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      Maternal diabetes and incidence of childhood cancer – a nationwide cohort study and exploratory genetic analysis

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          Abstract

          Background

          The etiology of childhood cancer is not well understood, but may be linked to prenatal and perinatal factors, such as maternal diabetes. However, this association has not been examined in depth. We aimed to determine if maternal diabetes is associated with risk of childhood brain tumor (CBT), leukemia (all types combined and acute lymphoblastic leukemia [ALL] separately), and lymphoma.

          Methods

          All children born in Sweden between 1973 and 2014 (n=4,239,965) were followed from birth until first cancer diagnosis, age 15 years, or December 31, 2015. Data on maternal diabetes, childhood cancer, and covariates were obtained from nationwide health registers. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated using Cox regression adjusted for potential confounders/mediators. Additionally, we performed an exploratory analysis using results from published genome-wide association studies and functional annotation.

          Results

          Maternal diabetes was associated with lower risk of CBT (adjusted IRR [95% CI]: 0.56 [0.35–0.91]) and higher risk of leukemia (adjusted IRR: 1.47 [1.13–1.92] for all leukemia combined and 1.64 [1.23–2.18] for ALL). These associations were similar for both maternal type 1 diabetes and gestational diabetes. Associations of five previously identified genetic loci were compatible with a causal effect of diabetes traits on neuroblastoma and common Hodgkin’s lymphoma.

          Conclusion

          Children whose mother had diabetes had lower risk of CBT and higher risk of leukemia, compared with children whose mother did not have diabetes. Our results are compatible with a role of prenatal and perinatal glycemic environment in childhood cancer etiology.

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          Most cited references26

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          A reference panel of 64,976 haplotypes for genotype imputation.

          We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.
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            Epidemiology of childhood cancer.

            The present contribution reports childhood cancer incidence and survival rates as well as time trends and geographical variation. The report is based on the databases of population-based cancer registries which joined forces in cooperative projects such as Automated Childhood Cancer Information System (ACCIS) and EUROCARE. According to these data, which refer to the International Classification of Childhood Cancer, leukemias, at 34%, brain tumors, at 23%, and lymphomas, at 12%, represent the largest diagnostic groups among the under 15-year-olds. The most frequent single diagnoses are: acute lymphoblastic leukemia, astrocytoma, neuroblastoma, non-Hodgkin lymphoma, and nephroblastoma. There is considerable variation between countries. Incidence rates range from 130 (British Isles) to 160 cases (Scandinavian countries) per million children. Incidence rates have shown an increase over time since the mid of the last century. In Europe, the yearly increase averages 1.1% for the 1978-1997 period and ranges from 0.6% for the leukemias to 1.8% for soft-tissue sarcomas. The probability of survival has risen considerably over the past decades, with the EUROCARE data showing an improvement of the relative risk of death by 8% when comparing the 2000-2002 time span to the 1995-1999 period. Regarding the years 1995-2002, the data show an overall 5-year survival probability of 81% for Europe and similar values for the USA. The data presented here describe the cancer situation with a specific, European focus. They are drawn from population-based cancer registries that ensure excellent data quality, and as a consequence represent the most valid European population-based data existing at present. It is also apparent that not all countries have data available from nationwide childhood cancer registries, a situation which warrants further improvement. 2010 Elsevier Ltd. All rights reserved.
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              A quality study of a medical birth registry.

              A quality control study was made of the Swedish Medical Birth Registry. This registry used one mode of data collection during 1973-1981 and another from 1982 onwards. The number of errors in the register was checked by comparing register information with a sample of the original medical records, and the variability in the use of diagnoses between hospitals was studied. Different types of errors were identified and quantified and the efficiency of the two methods of data collection evaluated.
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                Author and article information

                Journal
                Clin Epidemiol
                Clin Epidemiol
                Clinical Epidemiology
                Clinical Epidemiology
                Dove Medical Press
                1179-1349
                2017
                30 November 2017
                : 9
                : 633-642
                Affiliations
                [1 ]Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm
                [2 ]Department of Immunology, Genetics and Pathology
                [3 ]Science for Life Laboratory, Uppsala University, Uppsala, Sweden
                Author notes
                Correspondence: Hannah L Brooke, Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, PO Box 210, Stockholm 171 77, Sweden, Tel +46 8 5248 7537, Email hannah.brooke@ 123456ki.se
                [*]

                These authors contributed equally to this work

                Article
                clep-9-633
                10.2147/CLEP.S147188
                5716336
                29238226
                9a8b098b-eefb-486f-b680-e5caa9aa64cd
                © 2017 Deleskog et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Original Research

                Public health
                neoplasm,childhood,diabetes,fetal growth,perinatal environment
                Public health
                neoplasm, childhood, diabetes, fetal growth, perinatal environment

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