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; 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

doi: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

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-ZamoraAlfons 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

4 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 language	English
Journal	The Pharmacogenomics Journal
Volume	19
Issue number	1
Pages (from-to)	83-96
Number of pages	14
ISSN	1470-269X
DOIs	https://doi.org/10.1038/s41397-018-0057-x
Publication status	Published - 1 Feb 2019

Keywords

Antirheumatic Agents/therapeutic use
Arthritis, Rheumatoid/drug therapy
Case-Control Studies
Cytochrome P-450 CYP2C9/genetics
Cytochrome P-450 CYP3A/genetics
Estrogen Receptor beta/genetics
Female
Gonadal Steroid Hormones/genetics
Haplotypes/genetics
Humans
Male
Metabolic Detoxication, Phase I/genetics
Polymorphism, Single Nucleotide/genetics
Tumor Necrosis Factor-alpha/antagonists & inhibitors
Ubiquitin-Protein Ligases/genetics

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Canet, L. M., Sánchez-Maldonado, J. M., Cáliz, R., Rodríguez-Ramos, A., Lupiañez, C. B., Canhão, H., Martínez-Bueno, M., Escudero, A., Segura-Catena, J., Sorensen, S. B., Hetland, M. L., Soto-Pino, M. J., Ferrer, M. A., García, A., Glintborg, B., Filipescu, I., Pérez-Pampin, E., González-Utrilla, A., Nevot, M. Á. L., ... Sainz, J. (2019). Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients. The Pharmacogenomics Journal, 19(1), 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 et al.
In: The Pharmacogenomics Journal, Vol. 19, No. 1, 01.02.2019, p. 83-96.

Research output: Contribution to journal › Journal article › Research › peer-review

Canet, LM, Sánchez-Maldonado, JM, Cáliz, R, Rodríguez-Ramos, A, 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', The Pharmacogenomics Journal, vol. 19, no. 1, pp. 83-96. https://doi.org/10.1038/s41397-018-0057-x

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

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.",

keywords = "Antirheumatic Agents/therapeutic use, Arthritis, Rheumatoid/drug therapy, Case-Control Studies, Cytochrome P-450 CYP2C9/genetics, Cytochrome P-450 CYP3A/genetics, Estrogen Receptor beta/genetics, Female, Gonadal Steroid Hormones/genetics, Haplotypes/genetics, Humans, Male, Metabolic Detoxication, Phase I/genetics, Polymorphism, Single Nucleotide/genetics, Tumor Necrosis Factor-alpha/antagonists & inhibitors, Ubiquitin-Protein Ligases/genetics",

author = "Canet, {Luz M} and S{\'a}nchez-Maldonado, {Jose M} and Rafael C{\'a}liz and Ana Rodr{\'i}guez-Ramos 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",

year = "2019",

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doi = "10.1038/s41397-018-0057-x",

language = "English",

volume = "19",

pages = "83--96",

journal = "The Pharmacogenomics Journal",

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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 -

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

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Keywords

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