Chances of live birth after exposure to vitamin D-fortified margarine in women with fertility problems: results from a Danish population-based cohort study.

OBJECTIVE: To study the association between extra vitamin D from a mandatory margarine fortification program and chance of live birth among infertile women. DESIGN: Nationwide cohort study. SETTING: Not applicable. PATIENT(S): The study population consisted of 16,212 women diagnosed with infertility from June 1, 1980, to August 31, 1991. INTERVENTIONS(S): We took advantage of the mandatory vitamin D fortification program of margarine in Denmark that was abruptly stopped on May 31, 1985. The termination of the vitamin D fortification served as a cutoff point to separate the study population into various exposure groups. MAIN OUTCOME MEASURE(S): Odds ratios and 95% confidence intervals for the association between vitamin D exposure status and chance of a live birth within 12, 15, and 18 months after first infertility diagnosis. RESULT(S): Women who were diagnosed with infertility during the vitamin D-exposed period had an increased chance of a live birth compared with women diagnosed with infertility during the nonexposed period. For women diagnosed with infertility during the wash-out period, the chance of a live birth was also increased, but somewhat lower. Similar estimates were obtained with longer follow-up, in women with anovulatory infertility, and little seasonal variation was observed when calendar period of conception was applied. CONCLUSION(S): Our findings suggest that infertile women exposed to extra vitamin D from a margarine fortification program had an increased chance of live birth compared with women not exposed to extra vitamin D from fortification.

Coffee, tea and caffeine consumption and risk of primary infertility in women: a Danish cohort study.

INTRODUCTION: The aim of this study was to investigate whether consumption of coffee, tea and caffeine affects the risk of primary infertility in women. MATERIAL AND METHODS: We selected nulliparous Danish women aged 20-29 years from a prospective cohort and retrieved information on coffee and tea consumption from a questionnaire and an interview at enrollment. We assessed the women's fertility by linkage to the Danish Infertility Cohort and retrieved information on children and vital status from the Civil Registration System. All 7574 women included for analysis were followed for primary infertility from the date of enrollment (1991-1993) until 31 December 2010. Analyses were performed with Cox proportional hazard models. RESULTS: During follow up, primary infertility was diagnosed in 822 women. Compared with never consumers, the risk of primary infertility among women who drank coffee or tea was not affected. The risk of primary infertility was neither associated with an increasing number of daily servings of coffee (hazard ratio 1.00; 95% confidence interval (CI), 0.97-1.03) or tea (hazard ratio 1.01; 95% CI, 0.99-1.03) in consumers only. Concerning total caffeine consumption (from coffee and tea), the risk of infertility was similar among consumers compared with never consumers. Finally, none of the additional daily 100 mg of caffeine affected the risk among consumers only (hazard ratio 1.00; 95% CI 0.98-1.02). CONCLUSIONS: In this population-based cohort study, not restricted to women seeking pregnancy, we found no association between coffee, tea or total caffeine consumption and the risk of primary infertility in women.

The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin.

Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q protein was capable of promoting partial PARPi and cisplatin resistance relative to full-length BRCA1, both in vitro and in vivo Furthermore, spliceosome inhibitors reduced BRCA1-Δ11q levels and sensitized cells carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance. Cancer Res; 76(9); 2778-90. ©2016 AACR.

Coffee, tea, and caffeine consumption and risk of epithelial ovarian cancer and borderline ovarian tumors: Results from a Danish case-control study.

BACKGROUND: Epidemiological studies that have investigated the association between coffee, tea and caffeine consumption and ovarian cancer risk have produced conflicting results. Furthermore, only few studies have examined the role of coffee and tea consumption separately for borderline ovarian tumors. By use of data from a large Danish population-based case-control study, we examined the risk of ovarian tumors associated with coffee, tea, and caffeine consumption with a particular focus on characterizing risks by tumor behavior and histology. MATERIAL AND METHODS: From 1995 through 1999, we included 267 women with ovarian cancer, 115 women with borderline ovarian tumors and 911 randomly selected control women. All women completed a beverage frequency questionnaire with detailed information on coffee and tea consumption. Analyses were performed using multiple logistic regression models. RESULTS: Both coffee (OR = 0.90; 95% CI 0.84-0.97 per cup/day) and total caffeine consumption from coffee and tea combined (OR = 0.93; 95% CI 0.88-0.98 per 100 mg/day) decreased the risk of ovarian cancer. These associations were significant only for the serous and "other" subtypes of ovarian cancer. No relation between tea consumption and ovarian cancer risk was observed. The risk estimates for borderline ovarian tumors resembled those observed for ovarian cancer, but did not reach statistical significance. CONCLUSIONS: Our results indicate that coffee consumption and total caffeine consumption from coffee and tea combined is associated with a modest decreased risk of ovarian cancer. However, more biological studies are needed to identify bioactive chemical compounds in coffee that potentially could affect ovarian cancer development.

Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk.

SCOPE: We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. METHODS AND RESULTS: Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10⁻5) and rs828054 (OR = 1.06; p = 1 × 10⁻4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10⁻6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (p(interaction) = 0.03-0.006). CONCLUSION: Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.