Biomedical subjects

John D Potter

Publications and source records attributed to John D Potter.

At least 73 records · Page 4Linked to original sources

PubMed2004

Methylenetetrahydrofolate reductase genotype affects risk of relapse after hematopoietic cell transplantation for chronic myelogenous leukemia.

PURPOSE: Methylenetetrahydrofolate reductase (MTHFR) directs intracellular folate toward homocysteine metabolism and away from nucleotide synthesis. Two common MTHFR polymorphisms, C677T and A1298C, are associated with reduced enzyme activity. We evaluated the association of these polymorphisms with risk of relapse and bcr-abl mRNA transcript detection among 336 Caucasian patients who underwent allogeneic hematopoietic cell transplantation for chronic myelogenous leukemia. EXPERIMENTAL DESIGN: Data on the transplant course and folate-related exposures were abstracted from medical records. MTHFR C677T and A1298C genotypes were determined using polymerase chain reaction/restriction fragment length polymorphism and TaqMan assays. Qualitative bcr-abl mRNA testing was conducted using a two-step reverse transcription-polymerase chain reaction assay. Cox regression analysis was used to assess the association between MTHFR genotypes and time to relapse and bcr-abl mRNA detection. RESULTS: A statistically significant decreased risk of relapse was observed in patients with the variant A1298C genotype [1298AC, hazard ratio (HR)=0.48 and 95% confidence interval (CI)=0.26-0.88; 1298CC, HR=0.28 and 95% CI=0.09-0.84; P-trend <0.01). For the joint C677T/A1298C genotype, variant genotypes were associated with a decreased risk of relapse when compared with the wild-type 677CC/1298AA genotype. This risk was lowest for the 677CC/1298CC genotype (HR, 0.23; 95% CI, 0.08-0.72). MTHFR genotypes were not associated with bcr-abl transcript detection. CONCLUSIONS: These findings suggest that individuals with the 677CC/1298AA genotype are at higher risk of relapse after hematopoietic cell transplantation and that the balance of intracellular folate metabolites available for nucleotide synthesis (regulated by the relative activity of the MTHFR enzyme) may affect the progression from bcr-abl positivity to clinical relapse.

Adolescent↗

PubMed2004

XRCC1 and glutathione-S-transferase gene polymorphisms and susceptibility to radiotherapy-related malignancies in survivors of Hodgkin disease.

BACKGROUND: One of the most serious late effects of treatment for childhood cancer is the occurrence of subsequent malignancy. Survivors of Hodgkin disease (HD), in particular, have been shown to be at high risk of subsequent malignancy, the occurrence of which has been associated strongly with exposure to radiotherapy. METHODS: In the current study, the authors investigated the association between polymorphisms in 3 genes--glutathione-S-transferase M1 (GSTM1), glutathione-S-transferase T1 (GSTT1), and XRCC1, with roles in protection from a variety of DNA-damaging agents-and the risk of subsequent malignancy in 650 survivors of HD enrolled in the Childhood Cancer Survivor Study who had received radiotherapy. RESULTS: Individuals lacking GSTM1 but not GSTT1 were at increased risk of any subsequent malignancy (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.0-2.3), and for subsequent cancer within the radiation field (OR, 1.4; 95% CI, 0.9-2.1). A nonsignificant increased risk of thyroid carcinoma was observed in individuals lacking either GSTM1 (OR, 2.9; 95% CI, 0.8-10.9) or GSTT1 (OR, 3.7; 95% CI, 0.6-23.5). Individuals having the genotype of the arginine/glutamine polymorphism at codon 399 in the XRCC1 gene (R399) showed a nonsignificant increased risk of breast carcinoma compared with those without (OR, 1.4; 95% CI, 0.7-2.7), and a nonsignificant decreased risk against a subsequent thyroid carcinoma (OR, 0.6; 95% CI, 0.2-1.6). No differences in genotype frequencies were observed between survivors with basal cell carcinoma when compared with survivors without a subsequent cancer. CONCLUSIONS: These data illustrated the potential value of incorporating the collection of genomic DNA in longitudinal cohort studies of populations with well defined, potentially carcinogenic exposures. Evaluation of additional genetic polymorphisms in this cohort may help define genes that influence individual sensitivity to radiotherapy.

Adolescent↗

PubMed2004

Nutrition and physical activity and chronic disease prevention: research strategies and recommendations.

A shortage of credible information exists on practical dietary and physical activity patterns that have potential to reverse the national obesity epidemic and reduce the risk of major cancers and other chronic diseases. Securing such information is a challenging task, and there is considerable diversity of opinion concerning related research designs and priorities. Here, we put forward some perspectives on useful methodology and infrastructure developments for progress in this important area, and we list high-priority research topics in the areas of 1) assessment of nutrient intake and energy expenditure; 2) development of intermediate outcome biomarkers; 3) enhancement of cohort and cross-cultural studies; and 4) criteria for and development of full-scale nutrition and physical activity intervention trials.

Biomarkers↗

PubMed2004

Dairy foods, calcium, and colorectal cancer: a pooled analysis of 10 cohort studies.

BACKGROUND: Studies in animals have suggested that calcium may reduce the risk of colorectal cancer. However, results from epidemiologic studies of intake of calcium or dairy foods and colorectal cancer risk have been inconclusive. METHODS: We pooled the primary data from 10 cohort studies in five countries that assessed usual dietary intake by using a validated food frequency questionnaire at baseline. For most studies, follow-up was extended beyond that in the original publication. The studies included 534 536 individuals, among whom 4992 incident cases of colorectal cancer were diagnosed between 6 and 16 years of follow-up. Pooled multivariable relative risks for categories of milk intake and quintiles of calcium intake and 95% confidence intervals (CIs) were calculated. All statistical tests were two-sided. RESULTS: Milk intake was related to a reduced risk of colorectal cancer. Compared with the lowest category of intake (<70 g/day), relative risks of colorectal cancer for increasing categories (70-174, 175-249, and > or =250 g/day) of milk intake were 0.94 (95% CI = 0.86 to 1.02), 0.88 (95% CI = 0.81 to 0.96), and 0.85 (95% CI = 0.78 to 0.94), respectively (P(trend)<.001). Calcium intake was also inversely related to the risk of colorectal cancer. The relative risk for the highest versus the lowest quintile of intake was 0.86 (95% CI = 0.78 to 0.95; P(trend) =.02) for dietary calcium and 0.78 (95% CI = 0.69 to 0.88; P(trend)<.001) for total calcium (combining dietary and supplemental sources). These results were consistent across studies and sex. The inverse association for milk was limited to cancers of the distal colon (P(trend)<.001) and rectum (P(trend) =.02). CONCLUSION: Higher consumption of milk and calcium is associated with a lower risk of colorectal cancer.

Adenoma↗

PubMed2004

Effect of exercise on serum estrogens in postmenopausal women: a 12-month randomized clinical trial.

Elevated circulating estrogens and a sedentary lifestyle increase risk for breast cancer. The effect of exercise on circulating estrogens in sedentary postmenopausal women is unknown. The objective of this study was to examine the effects of a 12-month moderate-intensity exercise intervention on serum estrogens. We randomly assigned 173 sedentary, overweight (body mass index > 24.0 kg/m(2), body fat > 33%), postmenopausal women, ages 50-75 years, not using hormone therapy, living in the Seattle, Washington, area for the next year, and willing to be randomly assigned to an exercise intervention or stretching control group. The exercise intervention included facility and home-based exercise (45 min, 5 days/week moderate intensity sports/recreational exercise). A total of 170 (98.3%) women completed the study with exercisers averaging 171 min/week of exercise. After 3 months, exercisers experienced declines in estrone, estradiol, and free estradiol of 3.8, 7.7, and 8.2%, respectively, versus no change or increased concentrations in controls (P = 0.03, 0.07, and 0.02, respectively). At 12 months, the direction of effect remained the same, although the differences were no longer statistically significant. The effect was limited to women who lost body fat: women whose percentage of body fat [by dual energy x-ray absortiometry (DEXA)] decreased by >/==" BORDER="0">2% had statistically significant (comparing exercisers versus controls) decreases at 12 months of 11.9, 13.7, and 16.7% for serum estrone, estradiol, and free estradiol, respectively. We concluded that a 12-month moderate-intensity exercise intervention in postmenopausal women resulted in significant decreases in serum estrogens. The association between increased physical activity and reduced risk for postmenopausal breast cancer may be partly explained by effects on serum estrogens.

Aged↗

PubMed2004

Predictors of oral mucositis in patients receiving hematopoietic cell transplants for chronic myelogenous leukemia.

PURPOSE: Oral mucositis is a nearly universal and often severe complication following hematopoietic cell transplantation (HCT). The objective of this study was to evaluate factors predicting oral mucositis severity among 133 patients undergoing allogeneic HCT for chronic myelogenous leukemia. PATIENTS AND METHODS: All patients were transplanted between 1992 and 1999, were >or= 18 years of age, received either cyclophosphamide/total-body irradiation (TBI) or busulfan/cyclophosphamide conditioning regimens, and received four doses of methotrexate for graft-versus-host disease prophylaxis post-transplant. Oral mucositis was measured by a trained examiner every 2 to 3 days using the Oral Mucositis Index (OMI). Multiple linear regression analysis was used to identify predictors of mean OMI during days 6 to 12, 1 to 18, and the maximum OMI score between days 1 to 18. RESULTS: TBI containing conditioning regimens, body mass index >or= 25, and methylenetetrahydrofolate reductase 677 TT genotype were found to be predictive of higher mean OMI scores (P <.05). Pretransplant multivitamin supplement use was associated with lower mean OMI scores compared to those who did not use supplements. Smoking status, race, pretransplant treatment with interferon-alfa or hydroxyurea, and patient/donor ABO compatibility were not associated with mean OMI scores. CONCLUSION: Patients who are scheduled to receive conditioning regimens containing TBI, have a pretransplant body mass index >or= 25, or carry the methylenetetrahydrofolate reductase 677 TT genotype should be considered at greater risk of developing oral mucositis following HCT. Future studies should investigate whether multivitamin supplementation before HCT could reduce mucositis severity.

Adolescent↗

PubMed2004

TGFbeta1 polymorphism (L10P) and risk of colorectal adenomatous and hyperplastic polyps.

BACKGROUND: Transforming growth factor-beta1 (TGFbeta1) is a multifunctional signalling molecule with a wide array of roles. Animal experiments suggest that TGFbeta1 plays a biphasic role in carcinogenesis by protecting against the early formation of benign epithelial growths, but promoting malignant transformation of those growths that do develop. A polymorphism in the signal peptide sequence of the TGFbeta1 gene (L10P) has been associated with increased levels of plasma TGFbeta1 in individuals with the P allele. METHODS: We investigated whether this polymorphism was associated with the risk of colorectal adenomatous or hyperplastic polyps in a case-control study of individuals from Minnesota. Risk of colorectal polyps was evaluated separately for individuals with adenomatous polyps (n = 513) and hyperplastic polyps (n = 191) relative to polyp-free controls (n = 606) using logistic regression analysis. RESULTS: No overall association was seen between the L10P polymorphism and risk of colorectal adenomatous polyps. The age- and sex-adjusted odds ratios (OR) of developing colorectal hyperplastic polyps were 1.0 (95% CI: 0.7, 1.4) and 0.7 (95% CI: 0.4, 1.1) for individuals with the LP and PP genotypes, respectively, compared with individuals with the LL genotype. When stratified by smoking, evidence for a decreased risk of hyperplastic polyps associated with the P allele was seen only among ever smokers (P for trend = 0.05). CONCLUSIONS: Whereas adenoma risk did not vary by TGFbeta1 L10P genotype, these results suggest that the L10P variant allele may have a protective role in the development of colorectal hyperplastic polyps, possibly consistent with its role as an inhibitor of epithelial growths.

Adenomatous Polyps↗

PubMed2004

Marsupial BRCA1: conserved regions in mammals and the potential effect of missense changes.

More than half of the reported missense changes in the breast cancer susceptibility protein BRCA1 occur in exon 11, but none has been clearly identified as disease associated and only 28 are designated 'probable' neutral polymorphisms. Previously, in a comparison of sequences from 57 eutherian mammal species, we found seven 'highly conserved regions' between amino acids 282 and 1103, and identified 38 missense changes as likely to disrupt gene function. These conserved regions were also present in birds and amphibians and included only six of the mutations predicted to affect function. In this new analysis, we hypothesized that using 37 ancestral sequences derived from the 57 GenBank sequences and including eight marsupial sequences would allow us to identify regions unique to mammals and refine our predictions of disease-associated missense changes. We identified 13 conserved regions, three of which appear to be unique to mammals, and 21 likely disease-associated missense changes, 11 of which occur in conserved regions. Seven regions identified in this analysis, including the three found only in mammalian sequences, and nine missense changes predicted to affect function are in the putative STAT1-interaction domain, suggesting that the role of STAT1 in immune response is important to mammary function. The reduction in the number of missense changes predicted to be disease associated and the identification of conserved regions specific to mammals can facilitate the further study of the role of missense changes in BRCA1-associated breast cancers.

Amino Acid Sequence↗

PubMed2004

Antibiotic use in relation to the risk of breast cancer.

CONTEXT: Use of antibiotics may be associated with risk of breast cancer through effects on immune function, inflammation, and metabolism of estrogen and phytochemicals; however, clinical data on the association between antibiotic use and risk of breast cancer are sparse. OBJECTIVE: To examine the association between use of antibiotics and risk of breast cancer. DESIGN, SETTING, AND PARTICIPANTS: Case-control study among 2266 women older than 19 years with primary, invasive breast cancer (cases) enrolled in a large, nonprofit health plan for at least 1 year between January 1, 1993, and June 30, 2001, and 7953 randomly selected female health plan members (controls), frequency-matched to cases on age and length of enrollment. Cases were ascertained from the Surveillance, Epidemiology, and End Results cancer registry. Antibiotic use was ascertained from computerized pharmacy records. MAIN OUTCOME MEASURE: Association between extent of antibiotic use and risk of breast cancer. RESULTS: Increasing cumulative days of antibiotic use were associated with increased risk of incident breast cancer, adjusted for age and length of enrollment. For categories of increasing use (0, 1-50, 51-100, 101-500, 501-1000, and > or =1001 days), odds ratios (95% confidence intervals) for breast cancer were 1.00 (reference), 1.45 (1.24-1.69), 1.53 (1.28-1.83), 1.68 (1.42-2.00), 2.14 (1.60-2.88), and 2.07 (1.48-2.89) (P<.001 for trend). Increased risk was observed in all antibiotic classes studied and in a subanalysis having breast cancer fatality as the outcome. Among women with the highest levels of tetracycline or macrolide use, risk of breast cancer was not elevated in those using these antibiotics exclusively for acne or rosacea (indications that could be risk factors for breast cancer due to altered hormone levels), compared with those using them exclusively for respiratory tract infections, adjusted for age and length of enrollment (odds ratio, 0.91; 95% confidence interval, 0.44-1.87). CONCLUSIONS: Use of antibiotics is associated with increased risk of incident and fatal breast cancer. It cannot be determined from this study whether antibiotic use is causally related to breast cancer, or whether indication for use, overall weakened immune function, or other factors are pertinent underlying exposures. Although further studies are needed, these findings reinforce the need for prudent long-term use of antibiotics.

Adult↗

PubMed2004

VITamins And Lifestyle cohort study: study design and characteristics of supplement users.

Vitamin and mineral supplements are among the most commonly used drugs in the United States, despite limited evidence on their benefits or risks. This paper describes the design, implementation, and participant characteristics of the VITamins And Lifestyle (VITAL) Study, a cohort study of the associations of supplement use with cancer risk. A total of 77,738 men and women in western Washington State, aged 50-76 years, entered the study in 2000-2002 by completing a detailed questionnaire on supplement use, diet, and other cancer risk factors, and 70% provided DNA through self-collected buccal cell specimens. Supplement users were targeted in recruitment: 66% used multivitamins, 46% used individual vitamin C, 47% used individual vitamin E, and 46% used calcium, typically for 5-8 of the past 10 years. Analyses to identify confounding factors, the main study limitation, showed that regular nonsteroidal anti-inflammatory drug use, intake of fruits and vegetables, and recreational physical activity were strongly associated with supplement use (p < 0.001). The authors describe a follow-up system in which cancers, deaths, and changes of residence are tracked efficiently, primarily through linkage to public databases. These methods may be useful to other researchers implementing a large cohort study or designing a passive follow-up system.

Aged↗

PubMed2004

Frequent intentional weight loss is associated with lower natural killer cell cytotoxicity in postmenopausal women: possible long-term immune effects.

OBJECTIVE: Weight-loss attempts are likely to become more frequent as the prevalence of obesity rises. Repeated cycles of loss and gain are a common consequence of failed weight-loss attempts. The question of whether this pattern has negative health effects is unresolved. The objective of this research was to investigate associations between weight-loss history and current measures of immune function. DESIGN: The study design was a cross-sectional study. SUBJECTS: One hundred fourteen healthy, overweight, sedentary, postmenopausal women were recruited for an exercise intervention study and were currently weight stable. METHODS: History of intentional weight loss was assessed by questionnaire. Flow cytometry was used to measure natural killer cell (NK) cytotoxicity at four effector-to-target (E:T) ratios and for enumerating and phenotyping lymphocytes. Multiple linear regression analysis was used to investigate associations between weight loss within the past 20 years and current immune function. RESULTS: Women who reported ever intentionally losing >or=10 pounds had lower measured NK cytotoxicity than those who did not (24.7%+/-12.1% vs 31.1%+/-14.7%, respectively, at E:T 25:1; P=.01). Increasing frequency of previous intentional weight loss was associated with lower NK cytotoxicity (P=.003, trend). As an independent predictor, longer duration of recent weight stability was associated with higher NK cytotoxicity (21.6%+/-11.9%, 24.4%+/-11.0%, and 31.9%+/-14.4% for 2 to 5 years of weight stability, respectively; P=.0002, trend). The frequency of weight loss episodes was also associated with differences in the number and proportion of NK cells. CONCLUSIONS: This study provides evidence that frequent intentional weight loss may have long-term effects on immune function.

Aged↗

PubMed2004

Characteristics of childhood cancer survivors predicted their successful tracing.

OBJECTIVE: The Childhood Cancer Survivor Study is a retrospective cohort study that was initiated to explore late effects of childhood cancer and its therapies. We evaluated the characteristics of those requiring tracing and factors that influenced tracing success. STUDY DESIGN AND SETTING: Medical record review identified 20,051 eligible individuals from 25 institutions in the United States and Canada. Of these, 13,021 had a current address in the medical record at the treating institution, and 7,030 had an incorrect address and required tracing by a commercial firm. RESULTS: Tracing was successful for 4,188 persons (60%). Younger age at contact, shorter length of time since last contact, having a middle initial available, an uncommon last name, and socioeconomic factors were found to predict successful tracing. Compared to those with a current address available in medical records, subjects successfully traced were less likely to have accessed health care during the previous 2 years; and more likely to be current smokers, obese, and to report moderate to severe impairments (pain, functional status, and activity). CONCLUSION: These findings provide an empirical basis concerning determinants and predictors of tracing success. If tracing had not been performed in this cohort, spurious associations may have been obtained for some health outcomes of interest.

Adolescent↗

PubMed2004

Influence of demographic, physiologic, and psychosocial variables on adherence to a yearlong moderate-intensity exercise trial in postmenopausal women.

BACKGROUND: Few studies have examined the long-term adherence to a yearlong exercise intervention among postmenopausal women. We examined the patterns of adherence to a yearlong exercise intervention and the influence of demographic, physiologic, and psychosocial variables on patterns of adherence among 173 sedentary, overweight, postmenopausal women. METHODS: We collected demographic, physical activity (PA), physiologic, psychosocial, and medical history information at baseline and 12 months. The exercise prescription consisted of at least 45 min of moderate-intensity exercise 5 days/week for 12 months. We calculated several adherence variables. Associations between baseline variables and adherence levels were assessed in bivariate analyses and in multiple regression models. RESULTS: Women randomized to the exercise group (N = 87) participated in moderate-intensity sports or recreational PA on 3.7 +/- 1.4 days/week (79% of the prescribed 5 days/week) for 171 +/- 88 min/week (87% of the prescribed 225 min/week) over the yearlong trial period. Sixty-eight percent of the exercisers had a yearlong average PA level exceeding the national recommendation of 150 min/week. Being in the preparation stage vs. the contemplation stage of the transtheoretical model and a history of participating in any sports or recreational PA were significant predictors of adherence. CONCLUSIONS: Our findings provide important information for the design of future PA interventions and health promotion programs.

Aged↗

PubMed2004

The effect of CYP19 and COMT polymorphisms on exercise-induced fat loss in postmenopausal women.

OBJECTIVE: To examine whether genetic polymorphisms in CYP19 [intron 4 (TTTA)n; n = 7 to 13 and a 3-base pair deletion, which is in strong linkage disequilibrium with the seven repeat] and COMT (Val108/158Met) modified the change in BMI, total and percentage body fat, or subcutaneous and intra-abdominal fat during a year-long exercise intervention trial. These genes metabolize estrogens and androgens, which are important in body fat regulation. RESEARCH METHODS AND PROCEDURES: A randomized intervention trial was used, with an intervention goal of 225 min/wk of moderate-intensity exercise for one year. Participants (n = 173) were postmenopausal, 50 to 75 years old, sedentary, overweight or obese, and not taking hormone therapy at baseline. RESULTS: Exercisers with two vs. no CYP19 11-repeat alleles had a larger decrease in total fat (-3.1 kg vs. -0.5 kg, respectively, p = 0.01) and percentage body fat (-2.4% vs. -0.6%, respectively, p = 0.001). Exercisers with the COMT Met/Met vs. Val/Val genotype had a smaller decrease in percentage fat (-0.7% vs. -1.9%, respectively, p = 0.05). Among exercisers, women with the COMT Val/Val genotype and at least one copy of the CYP19 11-repeat allele vs. those with neither genotype/allele had a significantly larger decrease in BMI (-1.0 vs. +0.1 kg/m2, respectively, p = 0.009), total fat (-2.9 vs. -0.5 kg, respectively, p = 0.004), and percentage body fat (-2.6% vs. -0.4%, respectively, p < 0.001). DISCUSSION: Genetic polymorphisms in CYP19 and COMT may be important for body fat regulation and possibly modify the effect of exercise on fat loss in postmenopausal women.

Adipose Tissue↗

PubMed2004

Assessment of a one-page questionnaire on long-term recreational physical activity.

BACKGROUND: Physical activity is associated with a reduced risk of several chronic diseases. Although there is considerable published research on methods to assess current or recent recreational physical activity, there are few short, self-administered questionnaires designed to assess long-term physical activity. METHODS: We developed a one-page questionnaire to capture data on usual recreational physical activity during the preceding 10 years. This questionnaire was used in a cohort study of adults age 50 to 75 years residing in western Washington state. To examine the measurement characteristics of this questionnaire, we compared metabolic equivalent task (MET)-hours derived from this short questionnaire to MET-hours estimated from a detailed comparison interview in a subsample (n = 217) and to current body mass index (BMI; weight in kilograms/height in square meters) in the full sample of 57,811 persons. RESULTS: The age- and sex-adjusted partial Pearson correlation coefficient for total recreational activity between the 2 instruments was 0.68. In the full cohort, BMI was inversely correlated with physical activity as assessed by the one-page questionnaire (r = -0.22). CONCLUSIONS: This short questionnaire measures long-term physical activity at a level of precision appropriate to the examination of associations in studies of physical activity and disease.

Age Factors↗

PubMed2004

Association of CYP17, CYP19, CYP1B1, and COMT polymorphisms with serum and urinary sex hormone concentrations in postmenopausal women.

Women with high circulating estrogen concentrations have an increased risk of breast cancer; thus, it is important to understand factors, including genetic variability, that influence estrogen concentrations. Several genetic polymorphisms that may influence sex hormone concentrations have been identified, including CYP17 (5'-untranslated region T-->C), CYP19 [intron 4 (TTTA)(n = 7-13) and a 3-bp deletion (-3)], CYP1B1 (Val(432)Leu), and COMT (Val(108/158)Met). We examined associations between these polymorphisms and serum concentrations of estrogens, androgens, and sex hormone-binding globulin and urinary concentrations of 2- and 16alpha-hydroxyestrone in 171 postmenopausal women, using data from the prerandomization visit of an exercise clinical trial. Participants were sedentary, not taking hormone therapy, and had a body mass index >24.0. Compared with noncarriers, women carrying two CYP19 7r(-3) alleles had 26% lower estrone (P < 0.001), 19% lower estradiol (P = 0.01), 23% lower free estradiol (P = 0.01), and 22% higher sex hormone-binding globulin concentrations (P = 0.06). Compared with noncarriers, women carrying at least one CYP19 8r allele had 20% higher estrone (P = 0.003), 18% higher estradiol (P = 0.02), and 21% higher free estradiol concentrations (P = 0.01). Women with the COMT Met/Met genotype had 28% higher 2-hydroxyestrone (P = 0.08) and 31% higher 16alpha-hydroxyestrone concentrations (P = 0.02), compared with Val/Val women. Few associations were found for CYP17 and CYP1B1 or with serum androgen concentrations. This study provides further evidence that genetic variation may appreciably alter sex hormone concentrations in postmenopausal women not taking hormone therapy.

Aged↗

PubMed2004

MTHFR C677T and A1298C polymorphisms: diet, estrogen, and risk of colon cancer.

5,10-methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism, diverting metabolites toward methylation reactions or nucleotide synthesis. Using data from an incident case-control study (1608 cases and 1972 controls) we investigated two polymorphisms in the MTHFR gene, C677T and A1298C, and their associations with risk of colon cancer. All of the combined genotypes were evaluated separately, and the 1298AA/677CC (wild-type/wild-type) group was considered the reference group. Among both men and women, the 677TT/1298AA (variant/wild-type) genotype was associated with a small reduction in risk [men: odds ratio (OR), 0.7, 95% confidence interval (CI), 0.5-1.0; women: OR, 0.8, 95% CI, 0.5-1.2]. However, the 677CC/1298CC (wild-type/variant) genotype was associated with a statistically significant lower risk among women (OR, 0.6; 95% CI, 0.4-0.9) but not men. When the polymorphisms were considered individually, for A1298C a significant risk reduction associated with the homozygous variant CC genotype was seen among women only (OR, 0.6; 95% CI, 0.5-0.9), and nonstatistically significant reduced risks were observed for the variant 677 TT genotypes among both men and women. Stratification by nutrient intakes showed inverse associations with higher intakes of folate, vitamin B(2), B(6), B(12), and methionine among women with the MTHFR 677CC/1298AA genotypes, but not those with 677TT/1298AA. We observed opposite risk trends for both MTHFR variants, depending on whether women used hormone-replacement therapy or not (P for interaction = <.01). In summary, this study supports recent findings that the MTHFR A1298C polymorphism may be a predictor of colon cancer risk and have functional relevance. The possible interaction with hormone-replacement therapy warrants additional investigation.

Adult↗

PubMed2004

Methionine synthase D919G polymorphism, folate metabolism, and colorectal adenoma risk.

Methionine synthase [5-methyltetrahydrofolate-homocysteine S-methyltransferase (MTR)] is involved in folate-mediated one-carbon metabolism, a pathway known to play a role in colorectal carcinogenesis. We investigated whether the MTR D919G polymorphism was associated with risk of colorectal adenoma in a colonoscopy-based study of 513 cases and 609 controls from Minneapolis, MN. Adenoma risk appeared nonsignificantly increased among women with DG or GG genotype [adjusted odds ratio (OR) versus DD, 1.4; 95% confidence interval (CI), 0.9-2.1] but not men (OR, 1.0; 95% CI, 0.7-1.5). An interaction with methionine intake was observed among women, such that low versus high intake was associated with a 2.3-fold increased risk only among those with DG or GG genotype (95% CI, 1.1-4.9; P for interaction = 0.05). Similarly, risk associated with alcohol intake was not elevated among women with the DD genotype; however, consumption of >7 g of alcohol/day versus none was associated with an increased risk among women with DG or GG genotype (adjusted OR, 2.5; 95% CI, 1.4-4.4; P for interaction = 0.03). An interaction between MTR D919G and the thymidylate synthase (TS or TYMS) 3'-untranslated region polymorphism 1494del6 was also observed among women (P for interaction = 0.007). No evidence of interaction with intake of folate, vitamin B(12), or vitamin B(6) or with genotype at MTHFR C677T or the TS enhancer region 28-bp repeat polymorphism was seen. These findings add to what is known about the complexities of genetic variations in one-carbon-metabolizing enzymes in relation to colorectal carcinogenesis.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗