Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts
We aimed to validate the association of 28 GWAS-identified genetic variants for response to TNF inhibitors (TNFi) in a discovery cohort of 1361 rheumatoid arthritis (RA) patients monitored in routine care and ascertained through the REPAIR consortium and DANBIO registry. We genotyped selected marker...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.672255/full |
| _version_ | 1818894129046749184 |
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| author | Jose Manuel Sánchez-Maldonado Jose Manuel Sánchez-Maldonado Jose Manuel Sánchez-Maldonado Rafael Cáliz Rafael Cáliz Rafael Cáliz Miguel Ángel López-Nevot Miguel Ángel López-Nevot Antonio José Cabrera-Serrano Antonio José Cabrera-Serrano Antonio José Cabrera-Serrano Ana Moñiz-Díez Ana Moñiz-Díez Ana Moñiz-Díez Helena Canhão Helena Canhão Rob Ter Horst Luca Quartuccio Signe B. Sorensen Signe B. Sorensen Bente Glintborg Bente Glintborg Merete L. Hetland Merete L. Hetland Ileana Filipescu Eva Pérez-Pampin Pablo Conesa-Zamora Jerzy Swierkot Alfons A. den Broeder Salvatore De Vita Eva Rabing Brix Petersen Yang Li Yang Li Miguel A. Ferrer Alejandro Escudero Mihai G. Netea Mihai G. Netea Marieke J. H. Coenen Vibeke Andersen Vibeke Andersen Vibeke Andersen João E. Fonseca João E. Fonseca Manuel Jurado Manuel Jurado Manuel Jurado Katarzyna Bogunia-Kubik Eduardo Collantes Juan Sainz Juan Sainz Juan Sainz Juan Sainz |
| author_facet | Jose Manuel Sánchez-Maldonado Jose Manuel Sánchez-Maldonado Jose Manuel Sánchez-Maldonado Rafael Cáliz Rafael Cáliz Rafael Cáliz Miguel Ángel López-Nevot Miguel Ángel López-Nevot Antonio José Cabrera-Serrano Antonio José Cabrera-Serrano Antonio José Cabrera-Serrano Ana Moñiz-Díez Ana Moñiz-Díez Ana Moñiz-Díez Helena Canhão Helena Canhão Rob Ter Horst Luca Quartuccio Signe B. Sorensen Signe B. Sorensen Bente Glintborg Bente Glintborg Merete L. Hetland Merete L. Hetland Ileana Filipescu Eva Pérez-Pampin Pablo Conesa-Zamora Jerzy Swierkot Alfons A. den Broeder Salvatore De Vita Eva Rabing Brix Petersen Yang Li Yang Li Miguel A. Ferrer Alejandro Escudero Mihai G. Netea Mihai G. Netea Marieke J. H. Coenen Vibeke Andersen Vibeke Andersen Vibeke Andersen João E. Fonseca João E. Fonseca Manuel Jurado Manuel Jurado Manuel Jurado Katarzyna Bogunia-Kubik Eduardo Collantes Juan Sainz Juan Sainz Juan Sainz Juan Sainz |
| author_sort | Jose Manuel Sánchez-Maldonado |
| collection | DOAJ |
| description | We aimed to validate the association of 28 GWAS-identified genetic variants for response to TNF inhibitors (TNFi) in a discovery cohort of 1361 rheumatoid arthritis (RA) patients monitored in routine care and ascertained through the REPAIR consortium and DANBIO registry. We genotyped selected markers and evaluated their association with response to TNFi after 6 months of treatment according to the change in disease activity score 28 (ΔDAS28). Next, we confirmed the most interesting results through meta-analysis of our data with those from the DREAM cohort that included 706 RA patients treated with TNFi. The meta-analysis of the discovery cohort and DREAM registry including 2067 RA patients revealed an overall association of the LINC02549rs7767069 SNP with a lower improvement in DAS28 that remained significant after correction for multiple testing (per-allele ORMeta=0.83, PMeta=0.000077; PHet=0.61). In addition, we found that each copy of the LRRC55rs717117G allele was significantly associated with lower improvement in DAS28 in rheumatoid factor (RF)-positive patients (per-allele ORMeta=0.67, P=0.00058; PHet=0.06) whereas an opposite but not significant effect was detected in RF-negative subjects (per-allele ORMeta=1.38, P=0.10; PHet=0.45; PInteraction=0.00028). Interestingly, although the identified associations did not survive multiple testing correction, the meta-analysis also showed overall and RF-specific associations for the MAFBrs6071980 and CNTN5rs1813443 SNPs with decreased changes in DAS28 (per-allele ORMeta_rs6071980 = 0.85, P=0.0059; PHet=0.63 and ORMeta_rs1813443_RF+=0.81, P=0.0059; PHet=0.69 and ORMeta_rs1813443_RF-=1.00, P=0.99; PHet=0.12; PInteraction=0.032). Mechanistically, we found that subjects carrying the LINC02549rs7767069T allele had significantly increased numbers of CD45RO+CD45RA+ T cells (P=0.000025) whereas carriers of the LINC02549rs7767069T/T genotype showed significantly increased levels of soluble scavengers CD5 and CD6 in serum (P=0.00037 and P=0.00041). In addition, carriers of the LRRC55rs717117G allele showed decreased production of IL6 after stimulation of PBMCs with B burgdorferi and E coli bacteria (P=0.00046 and P=0.00044), which suggested a reduced IL6-mediated anti-inflammatory effect of this marker to worsen the response to TNFi. In conclusion, this study confirmed the influence of the LINC02549 and LRRC55 loci to determine the response to TNFi in RA patients and suggested a weak effect of the MAFB and CNTN5 loci that need to be further investigated. |
| first_indexed | 2024-12-19T18:23:35Z |
| format | Article |
| id | doaj.art-e4c5f12e835340ef831d54b5c7960d76 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T18:23:35Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-e4c5f12e835340ef831d54b5c7960d762022-12-21T20:10:54ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-10-011210.3389/fimmu.2021.672255672255Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large CohortsJose Manuel Sánchez-Maldonado0Jose Manuel Sánchez-Maldonado1Jose Manuel Sánchez-Maldonado2Rafael Cáliz3Rafael Cáliz4Rafael Cáliz5Miguel Ángel López-Nevot6Miguel Ángel López-Nevot7Antonio José Cabrera-Serrano8Antonio José Cabrera-Serrano9Antonio José Cabrera-Serrano10Ana Moñiz-Díez11Ana Moñiz-Díez12Ana Moñiz-Díez13Helena Canhão14Helena Canhão15Rob Ter Horst16Luca Quartuccio17Signe B. Sorensen18Signe B. Sorensen19Bente Glintborg20Bente Glintborg21Merete L. Hetland22Merete L. Hetland23Ileana Filipescu24Eva Pérez-Pampin25Pablo Conesa-Zamora26Jerzy Swierkot27Alfons A. den Broeder28Salvatore De Vita29Eva Rabing Brix Petersen30Yang Li31Yang Li32Miguel A. Ferrer33Alejandro Escudero34Mihai G. Netea35Mihai G. Netea36Marieke J. H. Coenen37Vibeke Andersen38Vibeke Andersen39Vibeke Andersen40João E. Fonseca41João E. Fonseca42Manuel Jurado43Manuel Jurado44Manuel Jurado45Katarzyna Bogunia-Kubik46Eduardo Collantes47Juan Sainz48Juan Sainz49Juan Sainz50Juan Sainz51Genomic Oncology Area, Centre for Genomics and Oncological Research (GENYO), Parque tecnológico de la Salud (PTS) Granada, Granada, SpainHematology Department, Virgen de las Nieves University Hospital, Granada, SpainInstituto de Investigación Biosanitaria (IBs) Granada, Granada, SpainGenomic Oncology Area, Centre for Genomics and Oncological Research (GENYO), Parque tecnológico de la Salud (PTS) Granada, Granada, SpainInstituto de Investigación Biosanitaria (IBs) Granada, Granada, SpainDepartment of Rheumatology, Virgen de las Nieves University Hospital, Granada, SpainInstituto de Investigación Biosanitaria (IBs) Granada, Granada, SpainImmunology Department, Virgen de las Nieves University Hospital, Granada, SpainGenomic Oncology Area, Centre for Genomics and Oncological Research (GENYO), Parque tecnológico de la Salud (PTS) Granada, Granada, SpainHematology Department, Virgen de las Nieves University Hospital, Granada, SpainInstituto de Investigación Biosanitaria (IBs) Granada, Granada, SpainGenomic Oncology Area, Centre for Genomics and Oncological Research (GENYO), Parque tecnológico de la Salud (PTS) Granada, Granada, SpainHematology Department, Virgen de las Nieves University Hospital, Granada, SpainInstituto de Investigación Biosanitaria (IBs) Granada, Granada, SpainEpiDoC Unit, CEDOC, NOVA Medical School and National School of Public Health, Universidade Nova de Lisboa, Lisbon, PortugalComprehensive Health Research Center (CHRC), NOVA Medical School, Lisbon, PortugalDepartment of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, Nijmegen, NetherlandsDepartment of Medical Area, Clinic of Rheumatology, University of Udine, Udine, Italy0Molecular Diagnostic and Clinical Research Unit, IRS-Center Sonderjylland, University Hospital of Southern Jutland, Aabenraa, Denmark1Institute of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark2The Danish Rheumatologic Biobank and Copenhagen Center for Arthritis Research (DANBIO) Registry, The Danish Rheumatologic Biobank and Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Rigshospitalet, Glostrup, Denmark3Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark2The Danish Rheumatologic Biobank and Copenhagen Center for Arthritis Research (DANBIO) Registry, The Danish Rheumatologic Biobank and Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Rigshospitalet, Glostrup, Denmark3Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark4Rheumatology Department, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca, Romania5Rheumatology Unit, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain6Clinical Analysis Department, Santa Lucía University Hospital, Cartagena, Spain7Department of Rheumatology and Internal Medicine, Wroclaw Medical University, Wroclaw, Poland8Radboud Institute for Health Sciences, Department of Rheumatology, Radboud University Medical Center, Nijmegen, NetherlandsDepartment of Medical Area, Clinic of Rheumatology, University of Udine, Udine, Italy9Department of Biochemistry and Immunology, University Hospital of Southern Jutland, Aabenraa, DenmarkDepartment of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands0Centre for Individualised Infection Medicine (CiiM) & Centre for Experimental and Clinical Infection Research (TWINCORE), Helmholtz-Centre for Infection Research (HZI) and The Hannover Medical School (MHH), Hannover, GermanyInstituto de Investigación Biosanitaria (IBs) Granada, Granada, Spain1Rheumatology Department, Reina Sofía Hospital/Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba, Córdoba, SpainDepartment of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands2Department for Immunology & Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany3Radboud Institute for Health Sciences, Department of Human Genetics, Radboud University Medical Center, Nijmegen, NetherlandsDepartment of Medical Area, Clinic of Rheumatology, University of Udine, Udine, Italy0Molecular Diagnostic and Clinical Research Unit, IRS-Center Sonderjylland, University Hospital of Southern Jutland, Aabenraa, Denmark4Institute of Regional Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark5Rheumatology and Metabolic Bone Diseases Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte (CHLN), Lisbon, Portugal6Rheumatology Research Unit, Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon Academic Medical Center, Lisbon, PortugalGenomic Oncology Area, Centre for Genomics and Oncological Research (GENYO), Parque tecnológico de la Salud (PTS) Granada, Granada, SpainHematology Department, Virgen de las Nieves University Hospital, Granada, SpainInstituto de Investigación Biosanitaria (IBs) Granada, Granada, Spain7Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland1Rheumatology Department, Reina Sofía Hospital/Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba, Córdoba, SpainGenomic Oncology Area, Centre for Genomics and Oncological Research (GENYO), Parque tecnológico de la Salud (PTS) Granada, Granada, SpainHematology Department, Virgen de las Nieves University Hospital, Granada, SpainInstituto de Investigación Biosanitaria (IBs) Granada, Granada, Spain8Department of Biochemistry and Molecular Biology I, University of Granada, Granada, SpainWe aimed to validate the association of 28 GWAS-identified genetic variants for response to TNF inhibitors (TNFi) in a discovery cohort of 1361 rheumatoid arthritis (RA) patients monitored in routine care and ascertained through the REPAIR consortium and DANBIO registry. We genotyped selected markers and evaluated their association with response to TNFi after 6 months of treatment according to the change in disease activity score 28 (ΔDAS28). Next, we confirmed the most interesting results through meta-analysis of our data with those from the DREAM cohort that included 706 RA patients treated with TNFi. The meta-analysis of the discovery cohort and DREAM registry including 2067 RA patients revealed an overall association of the LINC02549rs7767069 SNP with a lower improvement in DAS28 that remained significant after correction for multiple testing (per-allele ORMeta=0.83, PMeta=0.000077; PHet=0.61). In addition, we found that each copy of the LRRC55rs717117G allele was significantly associated with lower improvement in DAS28 in rheumatoid factor (RF)-positive patients (per-allele ORMeta=0.67, P=0.00058; PHet=0.06) whereas an opposite but not significant effect was detected in RF-negative subjects (per-allele ORMeta=1.38, P=0.10; PHet=0.45; PInteraction=0.00028). Interestingly, although the identified associations did not survive multiple testing correction, the meta-analysis also showed overall and RF-specific associations for the MAFBrs6071980 and CNTN5rs1813443 SNPs with decreased changes in DAS28 (per-allele ORMeta_rs6071980 = 0.85, P=0.0059; PHet=0.63 and ORMeta_rs1813443_RF+=0.81, P=0.0059; PHet=0.69 and ORMeta_rs1813443_RF-=1.00, P=0.99; PHet=0.12; PInteraction=0.032). Mechanistically, we found that subjects carrying the LINC02549rs7767069T allele had significantly increased numbers of CD45RO+CD45RA+ T cells (P=0.000025) whereas carriers of the LINC02549rs7767069T/T genotype showed significantly increased levels of soluble scavengers CD5 and CD6 in serum (P=0.00037 and P=0.00041). In addition, carriers of the LRRC55rs717117G allele showed decreased production of IL6 after stimulation of PBMCs with B burgdorferi and E coli bacteria (P=0.00046 and P=0.00044), which suggested a reduced IL6-mediated anti-inflammatory effect of this marker to worsen the response to TNFi. In conclusion, this study confirmed the influence of the LINC02549 and LRRC55 loci to determine the response to TNFi in RA patients and suggested a weak effect of the MAFB and CNTN5 loci that need to be further investigated.https://www.frontiersin.org/articles/10.3389/fimmu.2021.672255/fullGWASgenetic variantrheumatoid arthritisdrug responseTNF inhibitors |
| spellingShingle | Jose Manuel Sánchez-Maldonado Jose Manuel Sánchez-Maldonado Jose Manuel Sánchez-Maldonado Rafael Cáliz Rafael Cáliz Rafael Cáliz Miguel Ángel López-Nevot Miguel Ángel López-Nevot Antonio José Cabrera-Serrano Antonio José Cabrera-Serrano Antonio José Cabrera-Serrano Ana Moñiz-Díez Ana Moñiz-Díez Ana Moñiz-Díez Helena Canhão Helena Canhão Rob Ter Horst Luca Quartuccio Signe B. Sorensen Signe B. Sorensen Bente Glintborg Bente Glintborg Merete L. Hetland Merete L. Hetland Ileana Filipescu Eva Pérez-Pampin Pablo Conesa-Zamora Jerzy Swierkot Alfons A. den Broeder Salvatore De Vita Eva Rabing Brix Petersen Yang Li Yang Li Miguel A. Ferrer Alejandro Escudero Mihai G. Netea Mihai G. Netea Marieke J. H. Coenen Vibeke Andersen Vibeke Andersen Vibeke Andersen João E. Fonseca João E. Fonseca Manuel Jurado Manuel Jurado Manuel Jurado Katarzyna Bogunia-Kubik Eduardo Collantes Juan Sainz Juan Sainz Juan Sainz Juan Sainz Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts Frontiers in Immunology GWAS genetic variant rheumatoid arthritis drug response TNF inhibitors |
| title | Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts |
| title_full | Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts |
| title_fullStr | Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts |
| title_full_unstemmed | Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts |
| title_short | Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts |
| title_sort | validation of gwas identified variants for anti tnf drug response in rheumatoid arthritis a meta analysis of two large cohorts |
| topic | GWAS genetic variant rheumatoid arthritis drug response TNF inhibitors |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.672255/full |
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