Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
School of Public Health (Shenzhen), Sun Yat-Sen University, Shenzhen, China.
Diabetologia. 2022 Sep;65(9):1510-1518. doi: 10.1007/s00125-022-05725-2. Epub 2022 May 23.
AIMS/HYPOTHESIS: Observational studies have found an increased risk of latent autoimmune diabetes in adults (LADA) associated with low birthweight and adult overweight/obese status. We aimed to investigate whether these associations are causal, using a two-sample Mendelian randomisation (MR) design. In addition, we compared results for LADA and type 2 diabetes.
We identified 43 SNPs acting through the fetal genome as instrumental variables (IVs) for own birthweight 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 2634 cases and 5947 population controls. We used the inverse-variance weighted (IVW) estimator as our primary analysis, supplemented by a series of sensitivity analyses.
Genetically determined own birthweight was inversely associated with LADA (OR per SD [500 g] decrease in birthweight 1.68 [95% CI 1.01, 2.82]). In contrast, genetically predicted BMI in adulthood was positively associated with LADA (OR per SD [4.8 kg/m] increase in BMI 1.40 [95% CI 1.14, 1.71]). Robust results were obtained in a range of sensitivity analyses using other MR estimators or excluding some IVs. With respect to type 2 diabetes, the association with birthweight was not stronger than in LADA while the association with adult BMI was stronger than in LADA.
CONCLUSIONS/ INTERPRETATION: This study provides genetic support for a causal link between low birthweight, adult overweight/obese status and LADA.
目的/假设：观察性研究发现，低出生体重和成年超重/肥胖与成人隐匿性自身免疫性糖尿病（LADA）的风险增加有关。我们旨在使用两样本孟德尔随机化（MR）设计来研究这些关联是否具有因果关系。此外，我们比较了 LADA 和 2 型糖尿病的结果。
我们从早期生长遗传学联盟（EGG）和英国生物库（UK Biobank）的全基因组关联研究（GWAS）中确定了 43 个通过胎儿基因组起作用的 SNP，作为自身出生体重的工具变量（IVs）。我们从 UK Biobank 和遗传与人体测量特征研究联盟（GIANT）的 GWAS 中确定了 820 个作为成人 BMI 的 IVs。与 IVs 和 LADA 之间的关联的汇总统计数据是从唯一一项涉及 2634 例病例和 5947 例人群对照的 GWAS 中提取的。我们使用逆方差加权（IVW）估计量作为主要分析方法，并辅以一系列敏感性分析。
遗传决定的自身出生体重与 LADA 呈负相关（每降低 500 克出生体重的 OR [500 g] 为 1.68 [95%CI 1.01, 2.82]）。相比之下，成年期遗传预测的 BMI 与 LADA 呈正相关（每增加 4.8 千克/平方米 BMI 的 OR [4.8 kg/m] 为 1.40 [95%CI 1.14, 1.71]）。使用其他 MR 估计量或排除一些 IVs 的一系列敏感性分析得到了稳健的结果。关于 2 型糖尿病，与出生体重的关联并不强于 LADA，而与成人 BMI 的关联强于 LADA。
结论/解释：本研究为低出生体重、成年超重/肥胖与 LADA 之间存在因果关系提供了遗传证据。
