AbstractFamilial Mediterranean Fever (FMF) is an autosomal recessive genetic disorder, primarily observed in populations around the Mediterranean Sea, linked to MEFV gene mutations. These mutations disrupt inflammatory responses, increasing pyrin-protein production. Traditional diagnosis relies on clinical symptoms, family history, acute phase reactants, and excluding similar syndromes with MEFV testing, which is expensive and often inconclusive due to heterozygous mutations.

摘要家族性地中海热（FMF）是一种常染色体隐性遗传疾病，主要在地中海周围的人群中观察到，与MEFV基因突变有关。这些突变破坏了炎症反应，增加了吡啶蛋白的产生。传统的诊断依赖于临床症状，家族史，急性期反应物，并通过MEFV检测排除了类似的综合征，由于杂合突变，MEFV检测昂贵且通常不确定。

Here, we present a biosensor platform that detects differences in pyrin-protein levels between healthy and affected individuals, offering a cost-effective alternative to genetic testing. Our platform uses gold nanoparticle-based plasmonic chips enhanced with anti-pyrin antibodies, achieving a detection limit of 0.24 ng/mL with high specificity.

在这里，我们提供了一个生物传感器平台，可以检测健康个体和受影响个体之间吡啶蛋白水平的差异，为基因检测提供了一种经济高效的替代方法。。

The system integrates an optofluidic system and visible light spectroscopy for real-time analysis, with signal stability maintained for up to six months. Our technology will enhance FMF diagnosis accuracy, enabling early treatment initiation and providing a cost-effective alternative to genetic testing, thus improving patient care..

该系统集成了光流体系统和可见光光谱学进行实时分析，信号稳定性可维持长达六个月。我们的技术将提高FMF诊断的准确性，从而能够尽早开始治疗，并为基因检测提供一种经济高效的替代方法，从而改善患者护理。。

IntroductionFamilial Mediterranean Fever (FMF) is a recessive genetic disease that originates in the Mediterranean region, particularly affecting people of Armenian, Arab, Turkish, and Jewish ancestry. For example, it affects approximately 1 in 200–1000 individuals in these populations. While it is highly prevalent in countries surrounding the Eastern Mediterranean basin, there has been an increasing number of cases reported worldwide in recent years1,2,3.

引言家族性地中海热（FMF）是一种隐性遗传疾病，起源于地中海地区，特别影响亚美尼亚，阿拉伯，土耳其和犹太血统的人。例如，它影响这些人群中大约200-1000个人中的1个人。。

Mediterranean Fever (MEFV) gene, associated with FMF, was defined in 19974,5. FMF is characterized by specific symptoms such as episodes of fever, inflammation of serous membranes, and less frequently, complications like amyloidosis, joint restriction, and pericarditis, while it often causes leukocyte infiltration as well6,7,8,9,10,11.

地中海热（MEFV）基因与FMF相关，定义于19974,5。FMF的特征是特定症状，例如发烧，浆膜炎症，以及淀粉样变性，关节受限和心包炎等并发症，而它通常也会导致白细胞浸润6,7,8,9,10,11。

FMF is defined as the impairment of the body’s inflammatory response due to variants in the MEFV gene located on the short arm of chromosome 16. To date, more than 300 variants have been identified in the MEFV gene, with many of them commonly found in exon 1012,13. The MEFV gene encodes the pyrin protein, also known as marenostrin or TRIM2014,15,16.

FMF被定义为由于位于16号染色体短臂上的MEFV基因变异而导致的身体炎症反应受损。迄今为止，已经在MEFV基因中鉴定出300多种变体，其中许多常见于外显子1012,13。MEFV基因编码吡啶蛋白，也称为marenostrin或TRIM2014,15,16。

Consequently, variants in the MEFV gene affect the function of the pyrin protein17. The pyrin protein consists of 781 amino acids and has a molecular weight of 86 kDa16. It is primarily found in neutrophils and macrophages, playing a crucial role in the apoptosis and inflammatory pathways. Mutated pyrin leads to an excessive inflammatory response with uncontrolled secretion of interleukin-1β18,19,20.

因此，MEFV基因的变异会影响吡啶蛋白17的功能。吡啶蛋白由781个氨基酸组成，分子量为86kDa16。它主要存在于中性粒细胞和巨噬细胞中，在细胞凋亡和炎症途径中起着至关重要的作用。。

Variants in the MEFV gene result in an abnormal increase in pyrin protein synthesis and disrupt the regulation of inflammation by pyrin protein6. While the genetic autoinflammatory disease is typically diagnosed in childhood, some individuals ma.

MEFV基因的变异导致吡啶蛋白合成异常增加，并破坏吡啶蛋白6对炎症的调节。虽然遗传性自身炎症性疾病通常在儿童时期被诊断出来，但一些人可能患有这种疾病。

Data availability

数据可用性

Data supporting the findings of this study are available in the article, its Supplementary information, the source data file and from the corresponding author upon request. Source data are provided with this paper.

支持本研究结果的数据可在文章，其补充信息，源数据文件以及通讯作者的要求下获得。本文提供了源数据。

Code availability

代码可用性

Code used to generate findings are available in Zenodo repository66.

Zenodo repository66中提供了用于生成发现的代码。

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https://doi.org/10.5281/zenodo.13731628.Download referencesAcknowledgementsA.E.C. acknowledges the support of The Scientific and Technological Research Council of Türkiye (TÜBİTAK) through the 1005 – National New Ideas and New Products Research Funding Program (Project No. 119E649). This study was also supported in part by the EU Horizon 2020 ERA Chairs Project RareBoost (Project No.

https://doi.org/10.5281/zenodo.13731628.Download参考确认A。E、 C.感谢蒂尔基耶科学技术研究委员会（TÜBİTAK）通过1005-国家新想法和新产品研究资助计划（项目编号119E649）提供的支持。这项研究也得到了欧盟地平线2020年时代主席项目RAREBOST（项目编号）的部分支持。

952346).Author informationAuthor notesThese authors contributed equally: Idil Karaca Acari, Fatma Kurul.Authors and AffiliationsDepartment of Engineering Basic Sciences, Faculty of Engineering and Natural Sciences, Malatya Turgut Ozal University, Yesilyurt, Malatya, TurkeyIdil Karaca AcariIzmir Biomedicine and Genome Center, Balcova, Izmir, TurkeyFatma Kurul, Meryem Beyza Avci, S.

952346）。作者信息作者注意到这些作者做出了同样的贡献：Idil Karaca Acari，Fatma Kurul。作者和附属机构马来亚图尔古特·奥扎尔大学工程与自然科学学院工程基础科学系，马来亚叶斯柳特，土耳其伊迪尔·卡拉卡·阿卡里兹密尔生物医学与基因组中心，巴尔科娃，伊兹密尔，土基法特玛·库鲁尔，Meryem Beyza Avci，S。

Deniz Yasar & Arif E. CetinDepartment of Analytical Chemistry, Faculty of Pharmacy, Izmir Katip Celebi University, Cigli, Izmir, TurkeySeda Nur TopkayaDepartment of Pediatrics, Faculty of Medicine, Inonu University, Battalgazi, Malatya, TurkeyCeyhun AçarıDivision of Pediatric Rheumatology, Faculty of Medicine, Dokuz Eylul University, Balcova, Izmir, TurkeyErbil Ünsal & Balahan MakayDepartment of Chemistry, Faculty of Arts and Science, Inonu University, Battalgazi, Malatya, TurkeySüleyman Köytepe, Burhan Ateş, İsmet Yilmaz & Turgay SeçkinAuthorsIdil Karaca AcariView author publicationsYou can also search for this author in.

Deniz Yasar＆Arif E.CetinDepartment of Analytical Chemistry，Faculty，Izmir Katip Celebi University，Cigli，Izmir，TurkeySeda Nur TopkayaDepartment of Pediatrics，Faculty of Medicine，Inonu University，Battalgazi，Malatya，Turkeyeyhun Açarıdepartment of Pediatric Rhematology，Faculty，Dokuz Eylul University，Balcova，Izmir，TurkeyErbilÜnsal＆Balahan Makaye Inonu University，Battalgazi，Malatya，TurkeySüleyman Köytepe，Burhan Ateş，İsmet Yilmaz＆Turgay SeçkinAuthorsIdil Karaca AcariView作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsA.E.C. served as the principal investigator and provided supervision and funding for the project. I.K.A., S.N.T., C.A., and A.E.C. conceptualized the idea. M.B.A., S.D.Y., F.K., and A.E.C. constructed the optical, mechanical, and electrical read-out setup.

PubMed谷歌学术贡献。E、 C.担任首席研究员，并为项目提供监督和资金。一、 K.A.，S.N.T.，C.A。和A.E.C.将这个想法概念化。M、 B.A.，S.D.Y.，F.K。和A.E.C.构建了光学，机械和电气读数设置。

F.K. and A.E.C. conducted the label-free biosensing experiments. F.K., E.U., and B.M. carried out the patient sample collection and preparation. I.K.A., S.K., B.A., I.Y., and T.S. performed the nanoparticle synthesis. F.K. designed and fabricated all microfluidic apparatus. M.B.A. designed the system software.

F、 K.和A.E.C.进行了无标记生物传感实验。F、 K.，E.U。和B.M.进行了患者样品的收集和制备。一、 K.A.，S.K.，B.A.，I.Y。和T.S.进行了纳米颗粒合成。F、 K.设计并制造了所有微流体装置。M、 B.A.设计了系统软件。

All authors contributed to the preparation of the manuscript.Corresponding authorCorrespondence to.

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I.K.A., S.N.T., C.A., E.U., B.M., S.K., B.A., I.Y., T.S., and A.E.C. have a pending patent application for the pre-diagnostic technology presented in this paper. The remaining authors declare no competing interests.

一、 K.A.，S.N.T.，C.A.，E.U.，B.M.，S.K.，B.A.，I.Y.，T.S.和A.E.C.拥有本文介绍的预诊断技术的未决专利申请。其余作者声明没有利益冲突。

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Reprints and permissionsAbout this articleCite this articleKaraca Acari, I., Kurul, F., Avci, M.B. et al. A plasmonic biosensor pre-diagnostic tool for Familial Mediterranean Fever.

转载和许可本文引用本文Karaca Acari，I.，Kurul，F.，Avci，M.B.等人，一种用于家族性地中海热的等离子体生物传感器预诊断工具。

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