甲状腺功能减退症与溃疡性结肠炎之间的因果关系：一项双向孟德尔随机化研究。

Causal relationship between hypothyroidism and ulcerative colitis: a bidirectional Mendelian randomization study.

机构信息

Xi'an Medical University, Xi'an, 710021, Shaanxi, China.

Department of Gastroenterology, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710038, Shaanxi, China.

出版信息

BMC Gastroenterol. 2024 Oct 30;24(1):385. doi: 10.1186/s12876-024-03461-y.

DOI:10.1186/s12876-024-03461-y

PMID:39478467

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11526713/

Abstract

OBJECTIVE

Ulcerative colitis (UC) and Hashimoto's thyroiditis frequently cooccur in patients with multiple autoimmune conditions, but the specific association between UC and hypothyroidism is unknown. We used Mendelian randomization (MR) methods to determine the causal relationship between UC and hypothyroidism.

METHODS

We obtained single nucleotide polymorphisms (SNPs) related to ulcerative colitis (UC) and hypothyroidism from genome-wide association studies (GWAS) available in the public database of the Integrated Epidemiology Unit (IEU). To assess the causal relationship between UC and hypothyroidism, we employed MR-Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode methods. Sensitivity analyses were performed using Cochran's Q test, the horizontal pleiotropy test, and the leave-one-out (LOO) method to assess the reliability of the MR data. The genes corresponding to instrumental variables (IVs) were subjected to Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of the Genome (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) analysis to explore the mechanisms behind the causal relationships at the gene level.

RESULTS

Forward MR analysis indicated that hypothyroidism was associated with an increased risk of UC (IVW: P = 0.02, OR = 9.71, 95% confidence interval (CI) = 1.36-69.46). In contrast, reverse MR did not demonstrate a causal relationship between UC and hypothyroidism (IVW: P = 0.53). Sensitivity analysis proved the reliability of the results. The PPI network revealed CD247, CD80, and STAT4 as central genes. GO and KEGG analyses revealed significant enrichment of the T cell, gamma interferon (IFN-γ), and programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathways.

CONCLUSION

Hypothyroidism was a risk factor for UC. The balance of T-cell differentiation played an important role in the process of hypothyroidism-induced UC, and IL-21 might be the key to finding a cure. Enrichment of PD-1/PD-L1 might attenuate inflammation by suppressing the immune action of T cells.

摘要

目的

溃疡性结肠炎（UC）和桥本甲状腺炎常同时发生在患有多种自身免疫性疾病的患者中，但 UC 与甲状腺功能减退症之间的具体关联尚不清楚。我们使用孟德尔随机化（MR）方法来确定 UC 和甲状腺功能减退症之间的因果关系。

方法

我们从公共数据库整合流行病学单元（IEU）中获得与溃疡性结肠炎（UC）和甲状腺功能减退症相关的单核苷酸多态性（SNP）。为了评估 UC 和甲状腺功能减退症之间的因果关系，我们采用了 MR-Egger、加权中位数、逆方差加权（IVW）、简单模式和加权模式方法。使用 Cochran's Q 检验、水平多效性检验和留一法（LOO）来评估 MR 数据的可靠性，对敏感性分析进行了检验。对工具变量（IVs）对应的基因进行基因本体论（GO）功能注释、京都基因与基因组百科全书（KEGG）途径富集分析和蛋白质-蛋白质相互作用（PPI）分析，以探索基因水平因果关系的机制。

结果

正向 MR 分析表明，甲状腺功能减退症与 UC 的风险增加相关（IVW：P=0.02，OR=9.71，95%置信区间（CI）=1.36-69.46）。相反，反向 MR 并未显示 UC 和甲状腺功能减退症之间存在因果关系（IVW：P=0.53）。敏感性分析证明了结果的可靠性。PPI 网络显示 CD247、CD80 和 STAT4 是中心基因。GO 和 KEGG 分析显示 T 细胞、γ干扰素（IFN-γ）和程序性细胞死亡-1（PD-1）/程序性细胞死亡配体-1（PD-L1）途径有显著富集。