TY - JOUR
T1 - Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients
AU - Canet, Luz M
AU - Sánchez-Maldonado, Jose M
AU - Cáliz, Rafael
AU - Rodríguez-Ramos, Ana
AU - Lupiañez, Carmen B
AU - Canhão, Helena
AU - Martínez-Bueno, Manuel
AU - Escudero, Alejandro
AU - Segura-Catena, Juana
AU - Sorensen, Signe B
AU - Hetland, Merete L
AU - Soto-Pino, María José
AU - Ferrer, Miguel A
AU - García, Antonio
AU - Glintborg, Bente
AU - Filipescu, Ileana
AU - Pérez-Pampin, Eva
AU - González-Utrilla, Alfonso
AU - Nevot, Miguel Ángel López
AU - Conesa-Zamora, Pablo
AU - Broeder, Alfons den
AU - De Vita, Salvatore
AU - Jacobsen, Sven Erik Hobe
AU - Collantes-Estevez, Eduardo
AU - Quartuccio, Luca
AU - Canzian, Federico
AU - Fonseca, João E
AU - Coenen, Marieke J H
AU - Andersen, Vibeke
AU - Sainz, Juan
PY - 2019/2/1
Y1 - 2019/2/1
N2 - The aim of this case-control study was to evaluate whether 47 single-nucleotide polymorphisms (SNPs) in steroid hormone-related genes are associated with the risk of RA and anti-TNF drug response. We conducted a case-control study in 3 European populations including 2936 RA patients and 2197 healthy controls. Of those, a total of 1985 RA patients were treated with anti-TNF blockers. The association of potentially interesting markers in the discovery population was validated through meta-analysis with data from DREAM and DANBIO registries. Although none of the selected variants had a relevant role in modulating RA risk, the meta-analysis of the linear regression data with those from the DREAM and DANBIO registries showed a significant correlation of the CYP3A4rs11773597 and CYP2C9rs1799853 variants with changes in DAS28 after the administration of anti-TNF drugs (P = 0.00074 and P = 0.006, respectively). An overall haplotype analysis also showed that the ESR2GGG haplotype significantly associated with a reduced chance of having poor response to anti-TNF drugs (P = 0.0009). Finally, a ROC curve analysis confirmed that a model built with eight steroid hormone-related variants significantly improved the ability to predict drug response compared with the reference model including demographic and clinical variables (AUC = 0.633 vs. AUC = 0.556; PLR_test = 1.52 × 10-6). These data together with those reporting that the CYP3A4 and ESR2 SNPs correlate with the expression of TRIM4 and ESR2 mRNAs in PBMCs (ranging from P = 1.98 × 10-6 to P = 2.0 × 10-35), and that the CYP2C9rs1799853 SNP modulates the efficiency of multiple drugs, suggest that steroid hormone-related genes may have a role in determining the response to anti-TNF drugs.KEY POINTS• Polymorphisms within the CYP3A4 and CYP2C9 loci correlate with changes in DAS28 after treatment with anti-TNF drugs.• A haplotype including eQTL SNPs within the ESR2 gene associates with better response to anti-TNF drugs.• A genetic model built with eight steroid hormone-related variants significantly improved the ability to predict drug response.
AB - The aim of this case-control study was to evaluate whether 47 single-nucleotide polymorphisms (SNPs) in steroid hormone-related genes are associated with the risk of RA and anti-TNF drug response. We conducted a case-control study in 3 European populations including 2936 RA patients and 2197 healthy controls. Of those, a total of 1985 RA patients were treated with anti-TNF blockers. The association of potentially interesting markers in the discovery population was validated through meta-analysis with data from DREAM and DANBIO registries. Although none of the selected variants had a relevant role in modulating RA risk, the meta-analysis of the linear regression data with those from the DREAM and DANBIO registries showed a significant correlation of the CYP3A4rs11773597 and CYP2C9rs1799853 variants with changes in DAS28 after the administration of anti-TNF drugs (P = 0.00074 and P = 0.006, respectively). An overall haplotype analysis also showed that the ESR2GGG haplotype significantly associated with a reduced chance of having poor response to anti-TNF drugs (P = 0.0009). Finally, a ROC curve analysis confirmed that a model built with eight steroid hormone-related variants significantly improved the ability to predict drug response compared with the reference model including demographic and clinical variables (AUC = 0.633 vs. AUC = 0.556; PLR_test = 1.52 × 10-6). These data together with those reporting that the CYP3A4 and ESR2 SNPs correlate with the expression of TRIM4 and ESR2 mRNAs in PBMCs (ranging from P = 1.98 × 10-6 to P = 2.0 × 10-35), and that the CYP2C9rs1799853 SNP modulates the efficiency of multiple drugs, suggest that steroid hormone-related genes may have a role in determining the response to anti-TNF drugs.KEY POINTS• Polymorphisms within the CYP3A4 and CYP2C9 loci correlate with changes in DAS28 after treatment with anti-TNF drugs.• A haplotype including eQTL SNPs within the ESR2 gene associates with better response to anti-TNF drugs.• A genetic model built with eight steroid hormone-related variants significantly improved the ability to predict drug response.
KW - Antirheumatic Agents/therapeutic use
KW - Arthritis, Rheumatoid/drug therapy
KW - Case-Control Studies
KW - Cytochrome P-450 CYP2C9/genetics
KW - Cytochrome P-450 CYP3A/genetics
KW - Estrogen Receptor beta/genetics
KW - Female
KW - Gonadal Steroid Hormones/genetics
KW - Haplotypes/genetics
KW - Humans
KW - Male
KW - Metabolic Detoxication, Phase I/genetics
KW - Polymorphism, Single Nucleotide/genetics
KW - Tumor Necrosis Factor-alpha/antagonists & inhibitors
KW - Ubiquitin-Protein Ligases/genetics
U2 - 10.1038/s41397-018-0057-x
DO - 10.1038/s41397-018-0057-x
M3 - Journal article
C2 - 30287909
SN - 1470-269X
VL - 19
SP - 83
EP - 96
JO - The Pharmacogenomics Journal
JF - The Pharmacogenomics Journal
IS - 1
ER -