Date Published: August 1, 2017
Publisher: Public Library of Science
Author(s): J. C. Censin, Christoph Nowak, Nicholas Cooper, Peter Bergsten, John A. Todd, Tove Fall, Claudia Langenberg
Abstract: BackgroundThe incidence of type 1 diabetes (T1D) is increasing globally. One hypothesis is that increasing childhood obesity rates may explain part of this increase, but, as T1D is rare, intervention studies are challenging to perform. The aim of this study was to assess this hypothesis with a Mendelian randomization approach that uses genetic variants as instrumental variables to test for causal associations.Methods and findingsWe created a genetic instrument of 23 single nucleotide polymorphisms (SNPs) associated with childhood adiposity in children aged 2–10 years. Summary-level association results for these 23 SNPs with childhood-onset (<17 years) T1D were extracted from a meta-analysis of genome-wide association study with 5,913 T1D cases and 8,828 reference samples. Using inverse-variance weighted Mendelian randomization analysis, we found support for an effect of childhood adiposity on T1D risk (odds ratio 1.32, 95% CI 1.06–1.64 per standard deviation score in body mass index [SDS-BMI]). A sensitivity analysis provided evidence of horizontal pleiotropy bias (p = 0.04) diluting the estimates towards the null. We therefore applied Egger regression and multivariable Mendelian randomization methods to control for this type of bias and found evidence in support of a role of childhood adiposity in T1D (odds ratio in Egger regression, 2.76, 95% CI 1.40–5.44). Limitations of our study include that underlying genes and their mechanisms for most of the genetic variants included in the score are not known. Mendelian randomization requires large sample sizes, and power was limited to provide precise estimates. This research has been conducted using data from the Early Growth Genetics (EGG) Consortium, the Genetic Investigation of Anthropometric Traits (GIANT) Consortium, the Tobacco and Genetics (TAG) Consortium, and the Social Science Genetic Association Consortium (SSGAC), as well as meta-analysis results from a T1D genome-wide association study.ConclusionsThis study provides genetic support for a link between childhood adiposity and T1D risk. Together with evidence from observational studies, our findings further emphasize the importance of measures to reduce the global epidemic of childhood obesity and encourage mechanistic studies.
Partial Text: The incidence of type 1 diabetes (T1D) in children is rising globally, with reports of annual increases over the last decades of up to 3%–4% in Europe [1,2] and 5% in North America . The reasons for this rapid increase in T1D remain obscure . Years before overt T1D develops, autoantibodies against pancreatic islet cells can be detected , and the presence of at least 2 types of autoantibodies is diagnostic of early T1D . The etiology of T1D is generally thought to be autoimmune, where a chronic T lymphocyte-mediated autoimmune reaction is presumed to destroy the insulin-producing beta cells in the pancreas following a trigger event such as an infection [5–7]. This concept, however, has been challenged by recent observations [8,9]. The heritability of T1D is estimated to be 69% , but genetic variation alone cannot explain the recent rapid increase. Several environmental risk factors and potential triggers of the autoimmunity have been investigated, including intake of cow’s milk, breastfeeding practices, socioeconomic status, and enteroviral infections, but causal effects have not been proven .
The main finding of our study is that genetic variants predisposing to childhood adiposity may confer an increased risk of T1D, and we found evidence of a positive correlation between the effect on adiposity and T1D risk. Conditional on MR assumptions being satisfied, our study provides genetic support for a role of childhood adiposity in childhood T1D etiology. Our results support previous findings from observational studies and may indicate a link between the increase in global childhood obesity and T1D incidence in recent decades. We performed rigorous testing of MR assumptions and found evidence of (1) directional pleiotropy (biasing results towards the null) and (2) an association of the genetic score with smoking and birth weight. We therefore performed a series of methods robust to directional pleiotropy that confirmed the main results in favor of an effect of childhood adiposity on T1D independent of measured and unmeasured confounding effects.