Huang Haochen, Yu Bo, Yu Fengyun, Wu Zhen-Zhen, Xu Dong, Zhang Ling-Ling
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China.
National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, 100730, China.
Diabetol Metab Syndr. 2025 Jun 5;17(1):195. doi: 10.1186/s13098-025-01743-3.
Previous epidemiological observational studies have indicated an association between type 1 diabetes (T1DM) and systemic sclerosis (SSc). However, the potential causal relationship between T1DM and SSc remains unclear. Therefore, this Mendelian randomization (MR) study aims to investigate the bidirectional causal relationship between T1DM and SSc through a bidirectional two-sample mendelian randomization analysis.
We utilized SNP data aggregated from previously published genome-wide association studies (GWAS) and selected appropriate SNPs as instrumental variables (IVs). To explore the bidirectional causal relationship between T1DM and SSc, we conducted bidirectional Mendelian randomization analyses using various methods, including inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode approaches. Additionally, sensitivity analyses were performed to further validate the accuracy of the MR results.
Our MR analysis using 66 SNPs as IVs for T1DM showed a genetically determined association with an increased risk of SSc (IVW OR = 1.294, 95% CI 1.140-1.469, p < 0.001), consistent across MR-Egger, weighted median, and weighted mode methods, with no evidence of horizontal pleiotropy or heterogeneity, and robustness confirmed by leave-one-out analysis. Conversely, reverse MR analysis using 7 SNPs for SSc revealed no significant association with T1DM (IVW OR = 0.998, 95% CI 0.979-1.016, P = 0.798), consistent across all methods, with no evidence of pleiotropy or heterogeneity, and results confirmed as robust.
This pioneering mendelian randomization study reveals a causal link between genetic susceptibility to T1DM and an increased risk of SSc, though not vice versa, emphasizing the need for validation across diverse populations and further exploration of underlying mechanisms.
先前的流行病学观察性研究表明1型糖尿病（T1DM）与系统性硬化症（SSc）之间存在关联。然而，T1DM与SSc之间的潜在因果关系仍不清楚。因此，这项孟德尔随机化（MR）研究旨在通过双向双样本孟德尔随机化分析来探究T1DM与SSc之间的双向因果关系。
我们利用了从先前发表的全基因组关联研究（GWAS）中汇总的单核苷酸多态性（SNP）数据，并选择合适的SNP作为工具变量（IV）。为了探究T1DM与SSc之间的双向因果关系，我们使用了多种方法进行双向孟德尔随机化分析，包括逆方差加权（IVW）、MR-Egger、加权中位数和加权模式方法。此外，还进行了敏感性分析以进一步验证MR结果的准确性。
我们使用66个SNP作为T1DM的IV进行的MR分析显示，遗传决定的关联与SSc风险增加相关（IVW比值比[OR]=1.294，95%置信区间[CI]为1.140-1.469，p<0.001），在MR-Egger、加权中位数和加权模式方法中结果一致，没有水平多效性或异质性的证据，留一法分析证实了结果的稳健性。相反，使用7个SNP作为SSc的IV进行的反向MR分析显示与T1DM无显著关联（IVW OR=0.99, 95% CI 0.979-1.016, P=0.798），所有方法结果一致，没有多效性或异质性的证据，结果证实是稳健的。
这项开创性的孟德尔随机化研究揭示了T1DM遗传易感性与SSc风险增加之间的因果联系，但反之不然，强调需要在不同人群中进行验证并进一步探索潜在机制。
