Childhood adiposity and risk of type 1 diabetes: A Mendelian randomization study

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.

Genotypes of HLA, TCF7L2, and FTO as potential modifiers of the association between sweetened beverage consumption and risk of LADA and type 2 diabetes

“…In a recent study based on Swedish data, we showed that sweetened beverage consumption may also increase the risk of latent autoimmune diabetes in adults (LADA) [3]. One proposed mechanism for its association with diabetes is that high consumption of sweetened beverages may lead to excess energy intake resulting in increased BMI [4], which in turn is a strong risk factor not only for T2D [5], but also for autoimmune diabetes [6,7]. However, high BMI does not seem to fully explain the associations [1,3]; there may also be direct effects on glucose metabolism including increased insulin resistance [8] and induced beta cell apoptosis [9].…”

Identification of loci where DNA methylation potentially mediates genetic risk of type 1 diabetes

“…To disentangle the causal associations between DNAm and T1D risk, we employed the principles of Mendelian Randomization (MR), which is a powerful technique that has been used in both basic and clinical research [16][17][18][19][20]. Since genotypes are randomly determined at conception and not influenced by environmental confounders [21], they can be used as instruments to proxy exposures that are potentially influencing a trait, thereby mimicking a randomised controlled trial [22].…”

Potential mechanisms of sleeve gastrectomy for reducing weight and improving metabolism in patients with obesity

“…Obesity is a severe medical problem and a heavy burden on people's health and their families worldwide, as well as being considered one of the major risk factors for noncommunicable diseases [1,2]. Increasing evidence has indicated that an increasing number of children are becoming obese because of overeating and overnutrition, which directly leads to various chronic diseases, such as hypertension, coronary heart disease, and type 2 diabetes (T2D) [3][4][5]. The obesity of an individual is usually evaluated by the body mass index (BMI), which is calculated by dividing the weight (BW) in kilograms by the height in meters squared, and if an individual's BMI is 30 kg/m 2 , the individual is considered obese.…”