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Biomedical subjects

Meredith Yeager

Publications and source records attributed to Meredith Yeager.

At least 37 records · Page 2Linked to original sources
PubMed2006

Genetic variation of Cytochrome P450 1B1 (CYP1B1) and risk of breast cancer among Polish women.

Four single nucleotide polymorphisms (SNPs) in CYP1B1 (Ex2 + 143 C > G, Ex2 + 356 G > T, Ex3 + 251 G > C, Ex3 + 315 A > G) cause amino acid changes (R48G, A119S, L432V and N453S, respectively) and are associated with increased formation of catechol estrogens; however, epidemiologic evidence only weakly supports an association between these variants and breast cancer risk. Because genetic variability conferring increased susceptibility could exist beyond these putative functional variants, we comprehensively examined the common genetic variability within CYP1B1. A total of eight haplotype-tagging (ht)SNPs (including Ex3 + 315 A > G), in addition to two putatively functional SNPs (Ex2 + 143 C > G and Ex3 + 251 G > C), were selected and genotyped in a large case-control study of Polish women (1995 cases and 2296 controls). Haplotypes were estimated using the expectation-maximization algorithm, and overall differences in the haplotype distribution between cases and controls were assessed using a global score test. We also evaluated levels of tumor CYP1B1 protein expression in a subset of 841 cases by immunohistochemistry, and their association with genetic variants. In the Polish population, we observed two linkage disequilibrium (LD)-defined blocks. Neither haplotypes (global P-value of 0.99 and 0.67 for each block of LD, respectively), nor individual SNPs (including three putatively functional SNPs) were associated with breast cancer risk. CYP1B1 was expressed in most tumor tissues (98%), and the level of expression was not related to the studied genetic variants. We found little evidence for modification of the estimated effect of haplotypes or individual SNPs by age, family history of breast cancer, or tumor hormone receptor status. The present study provides strong evidence against the existence of a substantial overall association between common genetic variation in CYP1B1 and breast cancer risk.

Adult↗
PubMed2006

DRD2 genetic variation in relation to smoking and obesity in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

OBJECTIVES: Cigarette smoking is the leading cause of morbidity and mortality worldwide. We investigated the association between smoking behavior and genetic variations in the D2 dopamine receptor (DRD2), which mediates nicotine dependence. To assess the specificity of genetic effects, we also investigated other reward-motivated characteristics (obesity, alcohol consumption). METHODS: Four single nucleotide polymorphisms in DRD2 were genotyped in 2374 participants selected randomly from the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial after stratifying by sex, age, and smoking status. Smoking, obesity, and alcohol consumption were assessed by questionnaire. Single nucleotide polymorphism and haplotype associations were estimated using odds ratios (ORs) and 95% confidence intervals derived from conditional logistic regression models, adjusted for race/ethnicity. RESULTS: DRD2 polymorphisms were associated with the risk of remaining a current smoker and obesity. Current smokers were more likely than former smokers to possess the variant TaqIA allele (rsmusical sharp1800497) in a dose-dependent model (ORCT=1.2, ORTT=1.5, P for linear trend=0.007). The DRD2 haplotype T-C-T-A [TaqIA(C/T)-957(T/C)-IVS6-83(G/T)- -50977(A/G)] was more common among current than former smokers (OR=1.3, P=0.006), particularly among heavy smokers (21+ cigarettes per day; OR=1.6, P=0.006), and was more common among obese than normal weight individuals (OR=1.4, P=0.02). CONCLUSIONS: Genetic variation in DRD2 is a modifier of the reward-motivated characteristics, smoking and obesity. As fewer than 15% of smokers who attempt to quit are able to maintain abstinence for greater than 3 months, our results support that DRD2 is an appropriate molecular target for smoking cessation treatments. Our results further support evaluation of DRD2 antagonists for obesity therapies.

Aged↗
PubMed2006

Polymorphisms in cytokine genes and risk of Helicobacter pylori infection among Jamaican children.

BACKGROUND: Infection by Helicobacter pylori is often acquired during childhood. Recent studies suggest that inflammatory cytokines may play a role in susceptibility to, and disease phenotype caused by, H. pylori infection, but the association of host genetic variability with risk of H. pylori infection has not been studied in children. METHODS: We investigated the relationship between the risk of H. pylori antibody positivity and cytokine gene polymorphisms among 199 two-year-old Jamaicans. H. pylori seropositivity was determined by a validated research enzyme-linked immunosorbent assay. Real-time Taqman polymerase chain reaction was used to determine variants at 17 loci in 11 cytokine genes (IL1A, IL1B, IL2, TNF, TLR4, IL4, IL6, IL10, IL10RA, IL12A and IL13). We estimated the odds ratio and the 95% confidence interval for the association of genetic polymorphisms with H. pylori seropositivity, using logistic regression. RESULTS: Forty (20.1%) of 199 children were seropositive. Children's H. pylori seropositivity correlated highly with maternal H. pylori seropositivity (OR = 7.98, 95% CI = 1.05-60.60, p = .02). Children carrying IL1A-889T had a lower risk of H. pylori positivity, compared to those carrying -889C, with each T allele associated with 43% risk reduction (OR = 0.57, 95% CI = 0.33-0.99, p-trend = .05). No other loci we examined were associated with the risk of H. pylori seropositivity. CONCLUSIONS: The IL1A-889 T allele, known to express a higher level of cytokine IL-1alpha, is associated with a lower risk of H. pylori infection among Jamaican children. Our finding supports the hypothesis that an upregulation of pro-inflammatory cytokines may protect against persistent H. pylori colonization.

Alleles↗
PubMed2006

Genetic variation in the nucleotide excision repair pathway and bladder cancer risk.

Nucleotide excision repair (NER) is critical for protecting against damage from carcinogens in tobacco smoke. We evaluated the influence of common genetic variation in the NER pathway on bladder cancer risk by analyzing 22 single nucleotide polymorphisms (SNP) in seven NER genes (XPC, RAD23B, ERCC1, ERCC2, ERCC4, ERCC5, and ERCC6). Our study population included 1,150 patients with transitional cell carcinoma of the urinary bladder and 1,149 control subjects from Spain. Odds ratios (OR) and 95% confidence intervals (95% CI) were adjusted for age, gender, region, and smoking status. Subjects with the variant genotypes for SNPs in four of the seven genes evaluated had small increases in bladder cancer risk compared to subjects with the homozygous wild-type genotypes: RAD23B IVS5-15A>G (OR, 1.3; 95% CI, 1.1-1.5; P = 0.01), ERCC2 R156R (OR, 1.3; 95% CI, 1.1-1.6; P = 0.006), ERCC1 IVS5+33A>C (OR, 1.2; 95% CI, 1.0-1.5; P = 0.06; P(trend) = 0.04), and ERCC5 M254V (OR, 1.4; 95% CI, 1.0-2.0; P = 0.04). A global test for pathway effects indicated that genetic variation in NER characterized by the 22 SNPs analyzed in this study significantly predicts bladder cancer risk (P = 0.04). Pairwise comparisons suggested that carrying variants in two genes could result in substantial increases in risk. Classification tree analyses suggested the presence of subgroups of individuals defined by smoking and NER genotypes that could have substantial increases in risk. In conclusion, these findings provide support for the influence of genetic variation in NER on bladder cancer risk. A detailed characterization of genetic variation in key NER genes is warranted and might ultimately help identify multiple susceptibility variants that could be responsible for substantial joint increases in risk.

Adult↗
PubMed2006

Nucleotide excision repair gene polymorphisms and risk of advanced colorectal adenoma: XPC polymorphisms modify smoking-related risk.

OBJECTIVES: Nucleotide excision repair enzymes remove bulky damage caused by environmental agents, including carcinogenic polycyclic aromatic hydrocarbons found in cigarette smoke, a risk factor for colorectal adenoma. Among participants randomized to the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we studied the risk of advanced colorectal adenoma in relation to cigarette smoking and selected single nucleotide polymorphisms (SNP) in the nucleotide excision repair pathway. METHODS: Cases (n = 772) were subjects with left-sided advanced adenoma (>1 cm in size, high-grade dysplasia, or villous characteristics). Controls (n = 777) were screen-negative for left-sided polyps by sigmoidoscopy. DNA was extracted from blood samples and 15 common nonsynonymous SNPs in seven-nucleotide excision repair genes [XPC, RAD23B (hHR23B), CSB (ERCC6), XPD (ERCC2), CCNH, XPF (ERCC4), and XPG (ERCC5)] were genotyped. RESULTS: None of the studied SNPs were independently associated with advanced adenoma risk. Smoking was related to adenoma risk and XPC polymorphisms (R492H, A499V, K939Q) modified these effects (P(interaction) from 0.03-0.003). Although the three XPC variants were in linkage disequilibrium, a multivariate logistic regression tended to show independent protective effects for XPC 499V (P(trend) = 0.06), a finding supported by haplotype analysis (covariate-adjusted global permutation P = 0.03). CONCLUSIONS: Examining a spectrum of polymorphic variants in nucleotide excision repair genes, we found evidence that smoking-associated risks for advanced colorectal adenoma are modified by polymorphisms in XPC, particularly haplotypes containing XPC 499V.

Adenoma↗
PubMed2006

Metabolic gene variants and risk of non-Hodgkin's lymphoma.

Genes involved in metabolism of environmental chemical exposures exhibit sequence variability that may mediate the risk of non-Hodgkin's lymphoma. We evaluated associations between non-Hodgkin's lymphoma and 15 variants in AHR, CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2E1, GSTP1, GSTM3, EPHX1, NQO1, and PON1. Cases were identified from four Surveillance, Epidemiology, and End Results registries in the United States, and population-based controls were identified through random-digit dialing and Medicare eligibility files. Metabolic gene variants were characterized for the 1,172 (89% of total) cases and 982 (93%) controls who provided biological samples for genotyping. Subjects who were heterozygous or homozygous for the cytochrome P450 gene variant CYP1B1 V432L G allele were at slightly greater risk of non-Hodgkin's lymphoma [odds ratio (OR), 1.27; 95% confidence interval (95% CI), 0.97-1.65]; these results were consistent across B-cell lymphoma subtypes and among both non-Hispanic White and Black subjects, although not statistically significant. The CYP2E1 -1054T allele was associated with decreased risk of non-Hodgkin's lymphoma (CT and TT genotypes combined OR, 0.59; 95% CI, 0.37-0.93), and this pattern was observed among all histologic subtypes. The numbers of cases of particular subtypes were rather small for stable estimates, but we noted that the PON1 L55M AA allele, associated with slightly increased risk of non-Hodgkin's lymphoma (variant homozygotes OR, 1.36; 95% CI, 0.96-1.95), was most strongly associated with follicular non-Hodgkin's lymphoma and T-cell lymphoma, with ORs for variant homozygotes of 2.12 and 2.93, respectively. There was no overall association with non-Hodgkin's lymphoma for the other gene variants we examined. The modest effects we observed may reflect the context of exposures within the general population represented in our study.

Adult↗
PubMed2006

Lead, genetic susceptibility, and risk of adult brain tumors.

BACKGROUND: Although few etiologic factors for brain tumors have been identified, limited data suggest that lead may increase the risk of brain tumors, particularly meningioma. The ALAD G177C polymorphism affects the toxicokinetics of lead and may confer genetic susceptibility to adverse effects of lead exposure. METHODS: We examined occupational exposure to lead and risk of brain tumors in a multisite, hospital-based, case-control study of 489 patients with glioma, 197 with meningioma, and 799 non-cancer controls frequency matched on hospital, age, sex, race/ethnicity, and residential proximity to hospital. ALAD genotype was assessed by a Taqman assay for 355 glioma patients, 151 meningioma patients, and 505 controls. Exposure to lead was estimated using a rigorous questionnaire-based exposure assessment strategy incorporating lead measurement and other occupational data abstracted from published articles and reports. RESULTS: Increased risk of meningioma with occupational lead exposure (estimated by odds ratios and 95% confidence intervals) was most apparent in individuals with the ALAD2 variant allele, for whom risk increased from 1.1 (0.3-4.5) to 5.6 (0.7-45.5) and 12.8 (1.4-120.8) for estimated cumulative lead exposures of 1 to 49 microg/m3-y, 50 to 99 microg/m3-y, and >or=100 microg/m3-y, respectively, compared with unexposed individuals (two-sided P trend = 0.06). This relationship became stronger after excluding occupational lead exposures characterized by a low confidence level or occurring in the 10 years before meningioma diagnosis. Occupational lead exposure was not associated with glioma risk. CONCLUSIONS: Although our results indicate that lead may be implicated in meningioma risk in genetically susceptible individuals, these results need to be interpreted with caution given the small numbers of exposed cases with a variant genotype.

Adolescent↗
PubMed2006

A comprehensive analysis of the androgen receptor gene and risk of breast cancer: results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3).

INTRODUCTION: Androgens have been hypothesised to influence risk of breast cancer through several possible mechanisms, including their conversion to estradiol or their binding to the oestrogen receptor and/or androgen receptor (AR) in the breast. Here, we report on the results of a large and comprehensive study of the association between genetic variation in the AR gene and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). METHODS: The underlying genetic variation was determined by first sequencing the coding regions of the AR gene in a panel of 95 advanced breast cancer cases. Second, a dense set of markers from the public database was genotyped in a panel of 349 healthy women. The linkage disequilibrium relationships (blocks) across the gene were then identified, and haplotype-tagging single nucleotide polymorphisms (htSNPs) were selected to capture the common genetic variation across the locus. The htSNPs were then genotyped in the nested breast cancer cases and controls from the Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study, and Women's Health Study cohorts (5,603 breast cancer cases and 7,480 controls). RESULTS: We found no association between any genetic variation (SNP, haplotype, or the exon 1 CAG repeat) in the AR gene and risk of breast cancer, nor were any statistical interactions with known breast cancer risk factors observed. CONCLUSION: Among postmenopausal Caucasian women, common variants of the AR gene are not associated with risk of breast cancer.

Aged↗
PubMed2006

Cigarette smoking, N-acetyltransferase genes and the risk of advanced colorectal adenoma.

BACKGROUND: Cigarette use is associated with greater risk for colorectal adenoma, a colorectal cancer precursor. N-acetyltransferases, NAT1 and NAT2, are important enzymes involved in the metabolism of aromatic amine carcinogens present in cigarette smoke. Our interest is in the polymorphisms within the NAT1 and NAT2 genes that influence the tobacco-colorectal tumor relationship by impacting on the metabolic activation and detoxification of tobacco smoke-derived carcinogens. METHODS: In the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, we compared NAT1 and NAT2 gene variant distributions for 772 cases with left-sided advanced adenoma and 777 gender and age-matched controls. Individual NAT1 and NAT2 diplotypes were assigned and NAT2 acetylator phenotypes were derived. RESULTS: Risks for advanced colorectal adenoma were significantly increased among recent smokers (current smokers or those who quit less than 10 years ago) (odds ratio [OR] = 2.3, 95% confidence interval [CI]: 1.7-3.1) and among those who smoked more than 20 cigarettes per day (OR = 1.7, 95% CI: 1.3-2.2), compared with nonsmokers. Risk decreased with increasing NAT2 phenotypic activity (0: slow, 1: intermediate, and 2: rapid) (OR trend: 0.8; 95% CI: 0.7-1.0, p-trend = 0.04) overall. When stratified by smoking status, significant phenotype-associated trends were observed among recent smokers (OR trend = 0.4, 95% CI: 0.3-0.7, p trend <0.001) (p-interaction = 0.02), but not among past or nonsmokers. Diplotypes most strongly associated with lower risks in smokers were NAT2*4/*5B (OR = 0.3, 95% CI: 0.1-0.8, p = 0.01) and NAT2*4/*4 (OR = 0.2, 95% CI: 0.04-0.7, p = 0.02), categorized as intermediate and rapid acetylators, respectively. One NAT1 diplotype, NAT1*4/*10 (OR = 0.5, 95% CI: 0.3-0.9, p = 0.03), was also associated with a decreased risk in smokers. CONCLUSIONS: Our study indicated that NAT2 gene variants associated with a slow acetylator phenotype were more susceptible to the effects of tobacco smoking with respect to adenoma risk, providing leads for disease prevention.

Adenoma↗
PubMed2005

Prostaglandin-endoperoxide synthase 2 (PTGS2) gene polymorphisms and risk of biliary tract cancer and gallstones: a population-based study in Shanghai, China.

There is evidence that chronic inflammation predisposes to biliary tract cancer and that use of non-steroidal anti-inflammatory drugs (NSAIDs) is protective. Although the mechanisms by which NSAIDs lower cancer risk remain unclear, NSAIDs reduce prostaglandin production by blocking prostaglandin-endoperoxide synthase 2 (PTGS2, commonly known as COX-2), an enzyme induced by proinflammatory stimuli that is often overexpressed in malignant tissue. Since variants in the PTGS2 gene may modify the expression or function of its encoded enzyme to modulate the inflammatory response in the biliary tract, we examined the associations of eight PTGS2 polymorphisms (-645C-->T; Ex3 -8G-->C; IVS5 -275T-->G; IVS7 +111T-->C; Ex10 +127T-->C; Ex10 +686 --->ATTAT-->TTATA; Ex10 +837T-->C; Ex10 -90C-->T) with biliary tract cancer and stones in a population-based case-control study conducted in Shanghai, China. Genotyping was performed for 411 patients with biliary tract cancer (237 gallbladder, 127 extrahepatic bile duct and 47 ampulla of Vater), 895 patients with biliary stones (673 gallbladder, 222 bile duct), and 786 healthy individuals randomly selected from the population. Significant associations were seen only between the Ex10 +837T-->C marker and bile duct cancer risk. Relative to individuals with the TT genotype, those carrying the C allele (TC or CC genotype) had a 1.8-fold (95% confidence interval: 1.2-2.7) risk of bile duct cancer. Inferred haplotypes including this risk-conferring allele were also associated with increased bile duct cancer risk of similar magnitude. Our results suggest that a common PTGS2 variant increases bile duct cancer risk. Further investigation is needed to confirm and extend our findings in studies of biliary tract cancer that more comprehensively examine PTGS2 and other inflammation-related genes.

Age Factors↗
PubMed2005

Genetic variation in the sodium-dependent vitamin C transporters, SLC23A1, and SLC23A2 and risk for preterm delivery.

Vitamin C has been the focus of epidemiologic investigation in preterm delivery (<37 weeks' gestation), which is a leading cause of neonatal mortality and birth-related morbidity. There are two sodium-dependent membrane transporters encoded by SLC23A1 and SLC23A2, which have key roles in human vitamin C metabolism and which control dietary uptake, reabsorption, and tissue distribution of vitamin C. Using maternal DNA, the authors evaluated common single-nucleotide polymorphisms (SNPs) in SLC23A1 and SLC23A2 in a nested case-control analysis of the Pregnancy, Infection, and Nutrition Study (1995-2000) cohort. Of the associations observed for both haplotypes in SLC23A1 and individual SNPs in SLC23A2, the most robust finding is with an intron 2 variant in SLC23A2. Heterozygotes and homozygotes for this variant had a 1.7-fold (95% confidence interval: 0.9, 3.3) and a 2.7-fold (95% confidence interval: 1.2, 6.3) elevation in the risk of spontaneous preterm birth, respectively. Semi-Bayesian hierarchical regression analysis, which simultaneously adjusted for multiple SNPs within the same gene, gave comparable results. The authors' findings link genetic variants in the vitamin C transporters to spontaneous preterm birth, which may explain previous dietary associations. If the findings from this study are confirmed, they may serve as the foundation for genetic risk assessment of nutritional pathways in preterm birth.

Adult↗
PubMed2005

High level of functional polymorphism indicates a unique role of natural selection at human immune system loci.

Several studies have shown that immune system proteins have on average a higher rate of amino acid evolution between different species of mammals than do most other proteins. To test whether immune-system-expressed loci show a correspondingly elevated rate of within-species nonsynonymous (amino acid altering) polymorphism, we examined gene diversity (heterozygosity) at 4,911 single nucleotide polymorphism (SNP) sites at 481 protein-coding loci. At loci with nonimmune functions, gene diversity at nonsynonymous SNP sites was typically lower than that at silent SNP sites (those not altering the amino acid sequence) in the same gene, a pattern that is an evidence of purifying selection acting to eliminate slightly deleterious variants. However, this pattern was not seen at nonsynonymous SNPs causing conservative amino acid replacements in immune system proteins, indicating that the latter are subject to a reduced level of functional constraint. Similarly, immune system genes showed higher gene diversities in their 5' noncoding regions than did other proteins. These results identified certain immune system loci that are likely to be subject to balancing selection that acts to maintain polymorphism in either coding or regulatory regions.

Chromosomes, Human↗
PubMed2005

Polymorphisms in cytokine and cellular adhesion molecule genes and susceptibility to hematotoxicity among workers exposed to benzene.

Benzene is a recognized hematotoxin and leukemogen but its mechanism of action and the role of genetic susceptibility are still unclear. Cytokines, chemokines, and cellular adhesion molecules are soluble proteins that play an important regulatory role in hematopoiesis. We therefore hypothesized that variation in these genes could influence benzene-induced hematotoxicity. We analyzed common, well-studied single-nucleotide polymorphisms (SNPs) in 20 candidate genes drawn from these pathways in a study of 250 workers exposed to benzene and 140 unexposed controls in China. After accounting for multiple comparisons, SNPs in five genes were associated with a statistically significant decrease in total WBC counts among exposed workers [IL-1A (-889C>T), IL-4 (-1098T>G), IL-10 (-819T>C), IL-12A (8685G>A), and VCAM1 (-1591T>C)], and one SNP [CSF3 (Ex4-165C>T)] was associated with an increase in WBC counts. The adhesion molecule VCAM1 variant was particularly noteworthy as it was associated with a decrease in B cells, natural killer cells, CD4+ T cells, and monocytes. Further, VCAM1 (-1591T>C) and CSF3 (Ex4-165C>T) were associated, respectively, with decreased (P = 0.041) and increased (P = 0.076) CFU-GEMM progenitor cell colony formation in 29 benzene-exposed workers. This is the first report to provide evidence that SNPs in genes that regulate hematopoiesis influence benzene-induced hematotoxicity.

Adult↗
PubMed2005

Polymorphisms in the DNA nucleotide excision repair genes and lung cancer risk in Xuan Wei, China.

The lung cancer mortality rate in Xuan Wei County is among the highest in China and has been attributed to exposure to indoor smoky coal emissions that contain very high levels of polycyclic aromatic hydrocarbons (PAHs). Nucleotide excision repair (NER) plays a key role in reversing DNA damage from exposure to environmental carcinogens, such as PAHs, that form bulky DNA adducts. We studied single nucleotide polymorphisms (SNPs) and their corresponding haplotypes in 6 genes (ERCC1, ERCC2/XPD, ERCC4/XPF, ERCC5/XPG, RAD23B and XPC) involved in NER in a population-based case-control study of lung cancer in Xuan Wei. A total of 122 incident primary lung cancer cases and 122 individually matched controls were enrolled. Three linked SNPs in ERCC2 were associated with lung cancer with similar ORs; e.g., persons with the Gln allele at codon 751 had a 60% reduction of lung cancer (OR = 0.40, 95% CI 0.18-0.89). Moreover, one haplotype in ERCC2 was associated with a decreased risk of lung cancer (OR = 0.40, 95% CI 0.19-0.85) compared to the most common haplotype. In addition, subjects with one or 2 copies of the Val allele at codon 249 of RAD23B had a 2-fold increased risk of lung cancer (OR = 1.91, 95% CI 1.12-3.24). In summary, our results suggest that genetic variants in genes involved in the NER pathway may play a role in lung cancer susceptibility in Xuan Wei. However, due to the small sample size, additional studies are needed to evaluate these associations within Xuan Wei and in other populations with substantial environmental exposure to PAHs.

Adult↗
PubMed2005

Effects of natural selection on interpopulation divergence at polymorphic sites in human protein-coding Loci.

To develop new strategies for searching for genetic associations with complex human diseases, we analyzed 2784 single-nucleotide polymorphisms (SNPs) in 396 protein-coding genes involved in biological processes relevant to cancer and other complex diseases, with respect to gene diversity within samples of individuals representing the three major historic human populations (African, European, and Asian) and with respect to interpopulation genetic distance. Reduced levels of both intrapopulation gene diversity and interpopulation genetic distance were seen in the case of SNPs located within the 5'-UTR and at nonsynonymous SNPs, causing radical changes to protein structure. Reduction of gene diversity at SNP loci in these categories was evidence of purifying selection acting at these sites, which in turn causes a reduction in interpopulation divergence. By contrast, a small number of SNP sites in these categories revealed unusually high genetic distances between the two most diverged populations (African and Asian); these loci may have historically been subject to divergent selection pressures.

Databases, Genetic↗
PubMed2005

Green tea consumption, genetic susceptibility, PAH-rich smoky coal, and the risk of lung cancer.

Experimental evidence suggests that green tea (Camellia sinesis) may reduce the risk of lung cancer through several hypothesized mechanisms including scavenging oxidative radicals, inhibition of tumor initiation, and modulation of detoxification enzymes. However, epidemiologic results have not been consistent as to the relationship between green tea consumption and lung caner prevention. We employed a population-based case-control study of 122 cases and 122 controls to investigate the effect that green tea consumption may have on the risk of lung cancer and whether polymorphisms in 8-oxoguanine-DNA glycosylase (OGG1), glutathione-S-transferase M1 (GSTM1), and aldo-keto reductase 1C3 (AKR1C3) modify such an association. Daily green tea consumption was associated with a non-significant reduction in lung cancer risk. However, the effect of smoky coal exposure was higher for non-drinkers (odds ratio (OR)=4.93; 95% confidence interval (95% CI)=1.27-19.13) than for drinkers (OR=1.88; 95% CI=1.01-3.48). Further, among individuals with the OGG1 Cys(326) allele, daily consumption was associated with a 72% reduction (95% CI=0.09-0.94). Among GSTM1 null homozygotes, those who consumed green tea daily had a non-significant reduction in risk compared with non-consumers. Green tea consumption had no effect among OGG1 Ser(326) homozygotes or GSTM1 carriers. In addition, AKR1C3 genotype did not modulate the effect of green tea consumption. The chemopreventive effects of green tea in this population may be restricted to individuals who are particularly susceptible to oxidative stress and oxidative DNA damage.

Alcohol Oxidoreductases↗
PubMed2005

Selected DNA repair polymorphisms and gastric cancer in Poland.

Impaired DNA repair capacity may adversely affect cancer risk, particularly in subjects exposed to DNA damaging carcinogens, as found in tobacco smoke, or among subjects deficient for protective factors, as found in fruits and vegetables. We studied tobacco use, fruit and vegetable intake, and common non-synonymous single nucleotide polymorphisms in four DNA repair genes in relation to gastric cancer risk, in a population-based, case-control study of 281 incident gastric cancer cases and 390 controls, in Warsaw, Poland. Multivariate logistic regression analysis was performed to calculate odds ratios (OR) and 95% confidence intervals (CI). Increased risks of gastric cancer were found for smokers (OR=3.1, CI=1.9-5.1 for pack-years>or=40 versus never smokers) and subjects with low fruit intake (OR=2.2, CI=1.3-3.6 for 1st versus 4th quartile); risk associated with vegetable intake was not statistically significant. Allele frequencies among the controls were consistent with those previously reported for the 5 polymorphisms studied: XRCC1-Arg399Gln, XPD-Lys751Gln, MGMT-Ile143Val, Leu84Phe, and XRCC3-Thr241Met. None of the studied polymorphisms were independently associated with gastric cancer risk. Smoking-associated risks, however, were greatest for carriers of the XRCC1-399 ArgArg genotype (Pinteraction=0.004). Risks associated with low intake of fruits or vegetables tended to be modified by selected polymorphisms in XRCC1, XPD and MGMT (Pinteraction=0.1-0.2). Risk modification was not found for the other repair polymorphisms. Selected DNA repair polymorphisms did not have independent effects on gastric cancer risk; however, they may modify smoking- and probably diet-related risks for this disease. These results need replication in larger epidemiological studies of gastric cancer.

Adult↗