Birth weight, BMI in adulthood and latent autoimmune diabetes in adults: A Mendelian randomization study

Abstract

AimsObservational studies have found an increased risk of latent autoimmune diabetes in adults (LADA) associated with low birth weight and adult overweight/obesity. We aimed to investigate whether these associations are causal, using a two-sample Mendelian randomization (MR) design. In addition, we wanted to compare results for LADA and type 2 diabetes. MethodsWe identified 129 SNPs as instrumental variables (IVs) for birth weight from a genome-wide association study (GWAS) of the Early Growth Genetics Consortium (EGG) and the UK Biobank. We identified 820 SNPs as IVs for adult BMI from a GWAS of the UK Biobank and the Genetic Investigation of ANthropometric Traits consortium (GIANT). Summary statistics for the associations between IVs and LADA were extracted from the only GWAS involving 2,634 cases and 5,947 population controls. We used the inverse-variance weighted (IVW) estimator as our primary analysis, supplemented by a series of sensitivity analyses. ResultsGenetically determined birth weight was inversely associated with LADA (OR per SD [[~]500 g] decrease in birth weight: 2.02, 95% CI: 1.37-2.97). In contrast, genetically predicted BMI in adulthood was positively associated with LADA (OR per SD [[~]4.8 kg/m2] increase in BMI: 1.40, 95% CI: 1.14-1.71). Results persisted in a range of sensitivity analyses using other MR estimators or excluding some IVs. With respect to type 2 diabetes, the association with birth weight was not stronger than in LADA while the association with adult BMI was stronger than in LADA. Conclusions/ interpretationThis study provides genetic support for a causal link between low birth weight, adult overweight/obesity, and LADA. Research in contextO_LIWhat is already known about this subject? (maximum of 3 bullet points) Previous Mendelian randomization studies have found that both lower birth weight and higher adult BMI are associated with an increased risk of type 2 diabetes. In contrast, the evidence on latent autoimmune diabetes in adults (LADA) is very limited. Only a few observational studies indicated an inverse association between birth weight and LADA, or a positive association between adult BMI and LADA. C_LIO_LIWhat is the key question Are birth weight and adult adiposity causally associated with LADA? C_LIO_LIWhat are the new findings Genetically determined birth weight was inversely associated with LADA while genetically predicted BMI in adulthood was positively associated with LADA. The association with birth weight was not weaker for LADA than for type 2 diabetes, while adult BMI had a greater impact on type 2 diabetes than on LADA. C_LIO_LIHow might this impact on clinical practice in the foreseeable future Findings from this study indicate that measures should be taken to reduce the prevalence of adult overweight/obesity for the prevention of diabetes with and without an autoimmune component. The mechanism linking low birth weight to diabetes remains to be explored. C_LI