Associations between multiple immune-response-related proteins and neonatal infection: a proximity extension assay based proteomic study in cord plasma of twins

Background Given their immature immune system, neonates are highly susceptible to infection, a major cause of neonatal death. However, associations between immune-response-related proteins and risk of neonatal infection have yet been systematically investigated. Methods We conducted a nested case-control study of 149 twins (60 cases and 89 controls, including 34 pairs of discordant twins), within the Shenzhen Baoan Birth and Twin (SZBBTwin) cohort. Using proximity extension assay of Olink Proteomics, 92 immune-response-related proteins were measured in samples of cord plasma. All twins were followed for a diagnosis of infection from birth until 27 days of age. Wilcoxon rank-sum test was used to determine differentially expressed proteins (DEPs), and multivariable logistic regression was used to assess the associations of the levels of proteins with neonatal infection. The receiver operating characteristic curve was plotted to evaluate the predictive performance of DEPs. Enrichment analysis was performed to annotate potential functions and pathways of DEPs. Results Five DEPs (ITGA11, FCRL6, DDX58, SH2D1A, and EDAR) were identified for neonatal infection. A higher cord plasma level of integrin alpha 11 (ITGA11) was associated with a higher risk of neonatal infection in both the analyses of all twins and discordant twins. The area under the curve achieved 0.835 for the five DEPs. The identified DEPs were mainly involved in immune function and protein binding, and most of them were enriched in the nuclear factor kappa-B pathway. Conclusion Multiple immune-response-related proteins in cord plasma, particularly ITGA11, are associated with the risk of neonatal infection. Key point In this nested case-control study, 92 immune-response-related proteins were measured in cord plasma by proximity extension assay. A higher level of ITGA11 was associated with a higher risk of neonatal infection, in the analyses of all twins and discordant twins. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the Fundamental Research Funds for the Central Universities, Sun Yat-sen University (R. Chen, Grant No.: 22qntd4311), the 100 Talents Plan Foundation of Sun Yat-sen University (R. Chen, Grant No.: 58000-12230022), the Guangdong Basic and Applied Basic Research Fund (R. Chen, Grant No.: 2022A1515110417), the Science, Technology and Innovation Council of Shenzhen (X. Chen, Grant No.: JCYJ20190809152801661), and the National Natural Science Foundation of China (X. Chen, Grant No.: 82001652). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Baoan Women's and Children's Hospital gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors