Genetic variants within immune-modulating genes influence the risk of developing rheumatoid arthritis and anti-TNF drug response: a two-stage case–control study

• Published in: Pharmacogenetics and genomics Vol. 25; no. 9; pp. 432 - 443
• Main Authors: Canet, Luz M, Cáliz, Rafael, Lupiañez, Carmen B, Canhão, Helena, Martinez, Manuel, Escudero, Alejandro, Filipescu, Ileana, Segura-Catena, Juana, Soto-Pino, María J, Ferrer, Miguel A, García, Antonio, Romani, Lurdes, Pérez-Pampin, Eva, González-Utrilla, Alfonso, López Nevot, Miguel Ángel, Collantes, Eduardo, Fonseca, João E, Sainz, Juan
• Format: Journal Article
• Language: English
• Published: United States Copyright Wolters Kluwer Health, Inc. All rights reserved 01-09-2015
• Subjects: Adult; Aged; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - genetics; Case-Control Studies; European Continental Ancestry Group - genetics; Female; Genetic Predisposition to Disease; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - pharmacology; Interferon-gamma - antagonists & inhibitors; Interferon-gamma - genetics; Interleukin-4 - genetics; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptors, Interleukin-8B - genetics; Regression Analysis
• ISSN: 1744-6872; 1744-6880
• DOI: 10.1097/FPC.0000000000000155

BACKGROUNDRheumatoid 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.
MATERIALS AND METHODSTo 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.
RESULTSLogistic 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).
CONCLUSIONSOur 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.