PDF(Pubmed)
Abstract：
BACKGROUND: Observational studies have suggested an association between birth weight and type 2 diabetes mellitus, but the causality between them has not been established. We aimed to obtain the causal relationship between birth weight with T2DM and quantify the mediating effects of potential modifiable risk factors.
METHODS: Two-step, two-sample Mendelian randomization (MR) techniques were applied using SNPs as genetic instruments for exposure and mediators. Summary data from genome-wide association studies (GWAS) for birth weight, T2DM, and a series of fatty acids traits and their ratios were leveraged. The inverse variance weighted (IVW) method was the main analysis approach. In addition, the heterogeneity test, horizontal pleiotropy test, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test, and leave-one-out analysis were carried out to assess the robustness.
RESULTS: The IVW method showed that lower birth weight raised the risk of T2DM (β: -1.113, 95% CI: -1.573 ∼ -0.652). Two-step MR identified 4 of 17 candidate mediators partially mediating the effect of lower birth weight on T2DM, including ratio of polyunsaturated fatty acids to monounsaturated fatty acids (proportion mediated: 7.9%), ratio of polyunsaturated fatty acids to total fatty acids (7.2%), ratio of omega-6 fatty acids to total fatty acids (8.1%) and ratio of linoleic acid to total fatty acids ratio (6.0%).
CONCLUSIONS: Our findings supported a potentially causal effect of birth weight against T2DM with considerable mediation by modifiable risk factors. Interventions that target these factors have the potential to reduce the burden of T2DM attributable to low birth weight.
METHODS: Two-step, two-sample Mendelian randomization (MR) techniques were applied using SNPs as genetic instruments for exposure and mediators. Summary data from genome-wide association studies (GWAS) for birth weight, T2DM, and a series of fatty acids traits and their ratios were leveraged. The inverse variance weighted (IVW) method was the main analysis approach. In addition, the heterogeneity test, horizontal pleiotropy test, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test, and leave-one-out analysis were carried out to assess the robustness.
RESULTS: The IVW method showed that lower birth weight raised the risk of T2DM (β: -1.113, 95% CI: -1.573 ∼ -0.652). Two-step MR identified 4 of 17 candidate mediators partially mediating the effect of lower birth weight on T2DM, including ratio of polyunsaturated fatty acids to monounsaturated fatty acids (proportion mediated: 7.9%), ratio of polyunsaturated fatty acids to total fatty acids (7.2%), ratio of omega-6 fatty acids to total fatty acids (8.1%) and ratio of linoleic acid to total fatty acids ratio (6.0%).
CONCLUSIONS: Our findings supported a potentially causal effect of birth weight against T2DM with considerable mediation by modifiable risk factors. Interventions that target these factors have the potential to reduce the burden of T2DM attributable to low birth weight.
摘要：
背景：观察性研究表明出生体重与2型糖尿病之间存在关联，但是它们之间的因果关系尚未确定。我们旨在获得出生体重与T2DM之间的因果关系，并量化潜在可改变的危险因素的中介作用。
方法：两步，采用双样本孟德尔随机化(MR)技术,使用SNPs作为暴露和介质的遗传工具.来自出生体重的全基因组关联研究（GWAS）的汇总数据，T2DM,并利用了一系列脂肪酸性状及其比例。逆方差加权(IVW)方法是主要的分析方法。此外,异质性检验，水平多效性测试，孟德尔随机化多效性残差和异常值(MR-PRESSO)检验，并进行留一法分析以评估稳健性。
结果：IVW方法显示出生体重降低会增加T2DM的风险（β：-1.113，95％CI：-1.573~-0.652）。两步MR确定了17个候选介质中的4个，部分介导了较低出生体重对T2DM的影响，包括多不饱和脂肪酸与单不饱和脂肪酸的比例（介导的比例：7.9％），多不饱和脂肪酸与总脂肪酸的比例（7.2%），ω-6脂肪酸与总脂肪酸的比率(8.1%)和亚油酸与总脂肪酸的比率(6.0%)。
结论：我们的研究结果支持出生体重对T2DM的潜在因果效应，并通过可改变的危险因素进行相当大的中介作用。针对这些因素的干预措施有可能减轻低出生体重导致的T2DM负担。
方法：两步，采用双样本孟德尔随机化(MR)技术,使用SNPs作为暴露和介质的遗传工具.来自出生体重的全基因组关联研究（GWAS）的汇总数据，T2DM,并利用了一系列脂肪酸性状及其比例。逆方差加权(IVW)方法是主要的分析方法。此外,异质性检验，水平多效性测试，孟德尔随机化多效性残差和异常值(MR-PRESSO)检验，并进行留一法分析以评估稳健性。
结果：IVW方法显示出生体重降低会增加T2DM的风险（β：-1.113，95％CI：-1.573~-0.652）。两步MR确定了17个候选介质中的4个，部分介导了较低出生体重对T2DM的影响，包括多不饱和脂肪酸与单不饱和脂肪酸的比例（介导的比例：7.9％），多不饱和脂肪酸与总脂肪酸的比例（7.2%），ω-6脂肪酸与总脂肪酸的比率(8.1%)和亚油酸与总脂肪酸的比率(6.0%)。
结论：我们的研究结果支持出生体重对T2DM的潜在因果效应，并通过可改变的危险因素进行相当大的中介作用。针对这些因素的干预措施有可能减轻低出生体重导致的T2DM负担。
