title: Genetic variants within immune-modulating genes influence the risk of developing rheumatoid arthritis and anti-TNF drug response: a two-stage case-control study.
abstract: BACKGROUND
  Rheumatoid arthritis (RA) is a chronic autoimmune disease that arises as a result of the interaction between genetic and environmental factors. A growing body of research suggests that genetic variants within immune-related genes can influence the risk of developing the disease and affect drug response.
  
  
  METHODS
  To test this hypothesis, we carried out a comprehensive two-stage case-control study in a White population of 1239 White RA patients and 1229 healthy controls to investigate whether 49 single nucleotide polymorphisms within or near 17 immune-related genes modulate the risk of developing RA and antitumor necrosis factor (anti-TNF) drug response.
  
  
  RESULTS
  Logistic regression analyses showed that carriers of the IL4rs2070874T and IL4rs2243250T and IL8RBrs1126580A alleles or the IL8RBrs2230054C/C genotype had a significantly increased risk of developing RA [odds ratio (OR)=1.37, 95% confidence interval (CI) 1.13-1.67, P=0.0016; OR=1.24, 95% CI 1.03-1.49, P=0.020; OR=1.23, 95% CI 1.08-1.41, P=0.002 and OR=1.19, 95% CI 1.04-1.36, P=0.01, respectively]. The association of the IL4 variants was further supported by a meta-analysis including 7150 individuals (P =0.0010), whereas the involvement of the IL8RB locus in determining the susceptibility to RA was also supported by gene-gene interaction analyses that identified significant two-locus and three-locus interaction models including IL8RB variants that act synergistically to increase the risk of the disease (P=0.014 and 0.018). Interestingly, we also found that patients harbouring the IFNGrs2069705C allele showed a significantly better response to anti-TNF drugs than those patients carrying the wild-type allele (P=0.0075).
  
  
  CONCLUSIONS
  Our data suggest that IL4 and IL8RB loci may have a small-effect genetic impact on the risk of developing RA, whereas IFNG might be involved in modulating the response to anti-TNF drugs.
authors.affiliation: aGenomic Oncology Area bArea of Genomic Medicine, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government Departments of cRheumatology dImmunology, Virgen de las Nieves University Hospital, Granada eDepartment of Rheumatology, Reina Sofía Hospital/Maimónides Institut for Biomedical Research of CórdobaI (IMIBIC)/University of Córdoba, Córdoba fRheumatology Unit, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain gRheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa hDepartment of Rheumatology, Santa Maria Hospital-CHLN, Lisbon, Portugal iRheumatology Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Luz M
authors.initials: LM
authors.lastname: Canet
authors.forename: Rafael
authors.initials: R
authors.lastname: Cáliz
authors.forename: Carmen B
authors.initials: CB
authors.lastname: Lupiañez
authors.forename: Helena
authors.initials: H
authors.lastname: Canhão
authors.forename: Manuel
authors.initials: M
authors.lastname: Martinez
authors.forename: Alejandro
authors.initials: A
authors.lastname: Escudero
authors.forename: Ileana
authors.initials: I
authors.lastname: Filipescu
authors.forename: Juana
authors.initials: J
authors.lastname: Segura-Catena
authors.forename: María J
authors.initials: MJ
authors.lastname: Soto-Pino
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Ferrer
authors.forename: Antonio
authors.initials: A
authors.lastname: García
authors.forename: Lurdes
authors.initials: L
authors.lastname: Romani
authors.forename: Eva
authors.initials: E
authors.lastname: Pérez-Pampin
authors.forename: Alfonso
authors.initials: A
authors.lastname: González-Utrilla
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: López Nevot
authors.forename: Eduardo
authors.initials: E
authors.lastname: Collantes
authors.forename: João E
authors.initials: JE
authors.lastname: Fonseca
authors.forename: Juan
authors.initials: J
authors.lastname: Sainz
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000494:pharmacology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D023063:Receptors, Interleukin-8B / Q000235:genetics*; D012044:Regression Analysis; D044465:White People / Q000235:genetics
chemical_list: C573415:IFNG protein, human; C508598:IL4 protein, human; D007166:Immunosuppressive Agents; D023063:Receptors, Interleukin-8B; D015847:Interleukin-4; D007371:Interferon-gamma