Response to Infliximab in Crohn's Disease: Genetic Analysis Supporting Expression Profile.
Substantial proportion of Crohn's disease (CD) patients shows no response or a limited response to treatment with infliximab (IFX) and to identify biomarkers of response would be of great clinical and economic benefit. The expression profile of five genes (S100A8-S100A9, G0S2, TNFAIP6, and IL11) reportedly predicted response to IFX and we aimed at investigating their etiologic role through genetic association analysis. Patients with active CD (350) who received at least three induction doses of IFX were included and classified according to IFX response. A tagging strategy was used to select genetic polymorphisms that cover the variability present in the chromosomal regions encoding the identified genes with altered expression. Following genotyping, differences between responders and nonresponders to IFX were observed in haplotypes of the studied regions: S100A8-S100A9 (rs11205276* G/rs3014866* C/rs724781* C/rs3006488* A; P = 0.05); G0S2 (rs4844486* A/rs1473683* T; P = 0.15); TNFAIP6 (rs11677200* C/rs2342910* A/rs3755480* G/rs10432475* A; P = 0.10); and IL11 (rs1126760* C/rs1042506* G; P = 0.07). These differences were amplified in patients with colonic and ileocolonic location for all but the TNFAIP6 haplotype, which evidenced significant difference in ileal CD patients. Our results support the role of the reported expression signature as predictive of anti-TNF outcome in CD patients and suggest an etiological role of those top-five genes in the IFX response pathway.
Immunology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
Luz María
LM
Medrano
Gastroenterology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
Carlos
C
Taxonera
Gastroenterology Department, Virgen de las Nieves Hospital, 18014 Granada, Spain.
Cristina
C
González-Artacho
Immunology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
Virginia
V
Pascual
Gastroenterology Department, Virgen de las Nieves Hospital, 18014 Granada, Spain.
María
M
Gómez-García
Gastroenterology Department, Hospital Clínico Universitario de Santiago de Compostela, 15706 Santiago de Compostela, Spain.
Manuel
M
Barreiro-de Acosta
Gastroenterology Department, Alcorcón Hospital, 28922 Madrid, Spain.
José L
JL
Pérez-Calle
Gastroenterology Department, Fuenlabrada Hospital, 28942 Madrid, Spain.
Fernando
F
Bermejo
Gastroenterology Department, Ramón y Cajal Hospital, 28034 Madrid, Spain.
Antonio
A
López-Sanromán
Gastroenterology Department, La Paz Hospital, 28046 Madrid, Spain.
Dolores
D
Martín Arranz
Gastroenterology Department, Hospital Universitario La Princesa, Instituto de Investigación Sanitaria Princesa (IP), 28006 Madrid, Spain ; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28002 Madrid, Spain.
Javier P
JP
Gisbert
Gastroenterology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
Juan Luis
JL
Mendoza
Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Armilla, 18100 Granada, Spain.
Javier
J
Martín
Immunology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
Concepción
C
Núñez
Immunology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
Elena
E
Urcelay
D000293:Adolescent; D000328:Adult; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D040501:Calgranulin A / Q000235:genetics; D040502:Calgranulin B / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D003424:Crohn Disease / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D000069285:Infliximab / Q000627:therapeutic use*; D017370:Interleukin-11 / Q000235:genetics; D008297:Male; D055815:Young Adult
D018501:Antirheumatic Agents; D040501:Calgranulin A; D040502:Calgranulin B; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; C508073:G0S2 protein, human; D017370:Interleukin-11; C072273:TNFAIP6 protein, human; D000069285:Infliximab