Variation at interleukin-6 receptor gene is associated to joint damage in rheumatoid arthritis

Abstract

IntroductionInterleukin-6 (IL-6) cytokine signaling is key in Rheumatoid Arthritis (RA) pathophysiology. Blocking IL-6 receptor (IL6R) has proven to be a highly effective treatment to prevent joint damage. This study was performed to investigate the association between the genetic variation at IL6R gene and the severity of joint damage in RA.MethodsIL6R gene tagging SNPs (n = 5) were genotyped in a discovery group of 527 RA patients from 5 different university hospitals from Spain. For each marker, a linear regression analysis was performed using an additive model and adjusting for the years of evolution of the disease, autoantibody status, gender and age. Haplotypes combining the SNPs were also estimated and tested for association with the level of joint destruction. Using an independent cohort of 705 RA patients from 6 university hospitals we performed a validation study of the SNPs associated in the discovery phase.ResultsIn the discovery group we found a highly significant association between IL6R SNP rs4845618 and the level of joint destruction in RA (P = 0.0058, Pcorrected = 0.026), and a moderate association with SNP rs4453032 (P = 0.02, Pcorrected = 0.05). The resulting haplotype from both SNPs was more significantly associated with joint damage (P = 0.0037, Pcorrected = 0.011). Using the validation cohort, we replicated the association between the two IL-6R SNPs with the degree of joint destruction in RA (P = 0.007 and P = 0.04, meta-analysis P = 0.00011 and P = 0.0021, respectively), and the haplotype association (P = 0.0058, meta-analysis P = 6.64 e-5).ConclusionsGenetic variation at IL6R gene is associated with joint damage in RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0737-8) contains supplementary material, which is available to authorized users.

A functional variant of TLR10 modifies the activity of NFkB and may help predict a worse prognosis in patients with rheumatoid arthritis

“…All polymerase chain reactions (PCRs) and endpoint fluorescence readings were performed using an ABI PRISM 7900 HT sequence detection system (Applied Biosystems). The genotyping error was estimated by genotyping 20 % of samples in duplicate (error <1 %) [ 33 ].…”

“…The significance of the β regression coefficient was determined using the Wald test. As described previously, covariates in these genetic analyses included the years of disease evolution and the basal Disease Activity Score in 28 joints (DAS28) for the association of rs11466657 genotype with the level of joint damage [ 33 ] and the change in DAS28 at 12 weeks [ 35 ], respectively.…”

A pilot study of single nucleotide polymorphisms in the interleukin-6 receptor and their effects on pre- and post-transplant serum mediator level and outcome after allogeneic stem cell transplantation

“…rheumatoid arthritis, asthma and cardiovascular disease [27][28][29]. To evaluate if other independent SNPs in the IL-6R gene are important for serum levels or post-transplant outcomes we used the same tagging SNPs as described previously by Lopez-Lasanta et al [29]. In summary, each of the SNPs rs4379670, rs6698040, rs4845374, rs4453032 and rs4845618 tag independently approximately 100 different SNPs (r 2 above 0Á7) within the IL-6R gene.…”

Methylation Pattern of the SOCS3 and IL6R Promoters in Rheumatoid Arthritis

“…We also International Journal of Inflammation found no differences in the frequency of either SNP between RF-positive and RF-negative patients and ACPA-positive and ACPA-negative patients. Previous reports [11,31] have shown a possible association between IL6R polymorphisms and susceptibility to RA, as well as joint destruction in subjects with RA. Biological function of rs2228145 was reported by Garbers et al [32].…”