Lipid Adjustment in the Analysis of Environmental Contaminants and Human Health Risks

The literature on exposure to lipophilic agents such as polychlorinated biphenyls (PCBs) is conflicting, posing challenges for the interpretation of potential human health risks. Laboratory variation in quantifying PCBs may account for some of the conflicting study results. For example, for quantification purposes, blood is often used as a proxy for adipose tissue, which makes it necessary to model serum lipids when assessing health risks of PCBs. Using a simulation study, we evaluated four statistical models (unadjusted, standardized, adjusted, and two-stage) for the analysis of PCB exposure, serum lipids, and health outcome risk (breast cancer). We applied eight candidate true causal scenarios, depicted by directed acyclic graphs, to illustrate the ramifications of misspecification of underlying assumptions when interpreting results. Statistical models that deviated from underlying causal assumptions generated biased results. Lipid standardization, or the division of serum concentrations by serum lipids, was observed to be highly prone to bias. We conclude that investigators must consider biology, biologic medium (e.g., nonfasting blood samples), laboratory measurement, and other underlying modeling assumptions when devising a statistical plan for assessing health outcomes in relation to environmental exposures

Premenopausal endogenous oestrogen levels and breast cancer risk: a meta-analysis.

BACKGROUND: Many of the established risk factors for breast cancer implicate circulating hormone levels in the aetiology of the disease. Increased levels of postmenopausal endogenous oestradiol (E2) have been found to increase the risk of breast cancer, but no such association has been confirmed in premenopausal women. We carried out a meta-analysis to summarise the available evidence in women before the menopause. METHODS: We identified seven prospective studies of premenopausal endogenous E2 and breast cancer risk, including 693 breast cancer cases. From each study we extracted odds ratios of breast cancer between quantiles of endogenous E2, or for unit or s.d. increases in (log transformed) E2, or (where odds ratios were unavailable) summary statistics for the distributions of E2 in breast cancer cases and unaffected controls. Estimates for a doubling of endogenous E2 were obtained from these extracted estimates, and random-effect meta-analysis was used to obtain a pooled estimate across the studies. RESULTS: Overall, we found weak evidence of a positive association between circulating E2 levels and the risk of breast cancer, with a doubling of E2 associated with an odds ratio of 1.10 (95% CI: 0.96, 1.27). CONCLUSION: Our findings are consistent with the hypothesis of a positive association between premenopausal endogenous E2 and breast cancer risk

Investigation of glutathione S-transferase zeta and the development of sporadic breast cancer

BACKGROUND: Certain genes from the glutathione S-transferase superfamily have been associated with several cancer types. It was the objective of this study to determine whether alleles of the glutathione S-transferase zeta 1 (GSTZ1) gene are associated with the development of sporadic breast cancer. METHODS: DNA samples obtained from a Caucasian population affected by breast cancer and a control population, matched for age and ethnicity, were genotyped for a polymorphism of the GSTZ1 gene. After PCR, alleles were identified by restriction enzyme digestion and results analysed by chi-square and CLUMP analysis. RESULTS: Chi-squared analysis gave a χ(2) value of 4.77 (three degrees of freedom) with P = 0.19, and CLUMP analysis gave a T1 value of 9.02 with P = 0.45 for genotype frequencies and a T1 value of 4.77 with P = 0.19 for allele frequencies. CONCLUSION: Statistical analysis indicates that there is no association of the GSTZ1 variant and hence the gene does not appear to play a significant role in the development of sporadic breast cancer

Vitamin D and subsequent all-age and premature mortality: a systematic review

<br>Background: All-cause mortality in the population < 65 years is 30% higher in Glasgow than in equally deprived Liverpool and Manchester. We investigated a hypothesis that low vitamin D in this population may be associated with premature mortality via a systematic review and meta-analysis.</br> <br>Methods: Medline, EMBASE, Web of Science, the Cochrane Library and grey literature sources were searched until February 2012 for relevant studies. Summary statistics were combined in an age-stratified meta-analysis.</br> <br>Results: Nine studies were included in the meta-analysis, representing 24,297 participants, 5,324 of whom died during follow-up. The pooled hazard ratio for low compared to high vitamin D demonstrated a significant inverse association (HR 1.19, 95% CI 1.12-1.27) between vitamin D levels and all-cause mortality after adjustment for available confounders. In an age-stratified meta-analysis, the hazard ratio for older participants was 1.25 (95% CI 1.14-1.36) and for younger participants 1.12 (95% CI 1.01-1.24).</br> <br>Conclusions: Low vitamin D status is inversely associated with all-cause mortality but the risk is higher amongst older individuals and the relationship is prone to residual confounding. Further studies investigating the association between vitamin D deficiency and all-cause mortality in younger adults with adjustment for all important confounders (or using randomised trials of supplementation) are required to clarify this relationship.</br&gt

Physical activity and breast cancer survival

Physical activity improves quality of life after a breast cancer diagnosis, and a beneficial effect on survival would be particularly welcome. Four observational studies have now reported decreased total mortality among physically active women with breast cancer; the two largest have also reported decreased breast cancer specific mortality. The estrogen pathway and the insulin pathway are two potential mechanisms by which physical activity could affect breast cancer survival. Randomized trials are ongoing but trials of lifestyle factors are notoriously challenging to perform. Women with breast cancer have little to lose and may possibly gain from moderate exercise

Toenail selenium concentrations and bladder cancer risk in women and men

Prediagnostic selenium concentrations measured in archived toenails were inversely associated with bladder cancer risk in women (P for trend=0.02), but not in men, in a nested case–control study of 338 cases and 341 matched controls. These findings may be due to chance and more studies are needed to determine whether associations between selenium and bladder cancer risk differ by sex

CYP17 promoter polymorphism and breast cancer risk in males and females in relation to BRCA2 status

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldA T-C polymorphism in the promoter region of the CYP17 gene has been associated with male and female breast cancer risk as well as early-onset familial breast cancer. The potential role of this polymorphism was investigated in relation to breast cancer risk in Icelandic male and female carriers and noncarriers of a BRCA2 mutation. The study population consisted of 39 male and 523 female breast cancer cases and 309 male and 395 female controls. Of the cases, 15 males and 55 females carried a BRCA2 mutation. We did not find a significant association between male breast cancer risk and CYP17 genotypes. Among male breast cancer cases, the frequency of the CC genotype was higher among carriers of the 999del5 mutation (33.3%) than noncarriers (16.7%), although this difference also did not reach a statistical significance. No association was observed with breast cancer risk among females irrespective of menopausal status, stage of the disease or BRCA2 status. Our findings do not indicate a role for the CYP17 T-C polymorphism in female breast cancer, but a role in male carriers of a BRCA2 mutation could not be excluded because of the small sample size

Ovarian cancer risk and common variation in the sex hormone-binding globulin gene: a population-based case-control study

BACKGROUND: The sex hormone-binding globulin (SHBG) is a carrier protein that modulates the bio-availability of serum sex steroid hormones, which may be involved in ovarian cancer. We evaluated whether common genetic variation in SHBG and its 3' neighbor ATP1B2, in linkage disequilibrium, is associated with the risk of epithelial ovarian cancer. METHODS: The study population included 264 women with ovarian carcinoma and 625 controls participating in a population-based case-control study in Poland. Five common single nucleotide polymorphisms (SNPs) in SHGB and five in ATP1B2 were selected to capture most common variation in this region. RESULTS: None of the SNPs evaluated was significantly associated with ovarian cancer risk, including the putative functional SNPs SHBG D356N (rs6259) and -67G>A 5'UTR (rs1799941). However, our data were consistent with a decreased ovarian cancer risk associated with the variant alleles for these two SNPs, which have been previously associated with increased circulating levels of SHBG. CONCLUSION: These data do not support a substantial association between common genetic variation in SHBG and ovarian cancer risk

The contribution of inherited genotype to breast cancer

The etiology of breast cancer is complex, and is likely to involve the actions of genes at multiple levels along the multistage carcinogenesis process. These inherited genotypes include those that affect the propensity to be exposed to breast carcinogens, and those associated with breast tumorigenesis directly. In addition, inherited genotypes may influence response to breast cancer chemoprevention and treatment. Studies relating inherited genotypes with breast cancer incidence and mortality should consider a broader spectrum of genes and their potential roles in multistage carcinogenesis than have been typically evaluated to date. Understanding the role of inherited genotype at different stages of carcinogenesis could improve our understanding of cancer biology, may identify specific exposures or events that correlate with carcinogenesis, or target relevant biochemical pathways for the development of preventive or therapeutic interventions