CRB1相关遗传性视网膜营养不良患者血浆补体因子升高

Elevated Plasma Complement Factors in CRB1-Associated Inherited Retinal Dystrophies.

作者信息

Moekotte Lude, de Boer Joke H, Hiddingh Sanne, de Ligt Aafke, Nguyen Xuan-Thanh-An, Hoyng Carel B, Inglehearn Chris F, McKibbin Martin, Lamey Tina M, Thompson Jennifer A, Chen Fred K, McLaren Terri L, AlTalbishi Alaa, Panneman Daan M, Boonen Erica G M, Banfi Sandro, Bocquet Béatrice, Meunier Isabelle, De Baere Elfride, Koenekoop Robert, Oldak Monika, Rivolta Carlo, Roberts Lisa, Ramesar Raj, Strupaite-Šileikiene Rasa, Kohl Susanne, Farrar G Jane, van Vugt Marion, van Setten Jessica, Roosing Susanne, van den Born L Ingeborgh, Boon Camiel J F, van Genderen Maria M, Kuiper Jonas J W

机构信息

Department of Ophthalmology, University Medical Center Utrecht, Utrecht, the Netherlands.

Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.

出版信息

Invest Ophthalmol Vis Sci. 2025 Feb 3;66(2):55. doi: 10.1167/iovs.66.2.55.

DOI:10.1167/iovs.66.2.55

PMID:39982393

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11855139/

Abstract

PURPOSE

To determine the profile of inflammation-related proteins and complement system factors in the plasma of CRB1-associated inherited retinal dystrophies (CRB1-IRDs).

METHODS

We used the Olink Explore 384 Inflammation II panel for targeted proteomics in 30 cases and 29 controls (cohort I) to identify immune pathways involved in CRB1-IRDs. Genotyping was performed in cohort I and a second cohort of 123 patients from 14 countries and 1292 controls (cohort II).

RESULTS

A significant shift in complement cascade factors was observed in plasma proteomes of CRB1-IRD patients (enrichment for complement cascade, Padj = 3.03 × 10-15). We detected higher plasma levels of complement factor I and complement factor H [CFH] (q = 0.008 and q = 0.046, respectively, adjusted for age and sex), inhibitors of complement component 3 (C3), which correlated significantly (Pearson's coefficient >0.6) with elevated levels of C3 (q = 0.064). The CRB1 missense variants frequently found in patients showed a strong linkage disequilibrium with the common CFH variant rs7535263 (D' = 0.97 for p.(Cys948Tyr); D' = 1.0 for p.(Arg764Cys)), known to be linked with altered plasma CFH-related protein levels. Correction for the CFH genotype revealed significantly elevated plasma levels of CFH-related 2 (CFHR2) in CRB1-IRD patients (q = 0.041).

CONCLUSIONS

CRB1-IRDs are characterized by changes in plasma levels of complement factors and proteins of the innate immune system, and linkage between CRB1 and CFH genes implicates functional variants of the CFH-CFHR locus with specific pathogenic variants of CRB1.

摘要

目的

确定与CRB1相关的遗传性视网膜营养不良（CRB1-IRD）患者血浆中炎症相关蛋白和补体系统因子的概况。

方法

我们使用Olink Explore 384炎症II检测板对30例患者和29名对照（队列I）进行靶向蛋白质组学分析，以识别参与CRB1-IRD的免疫途径。在队列I以及来自14个国家的123例患者和1292名对照组成的第二个队列（队列II）中进行基因分型。

结果

在CRB1-IRD患者的血浆蛋白质组中观察到补体级联因子的显著变化（补体级联富集，Padj = 3.03×10-15）。我们检测到补体因子I和补体因子H [CFH]的血浆水平较高（分别经年龄和性别校正后，q = 0.008和q = 0.046），补体成分3（C3）的抑制剂与C3水平升高显著相关（Pearson系数>0.6）（q = 0.064）。患者中常见的CRB1错义变异与常见的CFH变异rs7535263显示出很强的连锁不平衡（p.(Cys948Tyr)的D' = 0.97；p.(Arg764Cys)的D' = 1.0），已知该变异与血浆CFH相关蛋白水平的改变有关。校正CFH基因型后发现，CRB1-IRD患者中CFH相关2（CFHR2）的血浆水平显著升高（q = 0.041）。