纤连蛋白FN1基因中的rs140926439变异体可保护英国生物银行队列中的APOEε4携带者免受阿尔茨海默病的侵害。

rs140926439 variant in the Fibronectin FN1 gene protects against Alzheimer's disease in APOEε4 carriers in the UK Biobank cohort.

作者信息

Lehrer Steven, Rheinstein Peter

机构信息

Icahn School of Medicine Mount Sinai.

Severn Health Solutions.

出版信息

Res Sq. 2024 Apr 19:rs.3.rs-4287946. doi: 10.21203/rs.3.rs-4287946/v1.

DOI:10.21203/rs.3.rs-4287946/v1

PMID:38699298

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11065070/

Abstract

BACKGROUND

A protective genetic variant in the fibronectin FN1 gene reduces the odds of developing AD by up to 70%. This variant, rs140926439, seems to prevent the buildup of excess fibronectin at the blood brain barrier. Increased fibronectin levels are typically observed in people with Alzheimer's Disease (AD), but the protective variant appears to counteract its effects.

METHODS

In the current study, we analyzed the relationship of FN1 SNP rs140926439, APOEε4, and AD in the UK Biobank cohort.

RESULTS

When rs140926439 was absent, 0.10% of APOEε2/3 carriers had AD while 0.40% of APOEε4 carriers or homozygotes had AD. This difference was significant (p < 0.001, 2 tail Fisher exact test). When rs140926439 was present, 0.10% of APOEε2/3 carriers had AD while 0.10% of APOEε4 carriers or homozygotes had AD. This difference was insignificant (p = 1). To examine the overall relationship of rs140926439 and APOE isoform to AD, we used the univariate general linear model, AD (present or absent) dependent variable, rs140926439 (present or absent) and APOE isoform (APOEε2/3 or APOEε4 carrier or homozygote) as fixed factors. The effect of rs140926439 was significant (p = 0.030). The effect of APOE isoform was significant (p = 0.034). There was also a significant interaction between rs140926439 and APOE isoform (p = 0.030).

CONCLUSION

Fibronectin is an adhesive molecule that is essential to wound healing, especially to the production of extracellular matrix and reepithelialization. Some cases of AD may be due to the initiation of the brain wound healing process, often in the absence of any actual wound. NSAIDS may reduce risk of AD because they potently inhibit wound healing. FN1 appears to be a key player in AD, and its protective variant could offer insights into potential therapeutic targets. However, further research is needed to fully understand the intricate mechanisms underlying AD and to develop effective treatments.

摘要

背景

纤连蛋白FN1基因中的一种保护性基因变异可将患阿尔茨海默病（AD）的几率降低多达70%。这种变异体rs140926439似乎能防止血脑屏障处过量纤连蛋白的积累。在阿尔茨海默病（AD）患者中通常观察到纤连蛋白水平升高，但这种保护性变异体似乎能抵消其影响。

方法

在本研究中，我们分析了英国生物银行队列中FN1单核苷酸多态性rs140926439、载脂蛋白Eε4（APOEε4）与AD之间的关系。

结果

当不存在rs140926439时，0.10%的APOEε2/3携带者患有AD，而0.40%的APOEε4携带者或纯合子患有AD。这种差异具有统计学意义（p < 0.001，双侧Fisher精确检验）。当存在rs140926439时，0.10%的APOEε2/3携带者患有AD，而0.10%的APOEε4携带者或纯合子患有AD。这种差异无统计学意义（p = 1）。为了研究rs140926439和APOE异构体与AD的总体关系，我们使用单变量一般线性模型，以AD（存在或不存在）为因变量，rs140926439（存在或不存在）和APOE异构体（APOEε2/3或APOEε4携带者或纯合子）为固定因素。rs140926439的效应具有统计学意义（p = 0.030）。APOE异构体的效应具有统计学意义（p = 0.034）。rsI40926439和APOE异构体之间也存在显著的相互作用（p = 0.030）。

结论

纤连蛋白是一种黏附分子，对伤口愈合至关重要，尤其是对细胞外基质的产生和上皮再形成。某些AD病例可能是由于脑部伤口愈合过程的启动，通常在没有任何实际伤口的情况下发生。非甾体抗炎药（NSAIDs）可能会降低AD的风险，因为它们能有效抑制伤口愈合。FN1似乎是AD中的关键因素，其保护性变异体可能为潜在治疗靶点提供线索。然而，需要进一步研究以充分了解AD背后复杂的机制并开发有效的治疗方法。