Angela L Mazul1, Clarice R Weinberg2, Stephanie M Engel3, Anna Maria Siega-Riz4, Fei Zou5, Kathryn S Carrier3, Patricia V Basta6, Zalman Vaksman7, John M Maris8, Sharon J Diskin8, Charlene Maxen9, Arlene Naranjo10, Andrew F Olshan3. 1. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States; Department of Otolaryngology, Washington University School of Medicine, St Louis, MO, 63110. Electronic address: amazul@wustl.edu. 2. Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences Durham, NC, United States. 3. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States. 4. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States; Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States. 5. Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States. 6. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States; Biospecimen Processing Center, University of North Carolina, Chapel Hill, NC, United States. 7. Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, United States. 8. Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. 9. Showers Center for Childhood Cancer and Blood Disorder, Akron Children's Hospital, Akron, OH, United States. 10. Department of Biostatistics, Colleges of Medicine and Public Health & Health Professions, University of Florida, Children's Oncology Group Statistics & Data Center, Gainesville, FL, United States.
Abstract
BACKGROUND: There is evidence vitamin A plays a role in neuroblastoma. Not only is 13-cis-retinoic acid used as maintenance therapy for high-risk cases, but prenatal vitamin intake use may decrease neuroblastoma risk. We hypothesized that single nucleotide polymorphisms (SNPs) in vitamin A-related genes are may be associated with neuroblastoma risk and potentially be modified by vitamin A intake. METHODS: The Neuroblastoma Epidemiology in North America (NENA) study recruited 563 case-parent sets through the Children's Oncology Group's Childhood Cancer Research Network. We ascertained dietary nutrient intake through questionnaires and genotyped 463 SNPs in vitamin A-related genes from saliva DNA. Offspring and maternal log-additive risk ratios (RR) and stratum-specific RR for gene-environment interaction were estimated with a log-linear model. We avoided false positives due to multiple testing by using the false discovery rate (FDR). RESULTS: When all neuroblastoma cases were considered together, no offspring variants met the significance criteria (FDR Q-value < 0.2). One maternal SNP (rs12442054) was associated with decreased risk of neuroblastoma (RR: 0.61; 95% Confidence Interval (CI): 0.47-0.79, Q = 0.076). When the cases were categorized according to prognostic risk category and age at onset, nine offspring SNPs were significantly associated with intermediate-risk neuroblastoma. Maternal rs6776706 was associated with (RR: 0.49; 95% CI: 0.33-0.72, Q = 0.161) high-risk neuroblastoma and maternal rs11103603 (RR: 0.60; 95% CI: 0.45-0.79, Q = 0.127) was associated with neuroblastoma aged <1 year. For gene-environment interaction, maternal rs729147 was associated with decreased risk of neuroblastoma among mothers with vitamin A consumption above the recommendation. CONCLUSIONS: Although there is biologic plausibility for the role of vitamin A in neuroblastoma, we found weak evidence of a relationship between vitamin A related genes and neuroblastoma.
BACKGROUND: There is evidence vitamin A plays a role in neuroblastoma. Not only is 13-cis-retinoic acid used as maintenance therapy for high-risk cases, but prenatal vitamin intake use may decrease neuroblastoma risk. We hypothesized that single nucleotide polymorphisms (SNPs) in vitamin A-related genes are may be associated with neuroblastoma risk and potentially be modified by vitamin A intake. METHODS: The Neuroblastoma Epidemiology in North America (NENA) study recruited 563 case-parent sets through the Children's Oncology Group's Childhood Cancer Research Network. We ascertained dietary nutrient intake through questionnaires and genotyped 463 SNPs in vitamin A-related genes from saliva DNA. Offspring and maternal log-additive risk ratios (RR) and stratum-specific RR for gene-environment interaction were estimated with a log-linear model. We avoided false positives due to multiple testing by using the false discovery rate (FDR). RESULTS: When all neuroblastoma cases were considered together, no offspring variants met the significance criteria (FDR Q-value < 0.2). One maternal SNP (rs12442054) was associated with decreased risk of neuroblastoma (RR: 0.61; 95% Confidence Interval (CI): 0.47-0.79, Q = 0.076). When the cases were categorized according to prognostic risk category and age at onset, nine offspring SNPs were significantly associated with intermediate-risk neuroblastoma. Maternal rs6776706 was associated with (RR: 0.49; 95% CI: 0.33-0.72, Q = 0.161) high-risk neuroblastoma and maternal rs11103603 (RR: 0.60; 95% CI: 0.45-0.79, Q = 0.127) was associated with neuroblastoma aged <1 year. For gene-environment interaction, maternal rs729147 was associated with decreased risk of neuroblastoma among mothers with vitamin A consumption above the recommendation. CONCLUSIONS: Although there is biologic plausibility for the role of vitamin A in neuroblastoma, we found weak evidence of a relationship between vitamin A related genes and neuroblastoma.
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