Sara Salvador-Martín1, Bartosz Kaczmarczyk1, Rebeca Álvarez2, Víctor Manuel Navas-López3, Carmen Gallego-Fernández4, Ana Moreno-Álvarez5, Alfonso Solar-Boga5, Cesar Sánchez6, Mar Tolin6, Marta Velasco7, Rosana Muñoz-Codoceo7, Alejandro Rodriguez-Martinez8, Concepción A Vayo9, Ferrán Bossacoma10, Gemma Pujol-Muncunill11, María J Fobelo12, Antonio Millán-Jiménez13, Lorena Magallares14, Eva Martínez-Ojinaga14, Inés Loverdos15, Francisco J Eizaguirre16, José A Blanca-García17, Susana Clemente18, Ruth García-Romero19, Vicente Merino-Bohórquez20, Rafael González de Caldas21, Enrique Vázquez2, Ana Dopazo2, María Sanjurjo-Sáez1, Luis A López-Fernández1. 1. Pharmacy Department, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain. 2. Genomics Unit, Spanish Nacional Center for Cardiovascular Diseases (CNIC), 28029 Madrid, Spain. 3. Pediatric Gastroenterology and Nutrition Unit, Hospital Regional Universitario de Málaga, IBIMA Multidisciplinary Group for Pediatric Research, 29010 Málaga, Spain. 4. Pharmacy Department, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain. 5. Pediatric Gastroenterology Unit, Department of Pediatrics, A Coruña University Hospital, 15006 A Coruña, Spain. 6. Gastroenterology Unit, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain. 7. Department of Pediatric Gastroenterology, Hospital Infantil Universitario Niño Jesús, 28009 Madrid, Spain. 8. Pediatric Gastroenterology, Hepatology and Nutrition Unit, Hospital Universitario Virgen del Rocio, 41013 Seville, Spain. 9. Pharmacy Service, Hospital Universitario Virgen del Rocio, 41013 Seville, Spain. 10. Fundació Sant Joan de Déu, Fundació Salut Emporda, 08950 Barcelona, Spain. 11. Department of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital Sant Joan de Déu, 08950 Barcelona, Spain. 12. Pharmacy Service, Hospital Virgen de Valme, 41014 Sevilla, Spain. 13. Pediatric Gastroenterology Unit, Hospital Virgen de Valme, 41014 Sevilla, Spain. 14. Department of Pediatric Gastroenterology, University Hospital La Paz, 28046 Madrid, Spain. 15. Pediatric Gastroenterology, Hepatology and Nutrition Unit, Hospital de Sabadell, Corporació Sanitària Universitària Parc Taulí, 08208 Barcelona, Spain. 16. Pediatric Gastroenterology Unit, Hospital Universitario Donostia, 20014 San Sebastián, Spain. 17. Pediatric Gastroenterology Unit, Hospital Puerta del Mar, 11009 Cadiz, Spain. 18. Pharmacy Unit, Hospital Universitario Vall d'Hebrón, 08035 Barcelona, Spain. 19. Pediatric Gastroenterology Unit, Hospital Infantil Miguel Servet, 50009 Zaragoza, Spain. 20. UGC Pharmacy Department, Hospital Virgen de la Macarena, 41009 Sevilla, Spain. 21. Pediatric Gastroenterology Unit, Hospital Reina Sofía, 14004 Córdoba, Spain.
Abstract
BACKGROUND: Up to 30% of patients with pediatric inflammatory bowel disease (IBD) do not respond to anti-Tumor Necrosis Factor (anti-TNF) therapy. The aim of this study was to identify pharmacogenomic markers that predict early response to anti-TNF drugs in pediatric patients with IBD. METHODS: An observational, longitudinal, prospective cohort study was conducted. The study population comprised 38 patients with IBD aged < 18 years who started treatment with infliximab or adalimumab (29 responders and nine non-responders). Whole gene expression profiles from total RNA isolated from whole blood samples of six responders and six non-responders taken before administration of the biologic and after two weeks of therapy were analyzed using next-generation RNA sequencing. The expression of six selected genes was measured for purposes of validation in all of the 38 patients recruited using qPCR. RESULTS: Genes were differentially expressed in non-responders and responders (32 before initiation of treatment and 44 after two weeks, Log2FC (Fold change) >0.6 or <-0.6 and p value < 0.05). After validation, FCGR1A, FCGR1B, and GBP1 were overexpressed in non-responders two weeks after initiation of anti-TNF treatment (Log2FC 1.05, 1.21, and 1.08, respectively, p value < 0.05). CONCLUSION: Expression of the FCGR1A, FCGR1B, and GBP1 genes is a pharmacogenomic biomarker of early response to anti-TNF agents in pediatric IBD.
BACKGROUND: Up to 30% of patients with pediatric inflammatory bowel disease (IBD) do not respond to anti-Tumor Necrosis Factor (anti-TNF) therapy. The aim of this study was to identify pharmacogenomic markers that predict early response to anti-TNF drugs in pediatric patients with IBD. METHODS: An observational, longitudinal, prospective cohort study was conducted. The study population comprised 38 patients with IBD aged < 18 years who started treatment with infliximab or adalimumab (29 responders and nine non-responders). Whole gene expression profiles from total RNA isolated from whole blood samples of six responders and six non-responders taken before administration of the biologic and after two weeks of therapy were analyzed using next-generation RNA sequencing. The expression of six selected genes was measured for purposes of validation in all of the 38 patients recruited using qPCR. RESULTS: Genes were differentially expressed in non-responders and responders (32 before initiation of treatment and 44 after two weeks, Log2FC (Fold change) >0.6 or <-0.6 and p value < 0.05). After validation, FCGR1A, FCGR1B, and GBP1 were overexpressed in non-responders two weeks after initiation of anti-TNF treatment (Log2FC 1.05, 1.21, and 1.08, respectively, p value < 0.05). CONCLUSION: Expression of the FCGR1A, FCGR1B, and GBP1 genes is a pharmacogenomic biomarker of early response to anti-TNF agents in pediatric IBD.
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