Plasma S-adenosylmethionine, DNMT polymorphisms, and peripheral blood LINE-1 methylation among healthy Chinese adults in Singapore

10.1186/1471-2407-13-389BMC Cancer13-BCMA

Association between class III obesity (BMI of 40-59 kg/m2) and mortality: A pooled analysis of 20 prospective studies

Background The prevalence of class III obesity (body mass index [BMI]≥40 kg/m2) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity. Methods and Findings In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex- and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19–83 y at baseline, classified as obese class III (BMI 40.0–59.9 kg/m2) compared with those classified as normal weight (BMI 18.5–24.9 kg/m2). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (1976–2009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40–44.9, 45–49.9, 50–54.9, and 55–59.9 kg/m2 was associated with an estimated 6.5 (95% CI: 5.7–7.3), 8.9 (95% CI: 7.4–10.4), 9.8 (95% CI: 7.4–12.2), and 13.7 (95% CI: 10.5–16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report. Conclusions Class III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight

Vitamin and mineral supplements in pregnancy and the risk of childhood acute lymphoblastic leukaemia: a case-control study

<p>Abstract</p> <p>Background</p> <p>An earlier case-control study from Western Australia reported a protective effect of maternal folic acid supplementation during pregnancy on the risk of childhood acute lymphoblastic leukaemia (ALL). The present study tested that association.</p> <p>Methods</p> <p>A national case-control study was conducted in New Zealand. The mothers of 97 children with ALL and of 303 controls were asked about vitamin and mineral supplements taken during pregnancy.</p> <p>Results</p> <p>There was no association between reported folate intake during pregnancy and childhood ALL (adjusted odds ratio (OR) 1.1, 95% confidence interval (CI) 0.5–2.7). Combining our results with the study from Western Australia and another study from Québec in a meta-analysis gave a summary OR of 0.9 (95% CI 0.8–1.1).</p> <p>Conclusion</p> <p>Our own study, of similar size to the Australian study, does not support the hypothesis of a protective effect of folate on childhood ALL. Neither do the findings of the meta-analysis.</p

Dietary fat intake and lung cancer risk: a pooled analysis

Purpose Dietary fat may play a role in lung carcinogenesis. Findings from epidemiologic studies, however, remain inconsistent. In this pooled analysis of 10 prospective cohort studies from the United States, Europe, and Asia, we evaluated the associations of total and specific types of dietary fat with lung cancer risk. Methods Cox regression was used to estimate hazard ratios (HRs) and 95% CIs in each cohort. Study-specific risk estimates were pooled by random- or fixed-effects meta-analysis. The first 2 years of follow-up were excluded to address potential influence of preclinical dietary changes. Results Among 1,445,850 participants, 18,822 incident cases were identified (mean follow-up, 9.4 years). High intakes of total and saturated fat were associated with an increased risk of lung cancer (for highest v lowest quintile: HR, 1.07 and 1.14, respectively; 95% CI, 1.00 to 1.15 and 1.07 to 1.22, respectively; P for trend for both < .001). The positive association of saturated fat was more evident among current smokers (HR, 1.23; 95% CI, 1.13 to 1.35; P for trend < .001) than former/never smokers (P for interaction = .004), and for squamous cell and small cell carcinoma (HR, 1.61 and 1.40, respectively; 95% CI, 1.38 to 1.88 and 1.17 to 1.67, respectively; P for trend for both < .001) than other histologic types (P for heterogeneity < .001). In contrast, a high intake of polyunsaturated fat was associated with a decreased risk of lung cancer (HR, 0.92; 95% CI, 0.87 to 0.98 for highest v lowest quintile; P for trend = .02). A 5% energy substitution of saturated fat with polyunsaturated fat was associated with a 16% to 17% lower risk of small cell and squamous cell carcinoma. No associations were found for monounsaturated fat. Conclusion Findings from this large, international cohort consortium suggest that modifying dietary fat intake (ie, replacing saturated fat with polyunsaturated fat) may reduce lung cancer risk, particularly among smokers and for squamous cell and small cell carcinoma

Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer

Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09–13.2), and in patients carrying the UGT1A1*28/*28 genotype, OR=4.43 (95% CI=1.30–15.2). Patients with UGT1A1*28/*28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70–27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01–2.45)

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukemia in a German study population

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) has a major impact on the regulation of the folic acid pathway due to conversion of 5,10-methylenetetrahydrofolate (methylene-THF) to 5-methyl-THF. Two common polymorphisms (677C>T and 1298A>C) in the gene coding for MTHFR have been shown to reduce MTHFR enzyme activity and were associated with the susceptibility to different disorders, including vascular disease, neural tube defects and lymphoid malignancies. Studies on the role of these polymorphisms in the susceptibility to acute lymphoblastic leukemia (ALL) led to discrepant results. METHODS: We retrospectively evaluated the association of the MTHFR 677C>T and 1298A>C polymorphisms with pediatric ALL by genotyping a study sample of 443 ALL patients consecutively enrolled onto the German multicenter trial ALL-BFM 2000 and 379 healthy controls. We calculated odds ratios of MTHFR genotypes based on the MTHFR 677C>T and 1298A>C polymorphisms to examine if one or both of these polymorphisms are associated with pediatric ALL. RESULTS: No significant associations between specific MTHFR variants or combinations of variants and risk of ALL were observed neither in the total patient group nor in analyses stratified by gender, age at diagnosis, DNA index, immunophenotype, or TEL/AML1 rearrangement. CONCLUSION: Our findings suggest that the MTHFR 677C>T and 1298A>C gene variants do not have a major influence on the susceptibility to pediatric ALL in the German population

Prediagnosis Leisure-Time Physical Activity and Lung Cancer Survival: A Pooled Analysis of 11 Cohorts

Background: Little is known about the association between physical activity before cancer diagnosis and survival among lung cancer patients. In this pooled analysis of 11 prospective cohorts, we investigated associations of prediagnosis leisuretime physical activity (LTPA) with all-cause and lung cancer–specific mortality among incident lung cancer patients. Methods: Using self-reported data on regular engagement in exercise and sports activities collected at study enrollment, we assessed metabolic equivalent hours (MET-h) of prediagnosis LTPA per week. According to the Physical Activity Guidelines for Americans, prediagnosis LTPA was classified into inactivity, less than 8.3 and at least 8.3 MET-h per week (the minimum recommended range). Cox regression was used to estimate hazard ratios (HRs) and 95% confidence interval (CIs) for all-cause and lung cancer–specific mortality after adjustment for major prognostic factors and lifetime smoking history. Results: Of 20 494 incident lung cancer patients, 16 864 died, including 13 596 deaths from lung cancer (overall 5-year relative survival rate ¼ 20.9%, 95% CI ¼ 20.3% to 21.5%). Compared with inactivity, prediagnosis LTPA of more than 8.3 MET-h per week was associated with a lower hazard of all-cause mortality (multivariable-adjusted HR ¼ 0.93, 95% CI ¼ 0.88 to 0.99), but not with lung cancer–specific mortality (multivariable-adjusted HR ¼ 0.99, 95% CI ¼ 0.95 to 1.04), among the overall population. Additive interaction was found by tumor stage (Pinteraction ¼ .008 for all-cause mortality and .003 for lung cancer–specific mortality). When restricted to localized cancer, prediagnosis LTPA of at least 8.3 MET-h per week linked to 20% lower mortality: multivariableadjusted HRs were 0.80 (95% CI¼ 0.67 to 0.97) for all-cause mortality and 0.80 (95% CI¼ 0.65 to 0.99) for lung cancer–specific mortality. Conclusions: Regular participation in LTPA that met or exceeded the minimum Physical Activity Guidelines was associated with reduced hazards of mortality among lung cancer patients, especially those with early stage cancer

Role of C677T and A1298C MTHFR, A2756G MTR and -786 C/T eNOS Gene Polymorphisms in Atrial Fibrillation Susceptibility

Hyperhomocysteinemia has been suggested to play a role in the NonValvular Atrial Fibrillation (NVAF) pathogenesis. Polymorphisms in genes coding for homocysteine (Hcy) metabolism enzymes may be associated with hyperhomocysteinemia and NVAF.456 NVAF patients and 912 matched controls were genotyped by an electronic microchip technology for C677T and A1298C MTHFR, A2756G MTR, and -786C/T eNOS gene polymorphisms. Hcy was determined by an immunoassay method.The genotype distribution of the four polymorphisms as well as genotype combinations did not differ in patients and controls. Hcy was higher in patients than in controls (15.2, 95%CI 14.7–15.7 vs 11.3, 95%CI 11.0–11.6 µmol/L; p<0.0001). In both populations, a genotype-phenotype association (p<0.0001) between Hcy and C677T MTHFR polymorphism was observed; in controls a significant (p = 0.029) association between tHcy and −786C/T eNOS polymorphism was also observed. At the multivariate analysis the NVAF risk significantly increased in the upper quartiles of Hcy compared to the lowest: OR from 2.8 (1.68–4.54 95%CI) in Q2 to 12.9 (7.96–21.06 95%CI) in Q4. or in combination