Publications (20)129.19 Total impact
-
Article: Polymorphisms in genes hydroxysteroid-dehydrogenase-17b type 2 and type 4 and endometrial cancer risk.
[show abstract] [hide abstract]
ABSTRACT: Hydroxysteroid-dehydrogenase-17b (HSD17b) genes control the last step in estrogen biosynthesis. The isoenzymes HSD17b2 and HSD17b4 in the uterus preferentially catalyze the conversion of estradiol, the most potent and active form of estrogen, to estrone, the inactive form of estrogen. Endometrial adenocarcinoma is linked to excessive exposure to estrogens. We hypothesized that single nucleotide polymorphisms (SNPs) in genes HSD17b2 and HSD17b4 may alter the enzyme activity, estradiol levels and risk of disease. Pairwise tag SNPs were selected from the HapMap Caucasian database to capture all known common (minor allele frequency >0.05) genetic variation with a correlation of at least 0.80. Forty-eight SNPs were genotyped in the case-control studies nested within the Nurses' Health Study (NHS) (cases=544, controls=1296) and the Women's Health Study (WHS) (cases=130, controls=389). The associations with endometrial cancer were examined using conditional logistic regression to estimate odds ratio and 95% confidence intervals adjusted for known risk factors. Results from the two studies were using fixed effects models. We additionally investigated whether SNPs are predictive of plasma estradiol and estrone levels in the NHS using linear regression. Four intronic SNPs were significantly associated with endometrial cancer risk (p-value<0.05). After adjustment for multiple testing, we did not observe any significant associations between SNPs and endometrial cancer risk or plasma hormone levels. This is the first study to comprehensively evaluate variation in HSD17b2 and HSD17b4 in relation to endometrial cancer risk. Our findings suggest that variation in HSD17b2 and HSD17b4 does not substantially influence the risk of endometrial cancer in Caucasians.Gynecologic Oncology 12/2010; 121(1):54-8. · 3.89 Impact Factor -
Article: Common genetic variation within IGFI, IGFII, IGFBP-1, and IGFBP-3 and endometrial cancer risk.
[show abstract] [hide abstract]
ABSTRACT: The insulin-like growth factor (IGF) pathway plays a critical role in the growth and development of the uterus and is believed to function as a mediator of steroid hormone actions in the endometrium. The local expression of genes encoding IGFs and IGF-binding proteins (IGFBPs) is important in determining IGF bioactivity in the uterus. Genetic variation in key genes within the IGF pathway may influence the rate of cellular proliferation and differentiation in the uterus and ultimately affect the risk of endometrial cancer. Our hypothesis is that variant alleles in key genes involved in the IGF pathway will influence the development of endometrial cancer. We conducted a case-control study nested within the Nurses' Health Study (NHS) and the Women's Health Study (WHS) to investigate the association between forty-four polymorphisms within IGFI, IGFII, IGFBP-1, and IGFBP-3 with endometrial cancer risk using 692 invasive endometrial cancer cases and 1723 matched controls. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the risk of endometrial cancer. We observed an inverse association with IGFII rs3741211 and endometrial cancer risk (OR=0.79 (95% CI: 0.63, 0.99)) and IGFII rs1004446 and endometrial cancer risk (OR=0.80 (95% CI: 0.68, 0.94)). We also observed an inverse association with IGFBP-3 rs2453839 and endometrial cancer risk (OR=0.81 (95%CI: 0.67, 0.98). However, we did not observe any statistically significant associations with the polymorphisms in IGFI and IGFBP1 and endometrial cancer risk. Genetic variation with IGFII and IGFBP-3 may influence endometrial cancer risk in Caucasians. Polymorphisms in IGFI and IGFBP-1 were not associated with endometrial cancer risk, but further research is needed.Gynecologic Oncology 11/2010; 120(2):174-8. · 3.89 Impact Factor -
Article: A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.
[show abstract] [hide abstract]
ABSTRACT: We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.Nature Genetics 10/2010; 42(11):978-84. · 35.53 Impact Factor -
Article: Telomere length and genetic analyses in population-based studies of endometrial cancer risk.
[show abstract] [hide abstract]
ABSTRACT: Telomeres are protective structures at the ends of linear chromosomes, regulated by a host of associated proteins. When telomeres become dysfunctional, genomic instability ensues. The vast majority of cells undergo apoptosis, although a rare cell may survive and become tumorigenic. The authors used conditional logistic regression to examine relative telomere length in peripheral blood leukocytes, genetic variants at telomere maintenance gene loci (TERT, TNKS2, POT1, TERF1, TERF2), and endometrial cancer risk in case-control studies nested within the Nurses' Health Study and the Women's Health Study. Relative telomere length was significantly inversely correlated with body mass index and weight gain since age 18 years. The authors did not observe a relationship between relative telomere length and endometrial cancer risk. Women in the shortest quartile had a multivariate-adjusted odds ratio (OR) of 1.20 (95% confidence interval [95% CI], 0.73-1.96; P for trend = .37) compared with women in the longest quartile. The authors found an elevation in endometrial cancer risk among women carrying at least 1 minor allele of RS2736122 (TERT; OR, 1.18; 95% CI, 1.01-1.38) or RS12412538 (TNKS2; OR, 1.16; 95% CI, 1.00-1.34). Relative telomere length was not associated with endometrial cancer risk. Other aspects of telomere maintenance remain to be explored.Cancer 09/2010; 116(18):4275-82. · 4.77 Impact Factor -
Article: Genetic variation in CYP11A1 and StAR in relation to endometrial cancer risk.
[show abstract] [hide abstract]
ABSTRACT: Together, steroidogenic acute regulator (StAR) and the cholesterol side chain cleavage enzyme (P450scc), which is encoded by CYP11A1, mediate the initial and rate-limiting step in steroidogenesis. Given the role of estrogens in endometrial carcinogenesis, we hypothesized that genetic variation in StAR and CYP11A1 genes may influence endometrial cancer risk. We genotyped four CYP11A1 tagging single nucleotide polymorphisms (SNPs) and two StAR SNPs in endometrial cancer case-control studies nested within the Nurses' Health Study (553 cases and 1339 controls) and the Women's Health Study (137 cases and 411 controls). We calculated odds ratios and 95% confidence intervals using conditional and unconditional logistic regression adjusted for endometrial cancer risk factors to examine the association between SNPs/haplotypes and endometrial cancer. We observed an increased risk for women carrying the variant allele for rs4555110 (odds ratio (OR)=1.3, 95% confidence interval (CI)=1.1-1.7), rs3825944 (OR=1.4, 95% CI=1.1-1.8), and rs7173655 (OR=1.3, 95% CI=1.0-1.7) CYP11A1 SNPs but no significant associations with CYP11A1 haplotypes. CYP11A1 SNPs were not predictive of plasma estradiol levels. We observed no associations between StAR SNPs and endometrial cancer risk. Genetic variants in CYP11A1 may influence endometrial cancer risk or may be markers for causal variants elsewhere. Polymorphisms in StAR are not associated with endometrial cancer risk, but further research is needed.Gynecologic Oncology 03/2010; 117(2):255-9. · 3.89 Impact Factor -
Article: A prospective study of androgen levels, hormone-related genes and risk of rheumatoid arthritis.
[show abstract] [hide abstract]
ABSTRACT: Rheumatoid arthritis (RA) is more common in females than males and sex steroid hormones may in part explain this difference. We conducted a case-control study nested within two prospective studies to determine the associations between plasma steroid hormones measured prior to RA onset and polymorphisms in the androgen receptor (AR), estrogen receptor 2 (ESR2), aromatase (CYP19) and progesterone receptor (PGR) genes and RA risk. We genotyped AR, ESR2, CYP19, PGR SNPs and the AR CAG repeat in RA case-control studies nested within the Nurses' Health Study (NHS), NHS II (449 RA cases, 449 controls) and the Women's Health Study (72 cases, and 202 controls). All controls were matched on cohort, age, Caucasian race, menopausal status, and postmenopausal hormone use. We measured plasma dehydroepiandrosterone sulfate (DHEAS), testosterone, and sex hormone binding globulin in 132 pre-RA samples and 396 matched controls in the NHS cohorts. We used conditional logistic regression models adjusted for potential confounders to assess RA risk. Mean age of RA diagnosis was 55 years in both cohorts; 58% of cases were rheumatoid factor positive at diagnosis. There was no significant association between plasma DHEAS, total testosterone, or calculated free testosterone and risk of future RA. There was no association between individual variants or haplotypes in any of the genes and RA or seropositive RA, nor any association for the AR CAG repeat. Steroid hormone levels measured at a single time point prior to RA onset were not associated with RA risk in this study. Our findings do not suggest that androgens or the AR, ESR2, PGR, and CYP19 genes are important to RA risk in women.Arthritis research & therapy 07/2009; 11(3):R97. · 4.27 Impact Factor -
Article: Genetic variations in UGT1A1 and UGT2B7 and endometrial cancer risk.
[show abstract] [hide abstract]
ABSTRACT: Uridine diphosphate-glucuronosyltransferases (UGTs) are a family of phase II-metabolizing enzymes involved in glucuronic acid conjugation of sex steroid hormones. UGT1A1 and UGT2B7 are expressed in the uterus and involved in the conjugation and elimination of estrogens. Chronic exposure to estrogens is associated with endometrial cancer. Functional polymorphisms have been identified in UGT1A1 and UGT2B7. We hypothesized that these variants may be associated with endometrial cancer risk. We conducted a case-control study nested within the Nurses' Health Study and the Women's Health Study to investigate the associations between five polymorphisms and endometrial cancer risk using 593 invasive endometrial cancer cases and 1545 controls. We did observe the suggestion of an inverse association with homozygote variant carriers of UGT1A1*28 and endometrial cancer risk. We did not observe significant associations between individual single nucleotide polymorphisms and UGT1A1 haplotypes and endometrial cancer risk. Our data suggest that these UGT polymorphisms do not contribute significantly to endometrial cancer risk.Pharmacogenetics and Genomics 04/2009; 19(3):239-43. · 3.48 Impact Factor -
Article: Two estrogen-related variants in CYP19A1 and endometrial cancer risk: a pooled analysis in the Epidemiology of Endometrial Cancer Consortium.
[show abstract] [hide abstract]
ABSTRACT: Common variants in CYP19A1 (the A alleles of rs749292 and rs727479) have been associated with a 10% to 20% increase in circulating estrogen levels in postmenopausal women. We hypothesized that the presence of one or both A alleles in these single nucleotide polymorphisms (SNP) is associated with increased endometrial cancer risk. We tested this hypothesis in a large pooled analysis of 4,998 endometrial cancer cases and 8,285 controls from 10 studies in the Epidemiology of Endometrial Cancer Consortium. The majority of women (>66%) were whites, with smaller proportions of other races and ethnic groups (blacks, Asians, and Latinas) also included in this pooled analysis. Unconditional logistic regression was used to model the association between SNPs/haplotypes and endometrial cancer risk. Carrying the A allele of either of these SNPs was associated with an increased risk of endometrial cancer, with pooled odds ratios per allele of 1.14, 95% confidence interval of 1.09-1.21, and P = 7.1 x 10(-7) for rs749292, and odds ratio per allele of 1.08, 95% confidence interval of 1.02-1.14, and P = 0.009 for rs727479. For rs749292, these associations were generally stronger among women age >or=55 years. For both SNPs, risk increased with increasing body mass index, and for rs727479, this pattern seemed stronger among women age >or=55 years (P interaction = 0.007). The combination of A alleles in the two SNPs, either by direct count or by haplotype analysis, did not increase risk above that observed for the individual SNPs. Our study provides evidence that CYP19A1 genetic variation influences susceptibility to endometrial cancer, particularly among older and obese women.Cancer Epidemiology Biomarkers & Prevention 01/2009; 18(1):242-7. · 4.12 Impact Factor -
Article: Novel breast cancer risk alleles and endometrial cancer risk.
[show abstract] [hide abstract]
ABSTRACT: Genome-wide association studies have identified several novel risk alleles for breast cancer. We hypothesized that genetic variants that are associated with breast cancer, a hormone-related disease, would also be associated with endometrial cancer, another hormone-related disease. We conducted a case-control study nested within the Nurses' Health Study and the Women's Health Study to investigate the associations between these 7 newly identified risk alleles for breast cancer and endometrial cancer risk using 692 invasive endometrial cancer cases and 1,723 matched controls. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the risk of endometrial cancer. In contrast to the breast cancer findings, we did not observe an increased risk of endometrial cancer. We observed an inverse association among rs2981582 (FGFR2) variant carriers [OR= 0.75 (95% CI: 0.60-0.95)]. We also observed a nonsignificant inverse association with rs889312 (MAP3K1) variant carriers [OR = 0.85 (95% CI: 0.68-1.05)] and rs1219648 (FGFR2) variant carriers [OR= 0.86 (95% CI: 0.69-1.06) and endometrial cancer risk. We did not observe associations with the other single nucleotide polymorphisms (SNPs) and endometrial cancer risk. Replication studies investigating these polymorphisms and endometrial cancer risk are warranted. However, our findings do suggest the potential importance of biological differences between endometrial and breast cancer with respect to the genes identified in the scans. The molecular mechanisms underlying these differences remain to be defined.International Journal of Cancer 10/2008; 123(12):2961-4. · 5.44 Impact Factor -
Article: MDM2 SNP309 is associated with endometrial cancer risk.
[show abstract] [hide abstract]
ABSTRACT: Mouse double-minute 2 homologue (MDM2) is a key negative regulator of p53, a tumor suppressor gene that initiates cell cycle arrest and apoptosis in response to DNA damage and other cellular stresses. A T > G polymorphism found in the promoter region of MDM2 (SNP309) increases MDM2 expression and thereby attenuates p53 activity. We genotyped the MDM2 polymorphism SNP309 in endometrial cancer case-control studies nested within the Nurses' Health Study (454 cases and 1,132 controls) and the Women's Health Study (137 cases and 411 controls). Due to a significant difference in genotype distribution by ethnicity, we restricted our analyses to Caucasians. We calculated odds ratios and 95% confidence intervals using conditional and unconditional logistic regression adjusted for age at menarche, parity and age at first birth, postmenopausal hormone use at diagnosis, age at menopause and menopausal status at diagnosis, first-degree family history of colon cancer, body mass index at diagnosis, and cigarette smoking status at diagnosis. Women with a heterozygous genotype had no greater risk whereas those with a homozygous variant genotype had a greater risk than women with a wild-type genotype for the MDM2 SNP309 (covariate-adjusted odds ratio, 1.87; 95% confidence interval, 1.29-2.73) for endometrial cancer. We observed no association between age at diagnosis and genotype. Women carrying two copies of the MDM2 SNP309 variant may be at greater risk of endometrial cancer.Cancer Epidemiology Biomarkers & Prevention 04/2008; 17(4):983-6. · 4.12 Impact Factor -
Article: Telomere length and risk of Parkinson's disease.
[show abstract] [hide abstract]
ABSTRACT: We investigated whether telomere length was associated with the risk of Parkinson's disease (PD) in a case-control study (96 cases and 172 age-matched controls) nested within the Health Professionals Follow-up Study. Relative ratio of telomere repeat copy number to single-gene copy number in peripheral blood leukocytes was determined by quantitative real time PCR. Men with shorter telomeres had a lower PD risk (multivariate adjusted relative risk for the lowest vs. the highest quartile 0.33; 95% confidence interval: 0.12-0.90). Our results suggest that, contrary to telomere attrition observed in several aging-related diseases, shorter telomeres are not associated with an increased risk of PD.Movement Disorders 02/2008; 23(2):302-5. · 4.51 Impact Factor -
Article: Telomere length and risk of Parkinson's disease
[show abstract] [hide abstract]
ABSTRACT: We investigated whether telomere length was associated with the risk of Parkinson's disease (PD) in a case-control study (96 cases and 172 age-matched controls) nested within the Health Professionals Follow-up Study. Relative ratio of telomere repeat copy number to single-gene copy number in peripheral blood leukocytes was determined by quantitative real time PCR. Men with shorter telomeres had a lower PD risk (multivariate adjusted relative risk for the lowest vs. the highest quartile 0.33; 95% confidence interval: 0.12–0.90). Our results suggest that, contrary to telomere attrition observed in several aging-related diseases, shorter telomeres are not associated with an increased risk of PD. © 2007 Movement Disorder SocietyMovement Disorders 01/2008; 23(2):302 - 305. · 4.51 Impact Factor -
Article: Cytochrome P450 1A1, cigarette smoking, and risk of endometrial cancer (United States).
[show abstract] [hide abstract]
ABSTRACT: Cytochrome P450 1A1 (CYP1A1) is involved in the metabolism of estradiol and the activation of polycyclic aromatic hydrocarbons found in tobacco products. Polymorphic variation in CYP1A1 activity may modify susceptibility to endometrial cancer through the oxidative metabolism of estradiol and the activation of tobacco-smoke constituents. We prospectively evaluated the associations between three common CYP1A1 polymorphisms and endometrial cancer risk, as well as the potential modification of these associations by cigarette smoking, in a case-control study nested within the Nurses' Health Study. We investigated the MspI restriction-site polymorphism, a C --> A transversion at nucleotide 4887 (Thr461Asn) and a A --> G transition at nucleotide 4889 (Ile462Val) among 456 women with endometrial cancer and 1,134 matched controls. We used conditional logistic regression to calculate the adjusted odds ratios (OR) and 95% confidence intervals (CI) to quantify the risk of endometrial cancer among subjects who had at least one variant allele compared with that of subjects homozygous for the wild-type allele. We did not observe any statistically significant associations between the MspI, Thr461Asn or Ile462Val polymorphisms and endometrial cancer risk or any significant effect modification by cigarette-smoking status. These data suggest that these three polymorphisms are not important in determining genetic susceptibility to endometrial cancer, although larger sample sizes are needed to confirm these findings.Cancer Causes and Control 12/2007; 18(10):1123-30. · 2.88 Impact Factor -
Article: Telomere length, cigarette smoking, and bladder cancer risk in men and women.
[show abstract] [hide abstract]
ABSTRACT: Truncated telomeres are among the defining characteristics of most carcinomas. Given the role of telomeres in tumorigenesis, we reasoned that constitutionally short telomeres might be associated with an increased risk of bladder cancer. Using quantitative real-time PCR, we measured relative telomere length in bladder cancer cases and healthy controls and evaluated the association between telomere length, cigarette smoking, and bladder cancer risk in a case-control study nested within the Health Professionals Follow-up Study and a case-control study nested within the Nurses' Health Study. Telomeres were significantly shorter in bladder cancer cases (n = 184) than in controls (n = 192). The mean relative telomere length in cases was 0.23 (SD, 0.16) versus 0.27 (SD, 0.15) in controls (P = 0.001). The adjusted odds ratio for bladder cancer was 1.88 (95% confidence interval, 1.05, 3.36) for individuals in the quartile with the shortest telomeres as compared with individuals in the quartile with the longest telomeres (P(trend) = 0.006). We observed a statistically significant difference in telomere length among men and women (P < 0.001); however, the interaction between gender, telomere length, and bladder cancer risk was not significant. We also observed a significant difference in telomere length across categories of pack-years of smoking (P = 0.01). These findings suggest that truncated telomeres are associated with an increased risk of bladder cancer.Cancer Epidemiology Biomarkers & Prevention 04/2007; 16(4):815-9. · 4.12 Impact Factor -
Article: Androgen receptor polymorphisms and endometrial cancer risk.
[show abstract] [hide abstract]
ABSTRACT: The androgen receptor (AR) gene is a transcription factor responsible for mediating the physiological effects of androgens. Evidence suggests that androgens and the androgen receptor are involved in uterine cell proliferation. A polymorphic CAG repeat in exon 1 of the AR gene encodes a polyglutamine tract that is inversely correlated with the transcriptional activity of this gene. We assessed the association between the functional CAG repeat polymorphism and AR haplotypes and the risk of endometrial cancer in two nested case-control studies within the Nurses' Health Study (n = 222 cases, 666 controls) and the Women's Health Study (n = 137 cases, 411 controls) using conditional and unconditional logistic regression. Associations between AR CAG repeat polymorphism and endometrial cancer risk were similar in the 2 case-control studies. In the pooled analysis, women with an average repeat allele > or =22 repeats compared to <22 repeats were at a statistically significant decreased risk of endometrial cancer (odds ratio (OR) = 0.76; 95% confidence interval (CI), 0.59-0.98). Women with one or two long alleles (> or =27 repeats) compared to both alleles <22 repeats were also at a statistically significant decreased risk (OR = 0.60; 95% CI, 0.36-0.99). We observed a modest yet statistically significant association for each one unit increase in the average repeat length and endometrial cancer risk (OR = 0.94; 95% CI, 0.88-1.00). Associations for the AR CAG average repeat length and endometrial cancer risk differed by menopausal status (p = 0.02). No significant associations between the AR haplotypes and endometrial cancer risk were observed. Our findings suggest that an increasing number of functional CAG repeats may be associated with endometrial carcinogenesis because of AR's reduced ability to recruit coregulators and other transcriptional components. (supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html).International Journal of Cancer 04/2006; 118(5):1261-8. · 5.44 Impact Factor -
Article: Hormonal and reproductive factors and the risk of bladder cancer in women.
[show abstract] [hide abstract]
ABSTRACT: Gender and cigarette smoking are among the most consistent predictors of bladder cancer risk. After adjustment for known risk factors, an excess risk remains for males, suggesting that other factors may be responsible for the gender differences. Given limited data on hormonal or reproductive factors and bladder cancer risk, the authors examined these factors among women in the US Nurses' Health Study cohort. During 26 years of follow-up (1976-2002), 336 incident cases of bladder cancer were diagnosed. Cox proportional hazards models were used to estimate incidence rate ratios and 95% confidence intervals between hormonal and reproductive factors and bladder cancer risk. Postmenopausal women, compared with premenopausal women, were at increased risk (incidence rate ratio = 1.93, 95% confidence interval: 0.99, 3.78). For postmenopausal women, early age at menopause (</=45 years) compared with late age at menopause (>/=50 years) was associated with a statistically significant increased risk of bladder cancer (incidence rate ratio = 1.63, 95% confidence interval: 1.20, 2.23). The association between age at menopause and bladder cancer risk was modified by cigarette smoking status (p for interaction = 0.01). The authors observed no significant associations of age at menarche, parity, age at first birth, and exogenous hormone use with bladder cancer risk. Findings suggest that menopausal status and age at menopause may play a role in modifying bladder cancer risk among women.American Journal of Epidemiology 02/2006; 163(3):236-44. · 5.22 Impact Factor -
Article: Polymorphisms in GSTT1, GSTM1, NAT1 and NAT2 genes and bladder cancer risk in men and women.
[show abstract] [hide abstract]
ABSTRACT: Cigarette smoking is an established risk factor for bladder cancer. Epidemiological and biological data suggest that genetic polymorphisms in activating and detoxifying enzymes may play a role in determining an individual's susceptibility to bladder cancer in particular when in combination with specific environmental exposures such as cigarette smoking. N-acetyltransferase (NAT) enzymes, NAT1 and NAT2, are involved in the activation and detoxification of tobacco smoke constituents. Polymorphisms in these genes alter the ability of these enzymes to metabolize carcinogens, as certain allelic combinations result in a slow or rapid acetylation phenotype. Glutathione S-transferases (GSTs) also detoxify tobacco smoke constituents, and polymorphisms within the GSTM1 and GSTT1 genes can result in a complete lack of enzyme activity. We assessed the association between common polymorphisms identified in the GSTM1, GSTT1, NAT1, and NAT2 genes and the risk of bladder cancer in two nested case-control studies within the Nurses' Health Study (n = 78 female cases, 234 female controls) and the Health Professionals' Follow-up Study (n = 139 male cases, 293 male controls). We also evaluated whether cigarette smoking modified the associations of the genotypes and bladder cancer risk in men and women. Overall, we observed no statistically significant associations between the polymorphisms and bladder cancer risk among men and women, although given our sample size, we had limited power to detect small to moderate effects. There was however the suggestion of an increased risk among female ever smokers with the NAT2 slow genotype and an increased risk in male never smokers with the GSTM1 null genotype. In summary, these prospective results are consistent with previous literature supporting associations between bladder cancer and the NAT2 slow acetylation and the GSTM1 null genotypes.BMC Cancer 02/2006; 6:239. · 3.01 Impact Factor -
Article: Association between catechol-O-methyltransferase and phobic anxiety.
[show abstract] [hide abstract]
ABSTRACT: The authors assessed the association between the catechol-O-methyltransferase (COMT) Val158Met polymorphism and scores on the phobic anxiety scale of the Crown-Crisp Experimental Index. A total of 1,234 women completed the Crown-Crisp Experimental Index phobic anxiety scale and were genotyped for the COMT polymorphism. The authors used unconditional logistic regression to compute odds ratios and 95% confidence intervals (CIs) to evaluate the association between the COMT genotype and phobic anxiety. The mean scores for the three genotypes were statistically significantly different. Compared to the COMT Met/Met genotype, the age-adjusted odds ratio for scoring >/=6 compared to scoring 0 or 1 were 1.15 (95% CI=0.71-1.85) and 1.99 (95% CI=1.17-3.40) for the COMT Val/Met and COMT Val/Val genotypes, respectively; a significant gene dosage effect was observed. Our results suggest that the functional COMT polymorphism is associated with the development of phobic anxiety.American Journal of Psychiatry 10/2004; 161(9):1703-5. · 12.54 Impact Factor -
Article: Cytochrome P450 1B1 and catechol-O-methyltransferase polymorphisms and endometrial cancer susceptibility.
[show abstract] [hide abstract]
ABSTRACT: Estrogen production and metabolism play critical roles in the development and pathogenesis of endometrial carcinoma. Cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) are two key enzymes in the estrogen metabolism pathway that result in the hydroxylation and conjugation of estradiol, respectively. We evaluated the association between the CYP1B1 Leu432Val and CYP1B1 Asn453Ser polymorphisms and the COMT Val158Met polymorphism and invasive endometrial cancer risk in a case-control study nested within the Nurses' Health Study (n = 222 cases, 666 controls). We also evaluated whether body mass index (BMI), postmenopausal hormone (PMH) use and cigarette smoking modified the associations of the CYP1B1 and COMT genotypes and endometrial cancer risk. Conditional logistic regression was used to calculate the adjusted odds ratios (OR) and 95% confidence intervals (CI) to quantify the risk of endometrial cancer among subjects who had at least one variant allele compared with subjects who were homozygous for the wild-type allele. Carriers of the CYP1B1 Ser allele had a statistically significant decreased risk of endometrial cancer (OR = 0.62; 95% CI, 0.42-0.91); there was no significant association between the CYP1B1 Val allele and endometrial cancer risk (OR = 1.10; 95% CI, 0.75-1.59). Compared with the COMT Val/Val wildtype genotype, the adjusted OR of endometrial cancer for women with the COMT Val/Met or COMT Met/Met genotype was 0.96 (95% CI, 0.65-1.43). We did not observe any effect modification by BMI, PMH use and cigarette smoking for the CYP1B1 and COMT genotypes. Our data suggest, that the CYP1B1 Ser allele may decrease endometrial cancer risk by altering the production of catechol estrogens. However, further studies are warranted to elucidate the role of CYP1B1 in endometrial cancer.Carcinogenesis 05/2004; 25(4):559-65. · 5.70 Impact Factor -
Article: The functional UGT1A1 promoter polymorphism decreases endometrial cancer risk.
[show abstract] [hide abstract]
ABSTRACT: UDP-glucuronosyltransferase (UGT) 1A1 is involved in the inactivation of estradiol (E(2)) and its oxidized metabolites. These metabolites have been shown to contribute to the development of endometrial cancer in animal studies. Thus UGT1A1 represents a candidate gene in endometrial carcinogenesis. In this study, we established the substrate specificity of UGT1A1 for E(2) and its 2- and 4-hydroxylated metabolites. Intrinsic clearances indicated that UGT1A1 had a preference for the glucuronidation of 2-hydroxyestradiol, a metabolite associated with antiproliferative activity. Expression analysis demonstrated that UGT1A1 is present in the nonmalignant endometrium. Subsequently, we sought to determine whether the common UGT1A1 promoter allele, UGT1A1*28 [A(TA)(7)TAA], which decreases gene transcription, was associated with endometrial cancer risk in a case-control study nested within the Nurses' Health Study (222 cases, 666 matched controls). Conditional logistic regression demonstrated a significant inverse association with the UGT1A1*28 allele and endometrial cancer risk. Compared with women homozygous for the UGT1A1*1 [A(TA)(6)TAA] allele, the adjusted odds ratio (OR) was 0.81 [95% confidence interval (CI), 0.56-1.16] for the UGT1A1*1/*28 genotype and 0.40 (95% CI, 0.21-0.75) for the homozygous UGT1A1*28 genotype (P(trend) = 0.007). There was a suggestion of an interaction by menopausal status [OR = 0.39 (95% CI, 0.18-0.85) for premenopausal women and OR = 0.79 (95% CI, 0.55-1.13) for postmenopausal women who carry the UGT1A1*28 allele (P(interaction) = 0.05)]. These observations suggest that lower expression of UGT1A1 decreases the risk of endometrial cancer by reducing the excretion of 2-hydroxyestradiol, the antiproliferative metabolite of E(2), in the endometrium.Cancer Research 03/2004; 64(3):1202-7. · 7.86 Impact Factor
Top co-authors
Top Journals
Institutions
-
2004–2010
-
Harvard University
- • Department of Epidemiology
- • Department of Medicine Brigham and Women's Hospital
Boston, MA, USA -
University Laval
Québec, Quebec, Canada
-
