsia or (H)ELLP syndrome were investigated at least 3 months' postpartum for the presence of 20210 G-A prothrombin gene variant and Factor V Leiden mutation. RESULTS: Four (3.5%) of the women had the 20210 G-A prothrombin gene variant, four (3.5%) women had the Factor V Leiden mutation, and one of these women carried both mutations. The prevalence of prothrombin 20210 G-A prothrombin and Factor V Leiden mutation in women with severe preeclampsia or (H)ELLP syndrome were comparable with the prevalence in the general Dutch population. The odds ratio for thromboembolism for carriers versus noncarriers was 22 (95% confidence interval: 1.7-303). Perinatal mortality was not significantly higher in women with any mutation [odds ratio: 1.5 (0.2-9.5)]. CONCLUSIONS: Although our study confirms that prothrombin 20210 G-A mutation and Factor V Leiden mutation are important genetic risk factors associated with thrombotic risk, these mutations appear not related to perinatal outcome in women with preeclampsia or (H)ELLP syndrome. It is unlikely that these mutations are of major importance for the development of severe preeclampsia or (H)ELLP syndrome.

Adult↗
PubMed2006

A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses.

Fasting glucose is associated with future risk of type 2 diabetes and ischemic heart disease and is tightly regulated despite considerable variation in quantity, type, and timing of food intake. In pregnancy, maternal fasting glucose concentration is an important determinant of offspring birth weight. The key determinant of fasting glucose is the enzyme glucokinase (GCK). Rare mutations of GCK cause fasting hyperglycemia and alter birth weight. The extent to which common variation of GCK explains normal variation of fasting glucose and birth weight is not known. We aimed to comprehensively define the role of variation of GCK in determination of fasting glucose and birth weight, using a tagging SNP (tSNP) approach and studying 19,806 subjects from six population-based studies. Using 22 tSNPs, we showed that the variant rs1799884 is associated with fasting glucose at all ages in the normal population and exceeded genomewide levels of significance (P=10-9). rs3757840 was also highly significantly associated with fasting glucose (P=8x10-7), but haplotype analysis revealed that this is explained by linkage disequilibrium (r2=0.2) with rs1799884. A maternal A allele at rs1799884 was associated with a 32-g (95% confidence interval 11-53 g) increase in offspring birth weight (P=.002). Genetic variation influencing birth weight may have conferred a selective advantage in human populations. We performed extensive population-genetics analyses to look for evidence of recent positive natural selection on patterns of GCK variation. However, we found no strong signature of positive selection. In conclusion, a comprehensive analysis of common variation of the glucokinase gene shows that this is the first gene to be reproducibly associated with fasting glucose and fetal growth.

Adult↗
PubMed2000

5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review.

The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism. The MTHFR gene is located on chromosome 1 (1p36.3), and two common alleles, the C677T (thermolabile) allele and the A1298C allele, have been described. The population frequency of C677T homozygosity ranges from 1% or less among Blacks from Africa and the United States to 20% or more among Italians and US Hispanics. C677T homozygosity in infants is associated with a moderately increased risk for spina bifida (pooled odds ratio = 1.8; 95% confidence interval: 1.4, 2.2). Maternal C677T homozygosity also appears to be a moderate risk factor (pooled odds ratio = 2.0; 95% confidence interval: 1.5, 2.8). The A 1298C allele combined with the C677T allele also could be associated with an increased risk for spina bifida. Some data suggest that the risk for spina bifida associated with C677T homozygosity may depend on nutritional status (e.g., blood folate levels, intake of vitamins) or on the genotype of other folate-related genes (e.g., cystathionine-beta-synthase and methionine synthase reductase). Studies of the C677T allele in relation to oral clefts, Down syndrome, and fetal anticonvulsant syndrome either have yielded conflicting results or have not been yet replicated.

Africa↗
PubMed2026

Single-cell expression quantitative trait locus Mendelian randomization reveals immune cell-specific causal regulatory networks and actionable targets in polycystic ovary syndrome.

ObjectiveTo systematically investigate whether the pathogenesis of polycystic ovary syndrome (PCOS) is causally related to dysregulated gene expression in specific immune cell subsets, and to evaluate the potential of these causal genes as actionable drug targets.MethodsThis study employed a two-sample Mendelian randomization (MR) framework using publicly available genome-wide association study (GWAS) summary statistics. The participant data included 797 PCOS cases and 140,558 controls (no direct patient recruitment was involved). Instrumental variables were derived from high-resolution immune cell-specific single-cell expression quantitative trait locus (sc-eQTL) data (OneK1K project) across 14 immune cell types. Primary analyses utilized the inverse-variance weighted (IVW) method. Shared causal variants were validated using Bayesian colocalization. Phenome-wide association analysis (PheWAS), external transcriptomic dataset validation (GSE8157), and DrugBank database screening were conducted for pleiotropy assessment and drug repositioning.ResultsMR analysis revealed genome-wide significant causal associations for GLIPR1 in non-classical monocytes (Mono NC) and XBP1 in CD4+ effector memory T cells (CD4 ET) with PCOS risk. Higher GLIPR1 expression was associated with a decreased PCOS risk (OR = 0.669, P = 4.34×10-6), whereas higher XBP1 expression was associated with an increased risk (OR = 1.406, P = 9.53×10-8). Colocalization analysis confirmed that GLIPR1 shares a causal variant with PCOS (PP.H4 = 96.73%). PheWAS and external validation confirmed the safety profile and significant upregulation (P = 0.03) of GLIPR1. Drug repositioning identified SOT-107, a Phase III protein therapy drug, as a potential interacting agent for GLIPR1.ConclusionsThis sc-eQTL MR study reveals immune cell-specific causal regulatory networks in PCOS. GLIPR1 in non-classical monocytes represents a high-confidence protective target, while XBP1 provides suggestive evidence for immune-mediated pathogenesis. The candidate drug SOT-107 highlights theoretical repositioning opportunities, though rigorous preclinical validation remains required.

Female↗
PubMed1998

[Musculoskeletal pain in pediatric patients. Prevalence and etiology in Primary Care].

OBJECTIVE: 1) To determine the number of clinic visits in primary care due to musculoskeletal pain in children > or = 3 years. 2) To describe the demographic characteristics of the population assessed for limb/back pain. 3) To characterize the etiology of musculoskeletal pain in a general pediatric clinic. PATIENTS AND METHODS: A prospective lineal study was performed between October 30, 1996 and January 14, 1997 in two urban general pediatric clinics located in the city of Madrid (Spain). During the period of the study, all consultations related to musculoskeletal pain were registered in a protocol form. In addition, a registry of all clinic visits was maintained during the study. RESULTS: During the study period, 43 clinic visits were due to musculoskeletal pain, representing 6.2% (43/692) of the clinic visits in children > or = 3 years of age (95% confidence interval 4.4-7.9%). The mean age was 9.8 years (+/- 3.2 years). These complaints, although statistically non-significant, were more frequent in children > or = 10 years old (53.4%) and in males (65.1%). The most frequent complaints were knee athralgias (30%), arthralgias of other joints (23%) and soft tissue pain (18%). These symptoms were usually due to overuse syndromes and normal skeletal growth variants. CONCLUSIONS: The increase of primary pediatric care age from 7 to 14 years of age is associated with an increase in the number of consultations related to musculoskeletal pain. This information should be kept in mind at the time of designing continuing medical education and training programs in pediatrics.

Adolescent↗
PubMed2001

Association between the T29-->C polymorphism in the transforming growth factor beta1 gene and breast cancer among elderly white women: The Study of Osteoporotic Fractures.

CONTEXT: Transgenic animal experiments suggest that increased expression of transforming growth factor beta1 (TGF-beta1) is protective against early tumor development, particularly in breast cancer. A T-->C (thymine to cytosine) transition in the 29th nucleotide in the coding sequence results in a leucine to proline substitution at the 10th amino acid and is associated with increased serum levels of TGF-beta1. OBJECTIVE: To determine whether an association exists between this TGF-beta1 polymorphism and breast cancer risk. DESIGN, SETTING, AND PARTICIPANTS: The Study of Osteoporotic Fractures, a prospective cohort study of white, community-dwelling women aged 65 years or older who were recruited at 4 US centers between 1986 and 1988. Three thousand seventy-five women who provided sufficient clinical information, buffy coat samples, and adequate consent for genotyping are included in this analysis. MAIN OUTCOME MEASURE: Breast cancer cases during a mean (SD) follow-up of 9.3 (1.9) years, verified by medical chart review and compared by genotype. RESULTS: Risk of breast cancer was similar in the 1124 women with the T/T genotype (56 cases; 5.4 per 1000 person-years) and the 1493 women with the T/C genotype (80 cases; 5.8 per 1000 person-years) but was significantly lower (P =.01) in the 458 women with the C/C genotype (10 cases; 2.3 per 1000 person-years). In analyses that adjusted for age, age at menarche, age at menopause, estrogen use, parity, body mass index, and bone mineral density, women with the C/C genotype had a significantly lower risk of developing breast cancer compared with women with the T/T or T/C genotype (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.17-0.75). There was no significant difference between the risk for women with the T/C genotype compared with women with the T/T genotype (adjusted HR, 1.04; 95% CI, 0.73-1.48). CONCLUSIONS: Our findings suggest that TGF-beta1 genotype is associated with risk of breast cancer in white women aged 65 years or older. Because the T allele is the common variant and confers an increased risk, it may be associated with a large proportion of breast cancer cases.

Aged↗
PubMed2004

Tumour formation within intestinal segments transposed to the urinary tract.

Patients and their urologists are quite rightly concerned about the possibility of neoplastic change within intestinal segments transposed to the lower urinary tract. This fear arises from the occurrence of latent adenocarcinoma arising from the urocolic anastomosis in approximately 10% of patients who underwent ureterosigmoidostomy in childhood. The present text provides an update of previous reviews and details work published since 1990 on epidemiological, experimental and clinical studies. Consideration of the collected evidence confirms the increased risk of colonic neoplasia following mixing of the faecal and urinary stream by ureterosigmoidostomy or its more recent variants. In contrast, the occurrence of tumours within transposed intestinal segments appears more likely to be related to the underlying urinary tract disease for which the surgery was performed rather than exposure of the intestinal mucosa to urine. This conclusion is, however, based on low level evidence and, despite the reassuring findings, caution is advised until more robust data are available to provide a confident risk assessment.

Adenocarcinoma↗
PubMed2006

Haplotypes of IL6 and IL10 and susceptibility to human T lymphotropic virus type I infection among children.

To characterize a host polygenic profile associated with susceptibility to human T lymphotropic virus type I (HTLV-I) infection, we examined common variants in 11 immune-related genes among Jamaican children born to HTLV-I-seropositive mothers. Compared with HTLV-I seronegatives, haplotypes of IL6 (-660G/-635C/-236G) and IL10 (-6653C/-1116G) were significantly associated with HTLV-I infection in children independent of maternal provirus load and duration of breast-feeding (odds ratio [OR], 4.5 [95% confidence interval {CI}, 1.2-17.6], and OR, 3.5 [95% CI, 1.4-9.0], respectively). Our findings are the first, to our knowledge, to suggest that host variation in both proinflammatory and anti-inflammatory genes could influence susceptibility to HTLV-I infection.

Child↗
PubMed1998

Villoglandular adenocarcinoma of the endometrium: a clinicopathologic study of 61 cases: a gynecologic oncology group study.

Papillary endometrioid or villoglandular adenocarcinoma (VGA) is a relatively common type of endometrial adenocarcinoma, but studies describing its behavior have yielded conflicting results. Patients with a component of VGA were identified in a review of 819 women entered in a Gynecology Oncology Group Study (Protocol 33) of clinical stages I and II endometrial adenocarcinoma. Cases with coexisting foci of serous or clear cell carcinoma were excluded from further consideration. Of the 61 cases that formed the study sample, there were 24 with pure villoglandular differentiation and 37 who were admixed with typical endometrioid adenocarcinoma (EA). The general clinicopathologic features of patients with pure and mixed VGA are compared with 469 patients with pure EA. The VGAs were better differentiated (grade 1 or 2--97% of VGA versus 74% EA, p = 0.001). but they were not significantly different with respect to median age, depth of invasion, or frequency of nodal spread. Six of the 61 patients with VGA died of their tumor. The disease-specific survival rate at 3 years for VGA is 94% (95% confidence interval: 0.88-0.99) compared with 88% (95% CI: 0.86-0.91) for EA. Two of the patients who died had pure villoglandular tumors and four had mixed villoglandular and endometrioid carcinoma. In view of the frequent admixture of VGA and EA and their generally similar biological characteristics, with a prognosis similar to that of typical EA, we conclude that VGA should be considered a variant of EA.

Adenocarcinoma, Mucinous↗
PubMed2006

Polymorphisms of the XRCC1, XRCC3 and XPD genes and risk of colorectal adenoma and carcinoma, in a Norwegian cohort: a case control study.

BACKGROUND: Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity, which may be associated with risk of developing cancer. For colorectal cancer the importance of mutations in mismatch repair genes has been extensively documented. Less is known about other DNA repair pathways in colorectal carcinogenesis. In this study we have focused on the XRCC1, XRCC3 and XPD genes, involved in base excision repair, homologous recombinational repair and nucleotide excision repair, respectively. METHODS: We used a case-control study design (157 carcinomas, 983 adenomas and 399 controls) to test the association between five polymorphisms in these DNA repair genes (XRCC1 Arg194Trp, Arg280His, Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln), and risk of colorectal adenomas and carcinomas in a Norwegian cohort. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by binary logistic regression model adjusting for age, gender, cigarette smoking and alcohol consumption. RESULTS: The XRCC1 280His allele was associated with an increased risk of adenomas (OR 2.30, 95% CI 1.19-4.46). The XRCC1 399Gln allele was associated with a reduction of risk of high-risk adenomas (OR 0.62, 95% CI 0.41-0.96). Carriers of the variant XPD 751Gln allele had an increased risk of low-risk adenomas (OR 1.40, 95% CI 1.03-1.89), while no association was found with risk of carcinomas. CONCLUSION: Our results suggest an increased risk for advanced colorectal neoplasia in individuals with the XRCC1 Arg280His polymorphism and a reduced risk associated with the XRCC1 Arg399Gln polymorphism. Interestingly, individuals with the XPD Lys751Gln polymorphism had an increased risk of low-risk adenomas. This may suggest a role in regression of adenomas.

Adenoma↗
PubMed2002

Single nucleotide polymorphisms in the 3' untranslated region of vascular endothelial growth factor gene in Japanese population with or without renal cell carcinoma.

We investigated native Japanese subjects whether C702T, C936T and G1612A polymorphisms in the 3' untranslated region (3'-UTR) of vascular endothelial growth factor (VEGF) gene are associated with the risk of renal cell carcinoma (RCC). Genomic DNAs from 145 RCC patients and 145 healthy controls were examined by polymerase chain reaction-based restriction fragment length polymorphism. Variant allele frequencies of C702T, C936T and G1612A were 0.00, 0.20 and 0.13 in the controls, respectively. The C702T and G1612A allele frequencies were significantly different between the Japanese population and the Caucasian population reported elsewhere. For each of C936T and G1612A polymorphisms, there was no statistically significant difference in the distribution of genotype frequencies between the cases and controls. Odds ratios and 95% confidence intervals computed by logistic regression analyses were not statistically significant. Stratification for the RCC cases according to pathological cell subtype, grade or stage failed to reveal any significant heterogeneity with respect to the genotype of each VEGF polymorphism. We revealed that there are significant ethnic differences in the C702T and G1612A allele frequencies, but suggested that C702T, C936T and G1612A polymorphisms in the 3'-UTR of VEGF gene are not associated with the risk of RCC, at least in Japanese population.

3' Untranslated Regions↗
PubMed2022

Comparison on Major Gene Mutations Related to Rifampicin and Isoniazid Resistance between Beijing and Non-Beijing Strains of Mycobacterium tuberculosis: A Systematic Review and Bayesian Meta-Analysis.

Objective: The Beijing strain of Mycobacterium tuberculosis (MTB) is controversially presented as the predominant genotype and is more drug resistant to rifampicin and isoniazid compared to the non-Beijing strain. We aimed to compare the major gene mutations related to rifampicin and isoniazid drug resistance between Beijing and non-Beijing genotypes, and to extract the best evidence using the evidence-based methods for improving the service of TB control programs based on genetics of MTB. Method: Literature was searched in Google Scholar, PubMed and CNKI Database. Data analysis was conducted in R software. The conventional and Bayesian random-effects models were employed for meta-analysis, combining the examinations of publication bias and sensitivity. Results: Of the 8785 strains in the pooled studies, 5225 were identified as Beijing strains and 3560 as non-Beijing strains. The maximum and minimum strain sizes were 876 and 55, respectively. The mutations prevalence of rpoB, katG, inhA and oxyR-ahpC in Beijing strains was 52.40% (2738/5225), 57.88% (2781/4805), 12.75% (454/3562) and 6.26% (108/1724), respectively, and that in non-Beijing strains was 26.12% (930/3560), 28.65% (834/2911), 10.67% (157/1472) and 7.21% (33/458), separately. The pooled posterior value of OR for the mutations of rpoB was 2.72 ((95% confidence interval (CI): 1.90, 3.94) times higher in Beijing than in non-Beijing strains. That value for katG was 3.22 (95% CI: 2.12, 4.90) times. The estimate for inhA was 1.41 (95% CI: 0.97, 2.08) times higher in the non-Beijing than in Beijing strains. That for oxyR-ahpC was 1.46 (95% CI: 0.87, 2.48) times. The principal patterns of the variants for the mutations of the four genes were rpoB S531L, katG S315T, inhA-15C > T and oxyR-ahpC intergenic region. Conclusion: The mutations in rpoB and katG genes in Beijing are significantly more common than that in non-Beijing strains of MTB. We do not have sufficient evidence to support that the prevalence of mutations of inhA and oxyR-ahpC is higher in non-Beijing than in Beijing strains, which provides a reference basis for clinical medication selection.

Isoniazid↗
PubMed2002

Glutathione S-transferase P1 and NADPH quinone oxidoreductase polymorphisms are associated with aberrant promoter methylation of P16(INK4a) and O(6)-methylguanine-DNA methyltransferase in sputum.

Inactivation of the p16(INK4a) tumor suppressor gene and O(6)-methylguanine-DNA methyltransferase (MGMT) DNA repair gene by aberrant promoter methylation appears to be an important step in respiratory carcinogenesis after exposure to tobacco smoke and radon progeny. The determinants of aberrant promoter methylation are not well characterized. Polymorphic variants of genes of which the products are involved in pathways that modulate and repair DNA damage after carcinogen exposure may affect the occurrence of de novo promoter methylation. On the basis of their associations with risk of lung cancer, we hypothesized that functional polymorphic variants of the NADPH quinone oxidoreductase, glutathione S-transferases P1 and M1, myeloperoxidase, and XRCC1 genes are associated with p16 and/or MGMT promoter methylation in sputum from cancer-free subjects at high risk for developing lung cancer. This hypothesis was tested by conducting a cross-sectional study of 70 former uranium miners from the Uranium Epidemiological Study cohort who were at high risk for lung cancer. The polymorphic variant genotypes were characterized through PCR-RFLP on DNA isolated from peripheral lymphocytes, and the methylation status of the p16 and MGMT promoters was determined by methylation-specific PCR on DNA isolated from sputum. Subjects who had at least one GSTP1 polymorphic allele (A-to-G at bp 104) had an increased risk for MGMT methylation [odds ratio (OR), 4.8; 95% confidence interval (CI), 1.2-18.6] or for either p16 or MGMT methylation (OR, 4.4; 95% CI, 1.3-14.2). Lack of a wild-type NADPH quinone oxidoreductase allele (C at bp 609) was also associated with methylation of either p16 or MGMT (OR, 3.1; 95% CI, 1.0-9.2). These results provide the first link between germ-line functional deficits in pathways that protect the cell from tobacco- and radon-induced DNA damage, and the development of aberrant promoter methylation of the p16 and MGMT genes in the respiratory epithelium of individuals at high risk for lung cancer.

Cyclin-Dependent Kinase Inhibitor p16↗