TY - JOUR
T1 - Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis
T2 - A Meta-Analysis of Two Large Cohorts
AU - Sánchez-Maldonado, Jose Manuel
AU - Cáliz, Rafael
AU - López-Nevot, Miguel Ángel
AU - Cabrera-Serrano, Antonio José
AU - Moñiz-Díez, Ana
AU - Canhão, Helena
AU - Ter Horst, Rob
AU - Quartuccio, Luca
AU - Sorensen, Signe B
AU - Glintborg, Bente
AU - Hetland, Merete L
AU - Filipescu, Ileana
AU - Pérez-Pampin, Eva
AU - Conesa-Zamora, Pablo
AU - Swierkot, Jerzy
AU - den Broeder, Alfons A
AU - De Vita, Salvatore
AU - Petersen, Eva Rabing Brix
AU - Li, Yang
AU - Ferrer, Miguel A
AU - Escudero, Alejandro
AU - Netea, Mihai G
AU - Coenen, Marieke J H
AU - Andersen, Vibeke
AU - Fonseca, João E
AU - Jurado, Manuel
AU - Bogunia-Kubik, Katarzyna
AU - Collantes, Eduardo
AU - Sainz, Juan
N1 - Copyright © 2021 Sánchez-Maldonado, Cáliz, López-Nevot, Cabrera-Serrano, Moñiz-Díez, Canhão, Ter Horst, Quartuccio, Sorensen, Glintborg, Hetland, Filipescu, Pérez-Pampin, Conesa-Zamora, Swierkot, den Broeder, De Vita, Petersen, Li, Ferrer, Escudero, Netea, Coenen, Andersen, Fonseca, Jurado, Bogunia-Kubik, Collantes and Sainz.
COPECARE
PY - 2021
Y1 - 2021
N2 - 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 LINC02549 rs7767069 SNP with a lower improvement in DAS28 that remained significant after correction for multiple testing (per-allele ORMeta=0.83, P Meta=0.000077; P Het=0.61). In addition, we found that each copy of the LRRC55 rs717117G allele was significantly associated with lower improvement in DAS28 in rheumatoid factor (RF)-positive patients (per-allele ORMeta=0.67, P=0.00058; P Het=0.06) whereas an opposite but not significant effect was detected in RF-negative subjects (per-allele ORMeta=1.38, P=0.10; P Het=0.45; P Interaction=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 MAFB rs6071980 and CNTN5 rs1813443 SNPs with decreased changes in DAS28 (per-allele ORMeta_rs6071980 = 0.85, P=0.0059; P Het=0.63 and ORMeta_rs1813443_RF+=0.81, P=0.0059; P Het=0.69 and ORMeta_rs1813443_RF-=1.00, P=0.99; P Het=0.12; P Interaction=0.032). Mechanistically, we found that subjects carrying the LINC02549 rs7767069T allele had significantly increased numbers of CD45RO+CD45RA+ T cells (P=0.000025) whereas carriers of the LINC02549 rs7767069T/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 LRRC55 rs717117G 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.
AB - 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 LINC02549 rs7767069 SNP with a lower improvement in DAS28 that remained significant after correction for multiple testing (per-allele ORMeta=0.83, P Meta=0.000077; P Het=0.61). In addition, we found that each copy of the LRRC55 rs717117G allele was significantly associated with lower improvement in DAS28 in rheumatoid factor (RF)-positive patients (per-allele ORMeta=0.67, P=0.00058; P Het=0.06) whereas an opposite but not significant effect was detected in RF-negative subjects (per-allele ORMeta=1.38, P=0.10; P Het=0.45; P Interaction=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 MAFB rs6071980 and CNTN5 rs1813443 SNPs with decreased changes in DAS28 (per-allele ORMeta_rs6071980 = 0.85, P=0.0059; P Het=0.63 and ORMeta_rs1813443_RF+=0.81, P=0.0059; P Het=0.69 and ORMeta_rs1813443_RF-=1.00, P=0.99; P Het=0.12; P Interaction=0.032). Mechanistically, we found that subjects carrying the LINC02549 rs7767069T allele had significantly increased numbers of CD45RO+CD45RA+ T cells (P=0.000025) whereas carriers of the LINC02549 rs7767069T/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 LRRC55 rs717117G 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.
KW - Adult
KW - Aged
KW - Alleles
KW - Arthritis, Rheumatoid/diagnosis
KW - Biomarkers
KW - Cohort Studies
KW - Disease Susceptibility
KW - Female
KW - Genetic Variation
KW - Genome-Wide Association Study/methods
KW - Genotype
KW - Humans
KW - Linkage Disequilibrium
KW - Male
KW - Middle Aged
KW - Pharmacogenomic Variants
KW - Polymorphism, Single Nucleotide
KW - Registries
KW - Treatment Outcome
KW - Tumor Necrosis Factor Inhibitors/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=85118846234&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.672255
DO - 10.3389/fimmu.2021.672255
M3 - Journal article
C2 - 34777329
SN - 1664-3224
VL - 12
SP - 672255
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 672255
ER -