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Bladder cancer results from the combined effects of environmental and genetic factors, smoking being the strongest risk factor. Evaluating absolute risks resulting from the joint effects of smoking and genetic factors is critical to assess the public health relevance of genetic information. Analyses included up to 3,942 cases and 5,680 controls of European background in seven studies. We tested for multiplicative and additive interactions between smoking and 12 susceptibility loci, individually and combined as a polygenic risk score (PRS). Thirty-year absolute risks and risk differences by levels of the PRS were estimated for U.S. males aged 50 years. Six of 12 variants showed significant additive gene-environment interactions, most notably NAT2 (P = 7 × 10(-4)) and UGT1A6 (P = 8 × 10(-4)). The 30-year absolute risk of bladder cancer in U.S. males was 6.2% for all current smokers. This risk ranged from 2.9% for current smokers in the lowest quartile of the PRS to 9.9% for current smokers in the upper quartile. Risk difference estimates indicated that 8,200 cases would be prevented if elimination of smoking occurred in 100,000 men in the upper PRS quartile compared with 2,000 cases prevented by a similar effort in the lowest PRS quartile (P(additive) = 1 × 10(-4)). Thus, the potential impact of eliminating smoking on the number of bladder cancer cases prevented is larger for individuals at higher than lower genetic risk. Our findings could have implications for targeted prevention strategies. However, other smoking-related diseases, as well as practical and ethical considerations, need to be considered before any recommendations could be made., (©2012 AACR.)

Background: Influence of folate/homocysteine conversion is considered to be important in the pathogenesis of Parkinson's disease (PD). However, association of the folate metabolic pathway gene polymorphisms with PD susceptibility remains unclear., Methods: To test this possibility in PD, we conducted a hospital-based case-control study constituting 211 patients and 218 age- and sex-matched controls of ethnic Chinese in Taiwan. Genotyping assay was performed to screen for polymorphisms of the methylenetetrahydrofolate reductase (MTHFR C677T), methyltetrahydrofolate-homocysteine methyltransferase (MTR A2756G), and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR A1049G and C1783T) genes and assess the association between these genotype polymorphisms and PD risk using logistic regression analysis., Results: Of these four non-synonymous polymorphisms, the MTRR 1049GG variant was significantly associated with PD susceptibility (OR=3.17, 95%CI=1.08-9.35). Furthermore, we stratified our patients based on the MTHFR 677TT genotype in different strata, a significant association between the joint effect of polymorphisms and PD risk was observed in those patients whose genotypes were MTRR A1049G/MTR A2756G or MTRR C1783T/MTR A2756G (P<0.05)., Conclusion: Our findings provide support for the synergistic effects of polymorphisms in the folate metabolic pathway genes in PD susceptibility; the increased PD risk would be more significant in carriers with the polymorphisms of MTHFR, MTR, and MTRR genes., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The etiology of concurrent stenoses of extracranial and intracranial vessels in patients with ischemic stroke is poorly understood, but hereditary factors are believed to be important. We aimed to determine whether genetic polymorphisms affecting homocysteine and lipid metabolism are associated with concurrent stenoses. The genotypes of 191 Han Chinese patients with acute ischemic stroke, of whom 47 (25%) had concurrent stenoses, and 167 healthy control patients in Hong Kong were examined for the following polymorphisms: paraoxonase 1 (PON1) Q192R, methylenetetrahydrofolate reductase (MTHFR) A222V, glutamate-cysteine ligase catalytic-subunit (GCLC)-129C>T, and oxidized low-density lipoprotein receptor (OLR) 3' untranslated region C>T (rs1050283). The genotype distributions of PON1 Q192R and MTHFR A222V, which affect lipid and homocysteine metabolism, differed significantly between patients with stroke and healthy controls. The presence of at least one R allele in PON1 Q192R and a TT allele in OLR rs1050283 were associated with concurrent stenoses. We also identified a possible association between the presence of at least one V allele in MTHFR A222V and concurrent stenoses. This study shows that genetic polymorphisms affecting homocysteine and lipid metabolism are possible risk factors for stroke and concurrent stenoses., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: Gamma-glutamyl carboxylation, a reaction essential for the biosynthesis of vitamin K-dependent coagulation factors, requires the participation of the gamma-glutamyl carboxylase (GGCX), vitamin K epoxide reductase (VKORC1), and NAD(P)H:quinone oxidoreductase (NQO1). We evaluated the role of these genotype polymorphisms in patients with large-artery atherosclerotic stroke., Methods: In this hospital-based case-control study, 117 patients who were categorized as having large-artery atherosclerotic stroke and 115 age- and gender-matched controls were recruited. Genotyping determination for the GGCX1 (Gln325Arg), NQO1 (Pro187Ser), and VKORC1 (rs9923231) polymorphisms was performed. The associations of genotype with ischemic stroke (IS) risk were examined., Results: A higher genotypic frequency of NQO1 C609T was found in the controls than in the patients, manifesting a 0.47-fold risk reduction in IS (95% CI=0.25-0.87). A tendency toward a reduced IS risk was statistically significant in those subjects who carried a greater number of the NQO1, GGCX, and VKORC1 polymorphisms (aOR=0.58, P(trend)=0.005). The synergistic effect of multiple genes on risk reduction was more significant in a subset of patients who were not alcoholics and who were non-smokers (P<0.05)., Conclusions: Compartmentation of coagulation factor metabolism may account for the preferential role of NQO1, GGCX, and VKORC1 polymorphisms to lower the risk for large-artery atherosclerotic stroke., (Copyright 2010 Elsevier B.V. All rights reserved.)

Background: Hypothetic mechanism of the individual vulnerability to oxidative stress through metabolism of environmental xenobiotics and genotypic polymorphisms has been considered to promote the development of Parkinson's disease (PD). In this case-control study, we determined the role of manganese-containing superoxide dismutase (MnSOD) and NAD(P)H: quinone oxidoreductase 1 (NQO1) genes in PD risk in a population with high prevalence of pesticide exposure., Methods: From southwestern region of Taiwan, we enrolled 153 patients with idiopathic PD and 155 healthy control subjects matched for age, sex and origin. Detailed questionnaires of face-to-face interviews among these subjects were collected. PCR-based restriction fragment length polymorphism (RFLP) assays were used to determine the genotypes of MnSOD (-9 T>C) and NQO1 (609 C>T) genes., Results: Exposure to pesticides associated with PD was significant among patients with an increased odds ratio (OR) of 1.69 (95%CI, 1.07-2.65), and this association remained significant after adjustment for age, sex, and cigarette smoking (aOR=1.68, 95%CI, 1.03-2.76, P=0.023). Considering genetic factors, there were no significant differences in frequencies of both genotypes of MnSOD and NQO1 polymorphisms between PD patients and the control subjects (P>0.05). However, this difference in genotype distribution was significant among subjects who had been exposed to pesticide, with aOR of 2.49 (95%CI, 1.18-5.26, P=0.0072) for MnSOD C allele and aOR of 2.42 (95%CI, 1.16-4.76, P=0.0089) for NQO1 T allele, respectively. Moreover, among subjects exposed to pesticide, the combined MnSOD/NQO1 variant genotype was significantly associated with a 4.09-fold increased risk of PD (95%CI, 1.34-10.64, P=0.0052)., Conclusion: Susceptible variants of MnSOD and NQO1 genes may interact with occupational pesticide exposure to increase PD risk in southwestern Taiwanese.

The reproductive hormone, estrogen, contributes to the development of breast cancer by binding to the estrogen receptor (ER) in the nucleus, triggering cell growth and tumor promotion. In addition to its role in regulating target genes and signaling pathways involved in cell cycle progression, the ER-signaling pathway may regulate the expression of chromatin-remodeling gene, Metastasis-associated 3 (MTA3), or interact with chromatin-remodeling protein, Metastasis-associated 1 (MTA1). The invasion-suppressor gene, E-Cadherin (E-Cad), has recently been identified as a downstream target gene regulated by the ER-MTA3 pathway via the transcriptional repressor, Snail, and the ER-MTA3-Snail-E-Cad pathway has therefore been evoked to explain the clinical observation that ER expression in breast cancer is generally associated with a better clinical outcome. Since E-Cad may play an initiating role during breast tumorigenesis, we hypothesized that this ER-signaling pathway may also determine susceptibility to breast cancer, and examined this in a multigenic case-control study of 468 incident breast cancer patients and 470 healthy controls by genotyping the single nucleotide polymorphisms (SNPs) in five genes (ER, MTA3, Snail, E-Cad, and MTA1) in the ER-signaling pathways. Support for this hypothesis came from the observations that (a) with the exception of Snail, which interacted differently with reproductive risk factors in relation to breast cancer risk, there was a joint effect of the SNPs of these genes and estrogen-related risk factors (age at first full-term pregnancy and obesity, measured by the body mass index) on breast cancer risk (p < 0.05); (b) a trend toward increased risk of developing breast cancer was seen in women harboring a greater number of putative high-risk genotypes of these genes in ER-signaling pathways; (c) this association between risk and the number of putative high-risk genotypes was stronger and more significant in women thought to have experienced higher estrogen level, i.e., obese women; and (d) the risk effect conferred by obesity was only significant in women with a higher number of putative high-risk genotypes of the ER-signaling genes. These epidemiological findings highlight the role of newly identified novel ER-related pathways in breast cancer development and provide a more comprehensive picture of the tumorigenic effect of estrogen in breast cancer development.

Background: Warfarin prevents thromboembolism in patients with prosthetic heart valvular replacement. Cytochrome P4502C9 (CYP2C9) is polymorphic in human and is principally responsible for the metabolism of warfarin. However, known CYP2C9 polymorphisms cannot entirely account for the low dose requirement of warfarin in Chinese-Taiwanese receiving mitral valve replacement. We screened a new polymorphism of CYP2C9 and investigated its role in warfarin sensitivity., Methods: We examined warfarin dose requirements in 239 Chinese-Taiwanese patients who had attended a cardiac surgery clinic in National Taiwan University Hospital. DNA samples were obtained from 106 Chinese-Taiwanese (37 patients and 69 unrelated healthy controls), and healthy control subjects of Caucasians (n=28) and African-Americans (n=28). Four out of those 37 patients were poor metabolizers of warfarin, and their DNA were subjected to sequencing analysis. Moreover, CYP2C9 genotyping analyses were performed using PCR-RFLP analysis. The chi2 test and Fisher's exact test were used to compare the differences of the allelic frequency and genotype. The association between warfarin dose requirement and genetic polymorphism of CYP2C9 was also analysed., Results: The mean daily warfarin dose was 3.11+/-1.62 mg for the maintenance of the international normalized ratio of 2 to 3 in 239 patients. A single nucleotide substitution from G to C was found in this study. This SNP, G-65/C, is in intron 3, 65 base pairs upstream of exon 4. The allelic frequencies of C-65 in healthy controls were 0.125, 0.058 and approximately 0 with respect to African-American, Chinese-Taiwanese and Caucasian, implying inter-ethnic variations of the C-65 allele. In addition, patients who were carrier of either the heterozygous or homozygous C-65 variant received half of the usual warfarin dose., Conclusion: The novel intronic G-65/C mutation appears to be inter-racially different in allelic frequency, and that the anticoagulation was affected in response to warfarin sensitivity in Chinese-Taiwanese patients receiving mitral valve replacement.

Estrogen has been suggested to trigger breast cancer development via an initiating mechanism involving its metabolite, catechol estrogen (CE). To examine this hypothesis, we carried out a multigenic case-control study of 469 incident breast cancer patients and 740 healthy controls to define the role of important genes involved in the different metabolic steps that protect against the potentially harmful effects of CE metabolism. We studied the 3 genes involved in CE detoxification by conjugation reactions involving methylation (catechol-O-methyltransferase, COMT), sulfation (sulfotransferase 1A1, SULT1A1), or glucuronidation (UDP-glucuronosyltransferase 1A1, UGT1A1), one (manganese superoxide dismutase, MnSOD) involved in protection against reactive oxidative species-mediated oxidation during the conversion of CE-semiquinone (CE-SQ) to CE-quinone (CE-Q), and 2 of the glutathione S-transferase superfamily, GSTM1 and GSTT1, involved in CE-Q metabolism. Support for this hypothesis came from the observations that (i) there was a trend toward an increased risk of breast cancer in women harboring a greater number of putative high-risk genotypes of these genes (p < 0.05); (ii) this association was stronger and more significant in those women who were more susceptible to estrogen [no history of pregnancy or older (> or =26 years) at first full-term pregnancy (FFTP)]; and (iii) the risks associated with having one or more high-risk genotypes were not the same in women having experienced different menarche-to-FFTP intervals, being more significant in women having been exposed to estrogen for a longer period (> or =12 years) before FFTP. Furthermore, because CE-Q can attack DNA, leading to the formation of double-strand breaks (DSB), we examined whether the relationship between cancer risk and the genotypic polymorphism of CE-metabolizing genes was modified by the genotypes of DSB repair genes, and found that a joint effect of CE-metabolizing genes and one of the two DSB repair pathways, the homologous recombination pathway, was significantly associated with breast cancer development. Based on comprehensive CE metabolizing gene profiles, our study provides support to the hypotheses that breast cancer can be initiated by estrogen exposure and that increased estrogen exposure confers a higher risk of breast cancer by causing DSB to DNA.