Metabolomic data presents challenges for epidemiological meta-analysis: a case study of childhood body mass index from the ECHO consortium.

INTRODUCTION: Meta-analyses across diverse independent studies provide improved confidence in results. However, within the context of metabolomic epidemiology, meta-analysis investigations are complicated by differences in study design, data acquisition, and other factors that may impact reproducibility. OBJECTIVE: The objective of this study was to identify maternal blood metabolites during pregnancy (> 24 gestational weeks) related to offspring body mass index (BMI) at age two years through a meta-analysis framework. METHODS: We used adjusted linear regression summary statistics from three cohorts (total N = 1012 mother-child pairs) participating in the NIH Environmental influences on Child Health Outcomes (ECHO) Program. We applied a random-effects meta-analysis framework to regression results and adjusted by false discovery rate (FDR) using the Benjamini-Hochberg procedure. RESULTS: Only 20 metabolites were detected in all three cohorts, with an additional 127 metabolites detected in two of three cohorts. Of these 147, 6 maternal metabolites were nominally associated (P < 0.05) with offspring BMI z-scores at age 2 years in a meta-analytic framework including at least two studies: arabinose (Coefmeta = 0.40 [95% CI 0.10,0.70], Pmeta = 9.7 × 10-3), guanidinoacetate (Coefmeta = - 0.28 [- 0.54, - 0.02], Pmeta = 0.033), 3-ureidopropionate (Coefmeta = 0.22 [0.017,0.41], Pmeta = 0.033), 1-methylhistidine (Coefmeta = - 0.18 [- 0.33, - 0.04], Pmeta = 0.011), serine (Coefmeta = - 0.18 [- 0.36, - 0.01], Pmeta = 0.034), and lysine (Coefmeta = - 0.16 [- 0.32, - 0.01], Pmeta = 0.044). No associations were robust to multiple testing correction. CONCLUSIONS: Despite including three cohorts with large sample sizes (N > 100), we failed to identify significant metabolite associations after FDR correction. Our investigation demonstrates difficulties in applying epidemiological meta-analysis to clinical metabolomics, emphasizes challenges to reproducibility, and highlights the need for standardized best practices in metabolomic epidemiology.

Bronchiolitis hospitalizations in rural New England: clues to disease prevention.

Background: An improved understanding of the clinico-epidemiology of bronchiolitis hospitalizations, a clinical surrogate of respiratory syncytial virus (RSV) disease, is critical to inform public health strategies for mitigating the in-patient burden of bronchiolitis in early life. Methods: A retrospective chart review was conducted of all bronchiolitis first admissions (N = 295) to the Children's Hospital at Dartmouth-Hitchcock, CHaD, between 1 November 2010 and 31 October 2017 using the relevant International Classification of Diseases (ICD)-9 and ICD-10 codes for this illness. Abstracted data included laboratory confirmation of RSV infection, severity of illness, duration of hospitalization, age at admission in days, weight at admission, prematurity, siblings, and relevant medical pre-existing conditions. Results: Admissions for bronchiolitis were strongly associated with age of the child, the calendar month of an infant's birth, and the presence of older children in the family. Medical risk factors associated with admission included premature birth and underlying cardiopulmonary disease. Conclusion: The very early age of hospitalization emphasizes the high penetration of RSV in the community, by implication the limited protection afforded by maternal antibody, and the complexity of protecting infants from this infection. Plain Language Summary: Although risks for respiratory syncytial virus (RSV)/bronchiolitis hospitalization are well described, few studies have examined, with precision, the age-related frequency and severity of RSV/bronchiolitis. We also explore the implications of RSV clinico-epidemiology for our understanding of the pathogenesis of the disease and development of optimal approaches to prevention.

Diet quality, common genetic polymorphisms, and bladder cancer risk in a New England population-based study.

PURPOSE: We examined the interaction between common genetic bladder cancer variants, diet quality, and bladder cancer risk in a population-based case-control study conducted in New England. METHODS: At the time of enrollment, 806 bladder cancer cases and 974 controls provided a DNA sample and completed a diet history questionnaire. Diet quality was assessed using the 2010 Alternate Healthy Eating Index (AHEI-2010) score. Single nucleotide polymorphisms (SNPs) reported in genome-wide association studies to be associated with bladder cancer risk were combined into a polygenic risk score and also examined individually for interaction with the AHEI-2010. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression. RESULTS: A 1-standard deviation increase in polygenic risk score was associated with higher bladder cancer risk (OR, 1.34; 95% CI 1.21-1.49). Adherence to the AHEI-2010 was not associated with bladder cancer risk (OR, 0.99; 95% CI 0.98-1.00) and the polygenic risk score did not appear to modify the association between the AHEI-2010 and bladder cancer risk. In single-SNP analyses, rs8102137 (bladder cancer risk allele, C) modified the association between the AHEI-2010 total score and bladder cancer risk, with the strongest evidence for the AHEI-2010 long chain fat guideline (OR for TT, 0.92; 95% CI 0.87-0.98; OR for CT, 1.02; 95% CI 0.96-1.08; OR for CC, 1.03; 95% CI 0.93-1.14; p for interaction, 0.02). CONCLUSIONS: In conclusion, rs8102137 near the cyclin E1 gene ( CCNE1 ) may be involved in gene-diet interactions for bladder cancer risk.

Diet Quality and Survival in a Population-Based Bladder Cancer Study.

Nutrition may impact bladder cancer survival. We examined the association between diet quality and overall and bladder cancer-specific survival. Bladder cancer cases from a population-based study reported pre-diagnosis diet. Diet quality was assessed using the 2010 Alternate Healthy Eating Index (AHEI-2010). Vital status was ascertained from the National Death Index. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using proportional hazards and competing risks regression models. Overall AHEI-2010 adherence was not associated with overall or bladder cancer-specific survival among non-muscle invasive bladder cancer (NMIBC) cases (HR, 1.00; 95% CI, 0.98-1.01; HR, 1.00; 95% CI, 0.97-1.02) or muscle invasive bladder cancer (MIBC) cases (HR, 0.99; 95% CI, 0.96-1.03; HR, 1.01, 95% CI 0.97-1.06). AHEI-2010 sugar-sweetened beverages adherence was associated with poorer overall survival (HR, 1.04; 95% CI, 1.01-1.08) and AHEI-2010 sodium adherence was associated with better overall and bladder cancer-specific survival after NMIBC diagnosis (HR, 0.92, 95% CI, 0.85-1.00; HR, 0.82; 95% CI, 0.68-0.98). AHEI-2010 fruit adherence was associated with poorer overall and bladder cancer-specific survival after MIBC diagnosis (HR, 1.17; 95% CI, 1.02-1.33; HR, 1.26; 95% CI, 1.03-1.55). Consumption of sugar-sweetened beverages, sodium, and fruit, not overall AHEI-2010 adherence, may be associated with bladder cancer survival.

Risk of melanoma following keratinocyte malignancies.

Patients diagnosed with keratinocyte cancer experience heightened risk for melanoma, yet patients who go on to develop this malignancy have not been well-characterized. We followed a population-based cohort of 2243 participants with histologically confirmed KC identified from dermatology and pathology practices who did not have a history of internal malignancy (1363 BCC, 880 SCC). A total of 77 participants went on to develop melanoma. Individual-level data were collected via personal interviews including demographic information and skin cancer risk factors, as well as KC tumor characteristics such as anatomic site and histologic subtype. Using adjusted Cox proportionate hazards models, older patients (age 61 or older vs 60 or younger) were at twofold increased risk for developing melanoma following KC (age 61-65 HR = 2.5; 95% CI = 1.3-4.6) (age > 65 HR = 2.0; 95% CI = 1.2-3.4) and women were at reduced risk compared to men (HR = 0.5; 95% CI = 0.3-0.8). Among patients with BCC, those with tumors on the trunk/limbs compared to the head/neck were at greater risk for subsequent melanoma (HR = 2.7; 95% CI = 1.3-5.7). Subsequent risk of melanoma also related to established risk factors including blond/red vs dark hair (HR = 1.9; 95% CI = 1.1-3.4), tendency to burn rather than tan (HR = 1.7; 95% CI = 1.0-2.7), ≥1 nevi on their back compared to no nevi (HR = 2.2; 95% CI = 1.2-3.8) and a history of ≥1 painful childhood sunburns vs none (HR = 2.1; 95% CI = 1.2-3.6). Thus, in addition to pigmentary traits, ultraviolet radiation (UVR)-related factors and clinical features of KC such as anatomic site may be useful in identifying patients at increased risk for melanoma after KC.

Cosmetic Tattooing and Early Onset Basal Cell Carcinoma: A Population-based Case-Control Study from New Hampshire.

BACKGROUND: Cosmetic tattoos use dyes with carcinogenic potential. Skin cancers arising in tattoos have been reported. METHODS: We investigated whether risk of early onset basal cell carcinoma was related to the site and colors of cosmetic tattoos as part of a population-based case-control study of cases (ages 25-50 years), identified from a state-wide surveillance system, and age- and gender-matched controls, selected from driver's license records, randomly assigned an anatomic site of the cases. RESULTS: One hundred fifty-six cases (17%) with early onset basal cell carcinoma and 213 controls (26%) reported cosmetic tattoos. Among those with tattoos, the adjusted odds ratio of basal cell carcinoma at the tattoo site compared to another site was 1.8 (95% confidence interval = 1.0, 3.2). We observed the strongest associations for yellow and green tattoo colors. CONCLUSION: Our preliminary findings support the possibility of an enhanced risk of early onset basal cell carcinomas at the site of cosmetic tattoos.

Dietary B Vitamin Intake Is Associated with Lower Urinary Monomethyl Arsenic and Oxidative Stress Marker 15-F2t-Isoprostane among New Hampshire Adults.

Background: Arsenic exposure has been associated with an increased risk of cardiovascular disease (CVD). Growing evidence suggests that B vitamins facilitate arsenic metabolism and may protect against arsenic toxicity. However, to our knowledge, few studies have evaluated this in US populations.Objective: Our objective was to examine whether higher B vitamin intake is associated with enhanced arsenic metabolism and lower concentrations of preclinical markers of CVD among New Hampshire adults.Methods: We used weighted quantile sum (WQS) regression to evaluate the collective impact of 6 dietary B vitamins (thiamin, riboflavin, folate, niacin, and vitamins B-6 and B-12) on 1) the proportion of arsenic metabolites in urine and 2) 6 CVD-related markers [including urinary 15-F2t-isoprostane (15-F2t-IsoP)] among 418 participants (26-75 y of age) from the New Hampshire Health Study. Contributions of arsenic metabolites to B vitamin-CVD marker associations were also explored in structural equation models.Results: In WQS models, the weighted sum of B vitamin intakes from food sources was inversely associated with the proportion of monomethyl arsenic species in urine (uMMA) (ß: -1.03; 95% CI: -1.91, -0.15; P = 0.02). Thiamin and vitamins B-6 and B-12 contributed the most to this association, whereas riboflavin had a negligible effect. Higher overall B vitamin intake was also inversely associated with 15-F2t-IsoP (ß: -0.21; 95% CI: -0.32, -0.11; P < 0.01), with equal contributions from the 6 B vitamins, which was partially explained by differences in the proportion of uMMA (indirect effect ß: -0.01; 95% CI: -0.04, -0.00).Conclusions: Among New Hampshire adults, higher intakes of certain B vitamins (particularly thiamin and vitamins B-6 and B-12 from food sources) may reduce the proportion of uMMA, an intermediate of arsenic metabolism that has been associated with an increased risk of CVD. Higher overall B vitamin intake may also reduce urinary 15-F2t-IsoP, a marker of oxidative stress and potential risk factor for CVD, in part by reducing the proportion of uMMA.

Urine Arsenic and Arsenic Metabolites in U.S. Adults and Biomarkers of Inflammation, Oxidative Stress, and Endothelial Dysfunction: A Cross-Sectional Study.

BACKGROUND: Arsenic (As) exposure has been associated with increased risk for cardiovascular disease (CVD) and with biomarkers of potential CVD risk and inflammatory processes. However, few studies have evaluated the effects of As on such biomarkers in U.S. populations, which are typically exposed to low to moderate As concentrations. OBJECTIVES: We investigated associations between As exposures and biomarkers relevant to inflammation, oxidative stress, and CVD risk in a subset of participants from the New Hampshire Health Study, a population with low to moderate As exposure (n=418). METHODS: Associations between toenail As, total urine As (uAs), and %uAs metabolites [monomethyl (%uMMAV), dimethyl (%uDMAV), and inorganic (%iAs) species] and plasma biomarkers, including soluble plasma vascular and cellular adhesion molecules (VCAM-1 and ICAM-1, respectively), matrix metalloproteinase-9 (MMP-9), tumor necrosis factor-α, plasminogen activator inhibitor-1 (PAI-1), and urinary oxidative stress marker 15-F2t-isoprostane (15-F2t-IsoP), were evaluated using linear regression models. RESULTS: Covariate-adjusted estimates of associations with a doubling of urinary As suggested an 8.8% increase in 15-F2t-IsoP (95% CI: 3.2, 14.7), and a doubling of toenail As was associated with a 1.7% increase in VCAM-1 (95% CI: 0.2, 3.2). Additionally, a 5% increase in %uMMA was associated with a 7.9% increase in 15-F2t-IsoP (95% CI: 2.1, 14.1), and a 5% increase in %uDMA was associated with a 2.98% decrease in 15-F2t-IsoP [(95% CI: -6.1, 0.21); p=0.07]. However, in contrast with expectations, a doubling of toenail As was associated with a 2.3% decrease (95% CI: -4.3, -0.3) in MMP-9, and a 5% increase in %uMMA was associated with a 7.7% decrease (95% CI: -12.6, -2.5) in PAI-1. CONCLUSION: In a cross-sectional study of U.S. adults, we observed some positive associations of uAs and toenail As concentrations with biomarkers potentially relevant to CVD pathogenesis and inflammation, and evidence of a higher capacity to metabolize inorganic As was negatively associated with a marker of oxidative stress. https://doi.org/10.1289/EHP2062.

Sex hormones and the risk of keratinocyte cancers among women in the United States: A population-based case-control study.

Men are at a higher risk of developing both squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) than women, but there is emerging evidence that women may be experiencing greater increases in the incidence rates of these malignancies than men. One possible explanation is the expanding use of sex steroids among women, although only a few studies have examined this hypothesis. As part of a population-based, case-control study of women in New Hampshire, USA, we sought to evaluate the risk of SCC, BCC, and early-onset BCC in relation to exogenous and endogenous sex hormones. We found that oral contraceptive (OC) use was associated with an increased risk of SCC (OR = 1.4, 95% CI = 1.1-1.8) and BCC (OR = 1.4, 95% CI = 1.0-1.8), particularly high estrogen dose (>50 mg) OC use. Hormone replacement therapy (HRT) use also related to SCC, with an elevated OR largely for progestin use (OR = 1.4, 95% CI = 1.1-1.8). Additionally, both OC use and combination HRT use were associated with more aggressive BCC subtypes. In contrast, menstrual and reproductive history did not appear to influence keratinocyte cancer risk in our data. Our findings provide evidence that use of sex steroids may enhance risk of keratinocyte cancer.

Alcohol consumption and risk of melanoma among women: pooled analysis of eight case-control studies.

While alcohol consumption is known to increase the risk of several types of cancer, evidence regarding the association between alcohol and melanoma is inconclusive. This pooled analysis was conducted to examine total alcohol consumption (grams per day), and type of alcohol consumed (beer, wine, beer and wine combined, and liquor) in relation to melanoma among women using original data from eight completed case-control studies (1886 cases and 2113 controls), with adjustment for the potential confounding effects of sun exposure-related factors. We found a positive association with ever consuming alcohol [adjusted pooled odds ratio (pOR) 1.3, 95 % confidence interval (CI) 1.1-1.5]. Specifically the pORs were 1.4 (95 % CI 1.1-1.8) for wine, 1.1 (95 % CI 0.9-1.5) for beer and 1.2 (95 % CI 1.0-1.4) for liquor. However, the pOR for the highest fourth of consumption compared with never consumption was 1.0 (95 % CI 0.7-1.3) without evidence of a trend with increasing amount of total alcohol, or separately with amount of beer, wine or liquor consumed. Stratifying by anatomic site of lesion, number of nevi, age group, or histologic subtype did not alter these results. Although the results showed a weak positive association between ever consuming alcohol and melanoma occurrence, our findings do not provide strong support for the hypothesis that alcohol consumption plays a role in the development of melanoma in women.

Development and validation of a melanoma risk score based on pooled data from 16 case-control studies.

BACKGROUND: We report the development of a cutaneous melanoma risk algorithm based upon seven factors; hair color, skin type, family history, freckling, nevus count, number of large nevi, and history of sunburn, intended to form the basis of a self-assessment Web tool for the general public. METHODS: Predicted odds of melanoma were estimated by analyzing a pooled dataset from 16 case-control studies using logistic random coefficients models. Risk categories were defined based on the distribution of the predicted odds in the controls from these studies. Imputation was used to estimate missing data in the pooled datasets. The 30th, 60th, and 90th centiles were used to distribute individuals into four risk groups for their age, sex, and geographic location. Cross-validation was used to test the robustness of the thresholds for each group by leaving out each study one by one. Performance of the model was assessed in an independent UK case-control study dataset. RESULTS: Cross-validation confirmed the robustness of the threshold estimates. Cases and controls were well discriminated in the independent dataset [area under the curve, 0.75; 95% confidence interval (CI), 0.73-0.78]. Twenty-nine percent of cases were in the highest risk group compared with 7% of controls, and 43% of controls were in the lowest risk group compared with 13% of cases. CONCLUSION: We have identified a composite score representing an estimate of relative risk and successfully validated this score in an independent dataset. IMPACT: This score may be a useful tool to inform members of the public about their melanoma risk.

Genetic polymorphisms modify bladder cancer recurrence and survival in a USA population-based prognostic study.

OBJECTIVE: To identify genetic variants that modify bladder cancer prognosis focusing on genes involved in major biological carcinogenesis processes (apoptosis, proliferation, DNA repair, hormone regulation, immune surveillance, and cellular metabolism), as nearly half of patients with bladder cancer experience recurrences reliable predictors of this recurrent phenotype are needed to guide surveillance and treatment. PATIENTS AND METHODS: We analysed variant genotypes hypothesised to modify these processes in 563 patients with urothelial-cell carcinoma enrolled in a population-based study of incident bladder cancer conducted in New Hampshire, USA. After diagnosis, patients were followed over time to ascertain recurrence and survival status, making this one of the first population-based studies with detailed prognosis data. Cox proportional hazards regression was used to assess the relationship between single nucleotide polymorphisms (SNPs) and prognosis endpoints. RESULTS: Patients with aldehyde dehydrogenase 2 (ALDH2) variants had a shorter time to first recurrence (adjusted non-invasive hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.29-2.78). There was longer survival among patients with non-invasive tumours associated with DNA repair X-ray repair cross-complementing protein 4 (XRCC4) heterozygous genotype compared with wild-type (adjusted HR 0.53, 95% CI 0.38-0.74). Time to recurrence was shorter for patients who had a variant allele in vascular cellular adhesion molecule 1 (VCAM1) and were treated with immunotherapy (P interaction < 0.001). CONCLUSIONS: Our analysis suggests candidate prognostic SNPs that could guide personalised bladder cancer surveillance and treatment.

Clinicopathological correlates of Gli1 expression in a population-based cohort of patients with newly diagnosed bladder cancer.

INTRODUCTION: Dysregulation of the hedgehog signaling pathway has been linked to the development and progression of a variety of different human tumors including cancers of the skin, brain, colon, prostate, blood, and pancreas. We assessed the clinicopathological factors that are potentially related to expression of Gli1, the transcription factor that is thought to be the most reliable marker of hedgehog pathway activation in bladder cancer. METHODS: Bladder cancer cases were identified from the New Hampshire State Cancer Registry as histologically confirmed primary bladder cancer diagnosed between January 1, 2002, and July 31, 2004. Immunohistochemical analysis was performed on a tissue microarray to detect Gli1 and p53 expression in these bladder tumors. We computed odds ratios (ORs) and their 95% CIs for Gli1 positivity for pathological category using T category (from TNM), invasiveness, and grade with both the World Health Organization 1973 and World Health Organization International Society of Urological Pathology criteria. We calculated hazard ratios and their 95% CI for Gli1 positivity and recurrence for both Ta-category and invasive bladder tumors (T1+). RESULTS: A total of 194 men and 67 women, whose tumors were assessable for Gli1 staining, were included in the study. No appreciable differences in Gli1 staining were noted by sex, age, smoking status, or high-risk occupation. Ta-category tumors were more likely to stain for Gli1 as compared with T1-category tumors (adjusted OR = 0.38, CI: 0.17-0.87). Similarly, low-grade (grades 1-2) tumors were more likely to stain for Gli1 as compared with high-grade tumors (grade 3) (adjusted OR = 0.44, CI: 0.21-0.93). In a Cox proportional hazards regression analysis, non-muscle-invasive bladder tumors expressing Gli1 were less likely to recur (adjusted hazard ratio = 0.48; CI: 0.28-0.82; P<0.05) than those in which Gli1 was absent. CONCLUSION: Our findings indicate that Gli1 expression may be a marker of low-stage, low-grade bladder tumors and an indicator of a reduced risk of recurrence in this group.

Body mass and smoking are modifiable risk factors for recurrent bladder cancer.

BACKGROUND: In the Western world, bladder cancer is the fourth most common cancer in men and the eighth most common in women. Recurrences frequently occur, and continued surveillance is necessary to identify and treat recurrent tumors. Efforts to identify risk factors that are potentially modifiable to reduce the rate of recurrence are needed. METHODS: Cigarette smoking behavior and body mass index were investigated at diagnosis for associations with bladder cancer recurrence in a population-based study of 726 patients with bladder cancer in New Hampshire, United States. Patients diagnosed with non-muscle invasive urothelial cell carcinoma were followed to ascertain long-term prognosis. Analysis of time to recurrence was performed using multivariate Cox regression models. RESULTS: Smokers experienced shorter time to recurrence (continuing smoker hazard ratio [HR] = 1.51, 95% confidence interval [CI] = 1.08-2.13). Although being overweight (body mass index > 24.9 kg/m(2) ) at diagnosis was not a strong independent factor (HR = 1.33, 95% CI = 0.94-1.89), among continuing smokers, being overweight more than doubled the risk of recurrence compared to smokers of normal weight (HR = 2.67, 95% CI = 1.14-6.28). CONCLUSIONS: These observational results suggest that adiposity is a risk factor for bladder cancer recurrence, particularly among tobacco users. Future intervention studies are warranted to evaluate whether both smoking cessation and weight reduction strategies reduce bladder tumor recurrences.

Photosensitizing agents and the risk of non-melanoma skin cancer: a population-based case-control study.

It is well-known that UV light exposure and a sun-sensitive phenotype are risk factors for the development of non-melanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). In this New Hampshire population-based case-control study, we collected data from 5,072 individuals, including histologically confirmed cases of BCC and SCC, and controls via a personal interview to investigate possible associations between photosensitizing medication use and NMSC. After adjustment for potentially confounding factors (e.g., lifetime number of painful sunburns), we found a modest increase in risk of SCC (odds ratio (OR)=1.2, 95% confidence interval (CI)=1.0-1.4) and BCC (OR=1.2, 95% CI=0.9-1.5), in particular early-onset BCC, (≤ 50 years of age) (OR=1.5, 95% CI=1.1-2.1) associated with photosensitizing medication use. For SCC the association was strongest among those with tendency to sunburn rather than tan. We also specifically found associations with BCC, and especially early-onset BCC, and photosensitizing antimicrobials. In conclusion, certain commonly prescribed photosensitizing medications may enhance the risk of developing SCC, especially in individuals with a sun-sensitive phenotype, and may increase the risk of developing BCC and incidence of BCC at a younger age.

HSD3B and gene-gene interactions in a pathway-based analysis of genetic susceptibility to bladder cancer.

Bladder cancer is the 4(th) most common cancer among men in the U.S. We analyzed variant genotypes hypothesized to modify major biological processes involved in bladder carcinogenesis, including hormone regulation, apoptosis, DNA repair, immune surveillance, metabolism, proliferation, and telomere maintenance. Logistic regression was used to assess the relationship between genetic variation affecting these processes and susceptibility in 563 genotyped urothelial cell carcinoma cases and 863 controls enrolled in a case-control study of incident bladder cancer conducted in New Hampshire, U.S. We evaluated gene-gene interactions using Multifactor Dimensionality Reduction (MDR) and Statistical Epistasis Network analysis. The 3'UTR flanking variant form of the hormone regulation gene HSD3B2 was associated with increased bladder cancer risk in the New Hampshire population (adjusted OR 1.85 95%CI 1.31-2.62). This finding was successfully replicated in the Texas Bladder Cancer Study with 957 controls, 497 cases (adjusted OR 3.66 95%CI 1.06-12.63). The effect of this prevalent SNP was stronger among males (OR 2.13 95%CI 1.40-3.25) than females (OR 1.56 95%CI 0.83-2.95), (SNP-gender interaction P = 0.048). We also identified a SNP-SNP interaction between T-cell activation related genes GATA3 and CD81 (interaction P = 0.0003). The fact that bladder cancer incidence is 3-4 times higher in males suggests the involvement of hormone levels. This biologic process-based analysis suggests candidate susceptibility markers and supports the theory that disrupted hormone regulation plays a role in bladder carcinogenesis.

Intake of α-linolenic acid and other fatty acids in relation to the risk of bladder cancer: results from the New Hampshire case-control study.

The role of dietary fat in bladder cancer aetiology is currently unclear due to few studies, equivocal findings and a lack of information on important dietary fatty acids. The aim of the present study was to investigate the association between the intake of major dietary fats and fatty acids and the risk of bladder cancer. A case-control study was conducted in New Hampshire, USA. Dietary data were collected from 322 cases and 239 controls, and OR and 95 % CI were calculated using unconditional logistic regression. Adjustment was made for potential confounders: sex, age, smoking status, pack-years smoked, cholesterol and energy intake. Statistically significant reduced odds of bladder cancer were observed for high intakes (highest quartile v. lowest quartile) of α-linolenic acid (ALA) (OR 0·26, 95 % CI 0·10, 0·65; P for trend = 0·01) and vegetable fat (OR 0·39, 95 % CI 0·18, 0·86; P for trend = 0·03). Borderline statistically significant reduced odds were detected for polyunsaturated fat (OR 0·43, 95 % CI 0·19, 0·98; P for trend = 0·07) and linoleic acid (OR 0·43, 95 % CI 0·19, 0·96; P for trend = 0·06). These fats and fatty acids were highly correlated and following adjustment for each other, the only potential inverse association to remain was for ALA. The present findings suggest that ALA may have a protective role against developing bladder cancer; however, further investigation and replication in other epidemiological studies are required. Future research should focus on the type, source and quantities of different dietary fatty acids consumed.