Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts

Abstract

We aimed to validate the association of 28 GWAS-identified genetic variants for response to TNF inhibitors (TNFi) in a discovery cohort of 1361 rheumatoid arthritis (RA) patients monitored in routine care and ascertained through the REPAIR consortium and DANBIO registry. We genotyped selected markers and evaluated their association with response to TNFi after 6 months of treatment according to the change in disease activity score 28 (ΔDAS28). Next, we confirmed the most interesting results through meta-analysis of our data with those from the DREAM cohort that included 706 RA patients treated with TNFi. The meta-analysis of the discovery cohort and DREAM registry including 2067 RA patients revealed an overall association of the LINC02549rs7767069 SNP with a lower improvement in DAS28 that remained significant after correction for multiple testing (per-allele ORMeta=0.83, PMeta=0.000077; PHet=0.61). In addition, we found that each copy of the LRRC55rs717117G allele was significantly associated with lower improvement in DAS28 in rheumatoid factor (RF)-positive patients (per-allele ORMeta=0.67, P=0.00058; PHet=0.06) whereas an opposite but not significant effect was detected in RF-negative subjects (per-allele ORMeta=1.38, P=0.10; PHet=0.45; PInteraction=0.00028). Interestingly, although the identified associations did not survive multiple testing correction, the meta-analysis also showed overall and RF-specific associations for the MAFBrs6071980 and CNTN5rs1813443 SNPs with decreased changes in DAS28 (per-allele ORMeta_rs6071980 = 0.85, P=0.0059; PHet=0.63 and ORMeta_rs1813443_RF+=0.81, P=0.0059; PHet=0.69 and ORMeta_rs1813443_RF-=1.00, P=0.99; PHet=0.12; PInteraction=0.032). Mechanistically, we found that subjects carrying the LINC02549rs7767069T allele had significantly increased numbers of CD45RO+CD45RA+ T cells (P=0.000025) whereas carriers of the LINC02549rs7767069T/T genotype showed significantly increased levels of soluble scavengers CD5 and CD6 in serum (P=0.00037 and P=0.00041). In addition, carriers of the LRRC55rs717117G allele showed decreased production of IL6 after stimulation of PBMCs with B burgdorferi and E coli bacteria (P=0.00046 and P=0.00044), which suggested a reduced IL6-mediated anti-inflammatory effect of this marker to worsen the response to TNFi. In conclusion, this study confirmed the influence of the LINC02549 and LRRC55 loci to determine the response to TNFi in RA patients and suggested a weak effect of the MAFB and CNTN5 loci that need to be further investigated.

Genetic Variants Associated with Biological Treatment Response in Inflammatory Bowel Disease: A Systematic Review

“…In the study of long-term response and non-response to IFX therapy, rs1813443, located in the intronic section of gene CNTN5 [55], has been associated with clinical and biochemical responses to IFX in Greek patients with Crohn's disease [39]. This result has similarly been observed for the TT genotype of the rs1568885 polymorphism, also located in gene CNTN5, showing a statistically significant relationship to partial response and resistance to IFX [39].…”

-Omic Approaches and Treatment Response in Rheumatoid Arthritis

“…Interestingly, the T-allele of this SNP correlated with a significantly increased number of T cells (CD45RO+CD45RA+), whereas patients carrying the TT genotype showed significantly increased serum levels of CD5 and CD6, which modulate T cells and certain subsets of B cells. Moreover, they also found that patients with positive rheumatoid factor carrying the G-allele of the LRRC55 rs717117 polymorphism presented a lower response to TNFi treatment [28].…”

“…Although a genetic variant (rs3794271) located at the PDE3A-SLCO1C1 locus did not reach genome-wide association with response to TNFi in the GWAS performed by Krintel et al [24], this polymorphism reached statistical significance in a later study carried out in a Spanish cohort, when data were combined in a meta-analysis [25]. However, three subsequent replication studies, some of them performed in large cohorts of RA patients, failed to validate these results [26][27][28].…”

“…However, stratification of patients according to each specific TNFi drug allowed the researchers to identify an association between the rs2378945 variant, located at the NUBPL locus, and a poor response to ETN [35]. In addition, a recent replication study of 28 GWAS-identified variants was performed in a cohort of 1361 RA patients treated with different TNFi from the REPAIR consortium and the DANBIO registry [28]. They also tried to validate the most interesting results by performing a meta-analysis with a cohort of 706 RA patients.…”

MTHFR c.665C>T and c.1298A>C Polymorphisms in Tailoring Personalized Anti-TNF-α Therapy for Rheumatoid Arthritis

“…Efficient pharmacogenetic markers, with the capability of promptly identifying patients with a lower chance to respond to therapy, could facilitate the provision of individually tailored therapies and ultimately prevent the progression of the disease. So far, several single nucleotide polymorphisms (SNPs) in different known loci such as NUBPL (rs2378945), NCTN5 (rs1813443), PLA2G4A (rs12142623 and rs4651370) [ 21 ], LINC02549 (rs7767069), LARRC55 (rs717117G) [ 22 ], MED15 (rs113878252), MAFB (rs6065221) [ 23 ], CD84 (rs6427528 and rs1503860) [ 24 ], TNF (rs1800629), EYA4 (rs17301249) [ 25 ], PDZD2 (rs1532269) [ 26 ], and CCL21 (rs2812378) [ 27 ] genes or in unknown loci, including rs4411591, rs7767069, rs1447722, and rs1568885 [ 21 ], have been identified, which are associated with a response to anti-TNF treatments in RA. The evidence supports an association between SNPs in the MTHFR genes c.665C>T (rs1801133, historically referred to as c.677C>T or C677T) and c.1298A>C (rs1801131) and the occurrence risk of RA [ 28 , 29 , 30 ] or the expression of inflammation markers [ 31 , 32 ], conditions during which inflammatory cytokines such as TNF-α, which is the direct target of TNF-α inhibitor drugs, play a fundamental role [ 33 ].…”