Association of the serological status of rheumatoid arthritis patients with two circulating protein biomarkers: A useful tool for precision medicine strategies
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints and presence of systemic autoantibodies, with a great clinical and molecular heterogeneity. Rheumatoid Factor (RF) and anti-citrullinated protein antibodies (ACPA) are routinely used for the diagno...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmed.2022.963540/full |
| _version_ | 1811197292100714496 |
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| author | Cristina Ruiz-Romero Cristina Ruiz-Romero Patricia Fernández-Puente Lucía González Anna Illiano Anna Illiano Lucía Lourido Rocío Paz Patricia Quaranta Eva Perez-Pampín Antonio González Francisco J. Blanco Francisco J. Blanco Valentina Calamia |
| author_facet | Cristina Ruiz-Romero Cristina Ruiz-Romero Patricia Fernández-Puente Lucía González Anna Illiano Anna Illiano Lucía Lourido Rocío Paz Patricia Quaranta Eva Perez-Pampín Antonio González Francisco J. Blanco Francisco J. Blanco Valentina Calamia |
| author_sort | Cristina Ruiz-Romero |
| collection | DOAJ |
| description | Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints and presence of systemic autoantibodies, with a great clinical and molecular heterogeneity. Rheumatoid Factor (RF) and anti-citrullinated protein antibodies (ACPA) are routinely used for the diagnosis of RA. However, additional serological markers are needed to improve the clinical management of this disease, allowing for better patient stratification and the desirable application of precision medicine strategies. In the present study, we investigated those systemic molecular changes that are associated with the RF and ACPA status of RA patients. To achieve this objective, we followed a proteomic biomarker pipeline from the discovery phase to validation. First, we performed an iTRAQ-based quantitative proteomic experiment on serum samples from the RA cohort of the Hospital of Santiago de Compostela (CHUS). In this discovery phase, serum samples from the CHUS cohort were pooled according to their RF/ACPA status. Shotgun analysis revealed that, in comparison with the double negative group (RF–/ACPA–), the abundance of 12 proteins was altered in the RF+/ACPA+ pool, 16 in the RF+/ACPA– pool and 10 in the RF-/ACPA+ pool. Vitamin D binding protein and haptoglobin were the unique proteins increased in all the comparisons. For the verification phase, 80 samples from the same cohort were analyzed individually. To this end, we developed a Multiple Reaction Monitoring (MRM) method that was employed in a comprehensive targeted analysis with the aim of verifying the results obtained in the discovery phase. Thirty-one peptides belonging to 12 proteins associated with RF and/or ACPA status were quantified by MRM. In a final validation phase, the serum levels of alpha-1-acid glycoprotein 1 (A1AG1), haptoglobin (HPT) and retinol-binding protein 4 (RET4) were measured by immunoassays in the RA cohort of the Hospital of A Coruña (HUAC). The increase of two of these putative biomarkers in the double seropositive group was validated in 260 patients from this cohort (p = 0.009 A1AG1; p = 0.003 HPT). The increased level of A1AG1 showed association with RF rather than ACPA (p = 0.023), whereas HPT showed association with ACPA rather than RF (p = 0.013). Altogether, this study has allowed a further classification of the RA seropositive patients into two novel clusters: RF+A1AG+ and ACPA+HPT+. The determination of A1AG1 and HPT in serum would provide novel information useful for RA patient stratification, which could facilitate the effective implementation of personalized medicine in routine clinical practice. |
| first_indexed | 2024-04-12T01:11:37Z |
| format | Article |
| id | doaj.art-efbdfe3e83ca4ddb9d8f39a77c4b2590 |
| institution | Directory Open Access Journal |
| issn | 2296-858X |
| language | English |
| last_indexed | 2024-04-12T01:11:37Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Medicine |
| spelling | doaj.art-efbdfe3e83ca4ddb9d8f39a77c4b25902022-12-22T03:54:05ZengFrontiers Media S.A.Frontiers in Medicine2296-858X2022-10-01910.3389/fmed.2022.963540963540Association of the serological status of rheumatoid arthritis patients with two circulating protein biomarkers: A useful tool for precision medicine strategiesCristina Ruiz-Romero0Cristina Ruiz-Romero1Patricia Fernández-Puente2Lucía González3Anna Illiano4Anna Illiano5Lucía Lourido6Rocío Paz7Patricia Quaranta8Eva Perez-Pampín9Antonio González10Francisco J. Blanco11Francisco J. Blanco12Valentina Calamia13Unidad de Proteómica, Grupo de Investigación de Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), A Coruña, SpainCentro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, SpainCentro de Investigaciones Científicas Avanzadas (CICA), Universidad de A Coruña (UDC), A Coruña, SpainUnidad de Proteómica, Grupo de Investigación de Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), A Coruña, SpainCEINGE—Advanced Biotechnology, Naples, ItalyDepartment of Chemical Sciences, University of Naples Federico II, Naples, ItalyUnidad de Proteómica, Grupo de Investigación de Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), A Coruña, SpainUnidad de Proteómica, Grupo de Investigación de Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), A Coruña, SpainUnidad de Proteómica, Grupo de Investigación de Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), A Coruña, SpainLaboratorio de Investigación 10 and Rheumatology Unit, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario de Santiago (CHUS), Santiago de Compostela, SpainLaboratorio de Investigación 10 and Rheumatology Unit, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario de Santiago (CHUS), Santiago de Compostela, SpainUnidad de Proteómica, Grupo de Investigación de Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), A Coruña, SpainGrupo de Investigación de Reumatología y Salud (GIR-S), Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Fisioterapia, Universidade da Coruña (UDC), A Coruña, SpainUnidad de Proteómica, Grupo de Investigación de Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), A Coruña, SpainRheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints and presence of systemic autoantibodies, with a great clinical and molecular heterogeneity. Rheumatoid Factor (RF) and anti-citrullinated protein antibodies (ACPA) are routinely used for the diagnosis of RA. However, additional serological markers are needed to improve the clinical management of this disease, allowing for better patient stratification and the desirable application of precision medicine strategies. In the present study, we investigated those systemic molecular changes that are associated with the RF and ACPA status of RA patients. To achieve this objective, we followed a proteomic biomarker pipeline from the discovery phase to validation. First, we performed an iTRAQ-based quantitative proteomic experiment on serum samples from the RA cohort of the Hospital of Santiago de Compostela (CHUS). In this discovery phase, serum samples from the CHUS cohort were pooled according to their RF/ACPA status. Shotgun analysis revealed that, in comparison with the double negative group (RF–/ACPA–), the abundance of 12 proteins was altered in the RF+/ACPA+ pool, 16 in the RF+/ACPA– pool and 10 in the RF-/ACPA+ pool. Vitamin D binding protein and haptoglobin were the unique proteins increased in all the comparisons. For the verification phase, 80 samples from the same cohort were analyzed individually. To this end, we developed a Multiple Reaction Monitoring (MRM) method that was employed in a comprehensive targeted analysis with the aim of verifying the results obtained in the discovery phase. Thirty-one peptides belonging to 12 proteins associated with RF and/or ACPA status were quantified by MRM. In a final validation phase, the serum levels of alpha-1-acid glycoprotein 1 (A1AG1), haptoglobin (HPT) and retinol-binding protein 4 (RET4) were measured by immunoassays in the RA cohort of the Hospital of A Coruña (HUAC). The increase of two of these putative biomarkers in the double seropositive group was validated in 260 patients from this cohort (p = 0.009 A1AG1; p = 0.003 HPT). The increased level of A1AG1 showed association with RF rather than ACPA (p = 0.023), whereas HPT showed association with ACPA rather than RF (p = 0.013). Altogether, this study has allowed a further classification of the RA seropositive patients into two novel clusters: RF+A1AG+ and ACPA+HPT+. The determination of A1AG1 and HPT in serum would provide novel information useful for RA patient stratification, which could facilitate the effective implementation of personalized medicine in routine clinical practice.https://www.frontiersin.org/articles/10.3389/fmed.2022.963540/fullrheumatoid arthritisbiomarkerhaptoglobinorosomucoid 1multiple reaction monitoring |
| spellingShingle | Cristina Ruiz-Romero Cristina Ruiz-Romero Patricia Fernández-Puente Lucía González Anna Illiano Anna Illiano Lucía Lourido Rocío Paz Patricia Quaranta Eva Perez-Pampín Antonio González Francisco J. Blanco Francisco J. Blanco Valentina Calamia Association of the serological status of rheumatoid arthritis patients with two circulating protein biomarkers: A useful tool for precision medicine strategies Frontiers in Medicine rheumatoid arthritis biomarker haptoglobin orosomucoid 1 multiple reaction monitoring |
| title | Association of the serological status of rheumatoid arthritis patients with two circulating protein biomarkers: A useful tool for precision medicine strategies |
| title_full | Association of the serological status of rheumatoid arthritis patients with two circulating protein biomarkers: A useful tool for precision medicine strategies |
| title_fullStr | Association of the serological status of rheumatoid arthritis patients with two circulating protein biomarkers: A useful tool for precision medicine strategies |
| title_full_unstemmed | Association of the serological status of rheumatoid arthritis patients with two circulating protein biomarkers: A useful tool for precision medicine strategies |
| title_short | Association of the serological status of rheumatoid arthritis patients with two circulating protein biomarkers: A useful tool for precision medicine strategies |
| title_sort | association of the serological status of rheumatoid arthritis patients with two circulating protein biomarkers a useful tool for precision medicine strategies |
| topic | rheumatoid arthritis biomarker haptoglobin orosomucoid 1 multiple reaction monitoring |
| url | https://www.frontiersin.org/articles/10.3389/fmed.2022.963540/full |
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