Genetically predicted inflammatory cytokine levels and risk of retinitis pigmentosa

This study aims to estimate the potential causal relationship between genetically predicted levels of inflammatory cytokine and retinitis pigmentosa (RP) by performing Mendelian randomization (MR). Single nucleotide polymorphisms (SNPs) were identified as instrumental variables (IVs) from publicly available genome-wide association study datasets. Inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods were applied in this MR analysis. IVW and MR-Egger were used to confirm heterogeneity and pleiotropy of identified IVs. Leave-one-SNP-out analysis was used to identify SNPs with potential impact. IVW results revealed that elevated levels of Tumor Necrosis Factor Alpha (TNF-α), Macrophage Inflammatory Protein-1a (MIP1a), and Monokine Induced by Gamma Interferon (MIG) were associated with higher RP risk (OR = 2.358, <i>p</i> = 0.050; OR = 2.583, <i>p</i> = 0.013; OR = 1.851, <i>p</i> = 0.015), while elevated levels of Interleukin-16 (IL-16) were associated with reduced RP risk (OR = 0.723, <i>p</i> = 0.019). The results of heterogeneity and pleiotropy (<i>p</i> &gt; 0.05) confirmed there was no pleiotropy and heterogeneity in our IVW analysis. The association of TNF-α, MIP1a, MIG and IL-16 with RP from sensitivity analyses using these two sets of restricted IVs remained stable. Our study provides evidence of potential causal relationships between several circulating cytokine levels and RP. Elevated levels of TNF-α, MIP1a, and MIG are associated with a higher risk of RP, while elevated levels of IL-16 are associated with a lower risk of RP. These cytokines may be novel biomarkers and therapeutic targets for RP.

本研究旨在通过孟德尔随机化（Mendelian randomization, MR）分析，探究遗传预测的炎症细胞因子水平与色素性视网膜炎（retinitis pigmentosa, RP）之间的潜在因果关联。研究从公开的全基因组关联研究（genome-wide association study, GWAS）数据集中筛选出单核苷酸多态性（single nucleotide polymorphisms, SNPs）作为工具变量（instrumental variables, IVs）。本MR分析采用了逆方差加权（Inverse-variance weighted, IVW）、MR-Egger、加权中位数、简单众数以及加权众数方法；其中IVW与MR-Egger用于验证筛选得到的IVs的异质性与多效性。留一SNP分析（Leave-one-SNP-out analysis）用于识别具有潜在影响的SNPs。IVW分析结果显示，肿瘤坏死因子-α（Tumor Necrosis Factor Alpha, TNF-α）、巨噬细胞炎症蛋白-1α（Macrophage Inflammatory Protein-1a, MIP1α）以及γ干扰素诱导单核细胞因子（Monokine Induced by Gamma Interferon, MIG）水平升高与色素性视网膜炎风险升高相关（优势比OR=2.358，*P*=0.050；OR=2.583，*P*=0.013；OR=1.851，*P*=0.015）；而白细胞介素-16（Interleukin-16, IL-16）水平升高则与色素性视网膜炎风险降低相关（OR=0.723，*P*=0.019）。异质性与多效性分析结果（*P*>0.05）证实，本研究的IVW分析中不存在多效性与异质性。采用两组受限IVs进行的敏感性分析显示，TNF-α、MIP1α、MIG以及IL-16与色素性视网膜炎的关联依然稳定。本研究为多种循环细胞因子水平与色素性视网膜炎之间存在潜在因果关联提供了证据。其中TNF-α、MIP1α与MIG水平升高会增加色素性视网膜炎的发病风险，而IL-16水平升高则会降低该风险。上述细胞因子或可成为色素性视网膜炎的新型生物标志物与治疗靶点。