Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients

Luz M Canet, Jose M Sánchez-Maldonado, Rafael Cáliz, Ana Rodríguez Ramos, Carmen B Lupiañez, Helena Canhão, Manuel Martínez-Bueno, Alejandro Escudero, Juana Segura-Catena, Signe B Sorensen, Merete L Hetland, María José Soto-Pino, Miguel A Ferrer, Antonio García, Bente Glintborg, Ileana Filipescu, Eva Pérez-Pampin, Alfonso González-Utrilla, Miguel Ángel López Nevot, Pablo Conesa-Zamora & 10 others Alfons den Broeder, Salvatore De Vita, Sven Erik Hobe Jacobsen, Eduardo Collantes-Estevez, Luca Quartuccio, Federico Canzian, João E Fonseca, Marieke J H Coenen, Vibeke Andersen, Juan Sainz

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)83-96
Number of pages9
JournalPharmacogenomics Journal
Volume19
Issue number1
Early online date5 Oct 2018
DOIs
Publication statusPublished - Feb 2019

Fingerprint

Rheumatoid Arthritis
Hormones
Enzymes
Pharmaceutical Preparations
Single Nucleotide Polymorphism
Steroids
Haplotypes
Cytochrome P-450 CYP3A
Therapeutics
ROC Curve
Area Under Curve
Registries
Meta-Analysis
Case-Control Studies
Genes
Genetic Models
Population
Linear Models
Demography
Messenger RNA

Keywords

  • ESTROGEN REPLACEMENT THERAPY
  • SEX-HORMONES
  • T-LYMPHOCYTES
  • ALPHA
  • RISK
  • ASSOCIATION
  • EXPRESSION
  • DIFFERENTIATION
  • INDUCTION
  • PREGNANCY

Cite this

Canet, Luz M ; Sánchez-Maldonado, Jose M ; Cáliz, Rafael ; Ramos, Ana Rodríguez ; Lupiañez, Carmen B ; Canhão, Helena ; Martínez-Bueno, Manuel ; Escudero, Alejandro ; Segura-Catena, Juana ; Sorensen, Signe B ; Hetland, Merete L ; Soto-Pino, María José ; Ferrer, Miguel A ; García, Antonio ; Glintborg, Bente ; Filipescu, Ileana ; Pérez-Pampin, Eva ; González-Utrilla, Alfonso ; Nevot, Miguel Ángel López ; Conesa-Zamora, Pablo ; Broeder, Alfons den ; De Vita, Salvatore ; Jacobsen, Sven Erik Hobe ; Collantes-Estevez, Eduardo ; Quartuccio, Luca ; Canzian, Federico ; Fonseca, João E ; Coenen, Marieke J H ; Andersen, Vibeke ; Sainz, Juan. / Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients. In: Pharmacogenomics Journal. 2019 ; Vol. 19, No. 1. pp. 83-96.
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abstract = "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.",
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author = "Canet, {Luz M} and S{\'a}nchez-Maldonado, {Jose M} and Rafael C{\'a}liz and Ramos, {Ana Rodr{\'i}guez} and Lupia{\~n}ez, {Carmen B} and Helena Canh{\~a}o and Manuel Mart{\'i}nez-Bueno and Alejandro Escudero and Juana Segura-Catena and Sorensen, {Signe B} and Hetland, {Merete L} and Soto-Pino, {Mar{\'i}a Jos{\'e}} and Ferrer, {Miguel A} and Antonio Garc{\'i}a and Bente Glintborg and Ileana Filipescu and Eva P{\'e}rez-Pampin and Alfonso Gonz{\'a}lez-Utrilla and Nevot, {Miguel {\'A}ngel L{\'o}pez} and Pablo Conesa-Zamora and Broeder, {Alfons den} and {De Vita}, Salvatore and Jacobsen, {Sven Erik Hobe} and Eduardo Collantes-Estevez and Luca Quartuccio and Federico Canzian and Fonseca, {Jo{\~a}o E} and Coenen, {Marieke J H} and Vibeke Andersen and Juan Sainz",
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Canet, LM, Sánchez-Maldonado, JM, Cáliz, R, Ramos, AR, Lupiañez, CB, Canhão, H, Martínez-Bueno, M, Escudero, A, Segura-Catena, J, Sorensen, SB, Hetland, ML, Soto-Pino, MJ, Ferrer, MA, García, A, Glintborg, B, Filipescu, I, Pérez-Pampin, E, González-Utrilla, A, Nevot, MÁL, Conesa-Zamora, P, Broeder, AD, De Vita, S, Jacobsen, SEH, Collantes-Estevez, E, Quartuccio, L, Canzian, F, Fonseca, JE, Coenen, MJH, Andersen, V & Sainz, J 2019, 'Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients', Pharmacogenomics Journal, vol. 19, no. 1, pp. 83-96. https://doi.org/10.1038/s41397-018-0057-x

Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients. / Canet, Luz M; Sánchez-Maldonado, Jose M; Cáliz, Rafael; Ramos, Ana Rodríguez; Lupiañez, Carmen B; Canhão, Helena; Martínez-Bueno, Manuel; Escudero, Alejandro; Segura-Catena, Juana; Sorensen, Signe B; Hetland, Merete L; Soto-Pino, María José; Ferrer, Miguel A; García, Antonio; Glintborg, Bente; Filipescu, Ileana; Pérez-Pampin, Eva; González-Utrilla, Alfonso; Nevot, Miguel Ángel López; Conesa-Zamora, Pablo; Broeder, Alfons den; De Vita, Salvatore; Jacobsen, Sven Erik Hobe; Collantes-Estevez, Eduardo; Quartuccio, Luca; Canzian, Federico; Fonseca, João E; Coenen, Marieke J H; Andersen, Vibeke; Sainz, Juan.

In: Pharmacogenomics Journal, Vol. 19, No. 1, 02.2019, p. 83-96.

Research output: Contribution to journalArticle

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 - Ramos, Ana Rodríguez

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

Y1 - 2019/2

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 - ESTROGEN REPLACEMENT THERAPY

KW - SEX-HORMONES

KW - T-LYMPHOCYTES

KW - ALPHA

KW - RISK

KW - ASSOCIATION

KW - EXPRESSION

KW - DIFFERENTIATION

KW - INDUCTION

KW - PREGNANCY

U2 - 10.1038/s41397-018-0057-x

DO - 10.1038/s41397-018-0057-x

M3 - Article

VL - 19

SP - 83

EP - 96

JO - Pharmacogenomics Journal

JF - Pharmacogenomics Journal

SN - 1470-269X

IS - 1

ER -