Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: Meta-analysis of data from genome-wide association studies

Chiara Fabbri; Katherine E. Tansey; Roy H. Perlis; Joanna Hauser; Neven Henigsberg; Wolfgang Maier; Ole Mors; Anna Placentino; Marcella Rietschel; Daniel Souery; Gerome Breen; Charles Curtis; Sang Hyuk Lee; Stephen Newhouse; Hamel Patel; Michael O'Donovan; Glyn Lewis; Gregory Jenkins; Richard M. Weinshilboum; Anne Farmer; Katherine J. Aitchison; Ian Craig; Peter McGuffin; Koen Schruers; Joanna M. Biernacka; Rudolf Uher; Cathryn M. Lewis

doi:10.1016/j.euroneuro.2018.05.009

Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: Meta-analysis of data from genome-wide association studies

Chiara Fabbri, Katherine E. Tansey, Roy H. Perlis, Joanna Hauser, Neven Henigsberg, Wolfgang Maier, Ole Mors, Anna Placentino, Marcella Rietschel, Daniel Souery, Gerome Breen, Charles Curtis, Sang Hyuk Lee, Stephen Newhouse, Hamel Patel, Michael O'Donovan, Glyn Lewis, Gregory Jenkins, Richard M. Weinshilboum, Anne FarmerKatherine J. Aitchison, Ian Craig, Peter McGuffin, Koen Schruers, Joanna M. Biernacka, Rudolf Uher, Cathryn M. Lewis

Medicine

Research output: Contribution to journal › Article › peer-review

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Abstract

Cytochrome (CYP) P450 enzymes have a primary role in antidepressant metabolism and variants in these polymorphic genes are targets for pharmacogenetic investigation. This is the first meta-analysis to investigate how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects. CYP2C19 metabolic phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most common CYP2C19 functional polymorphisms (rs4244285 and rs12248560) in Caucasians. These polymorphisms were genotyped or imputed from genome-wide data in four samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod, PGRN-AMPS). Treatment efficacy was assessed by standardized percentage symptom improvement and by remission. Side effect data were available at weeks 2–4, 6 and 9 in three samples. A fixed-effects meta-analysis was performed using EM as the reference group. Analysis of 2558 patients for efficacy and 2037 patients for side effects showed that PMs had higher symptom improvement (SMD = 0.43, CI = 0.19–0.66) and higher remission rates (OR = 1.55, CI = 1.23–1.96) compared to EMs. At weeks 2–4, PMs showed higher risk of gastro-intestinal (OR = 1.26, CI = 1.08–1.47), neurological (OR = 1.28, CI = 1.07–1.53) and sexual side effects (OR = 1.52, CI = 1.23–1.87; week 6 values were similar). No difference was seen at week 9 or in total side effect burden. PMs did not have higher risk of dropout at week 4 compared to EMs. Antidepressant dose was not different among CYP2C19 groups. CYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs being relatively rare among Caucasians (∼2%).

Original language	English
Pages (from-to)	945-954
Number of pages	10
Journal	European Neuropsychopharmacology
Volume	28
Issue number	8
DOIs	https://doi.org/10.1016/j.euroneuro.2018.05.009
Publication status	Published - Aug 2018

Bibliographical note

Funding Information:
N Henigsberg participated in clinical trials sponsored by pharmaceutical companies including GlaxoSmithKline and Lundbeck. D Souery is serving in national advisory boards or consulting for Janssen, TEVA, Glaxo Smith Kline. His center is receiving unrestricted financial support from Lundbeck and Fondation René de Spoellberghe. W Maier, KJ Aitchison, AE Farmer and P McGuffin have received consultancy fees and honoraria for participating in expert panels from pharmaceutical companies including Lundbeck and GlaxoSmithKline and Roche Diagnostics. Dr Perlis reported serving on scientific advisory boards or consulting for Genomind LLC, Healthrageous, Pfizer, Perfect Health, Proteus Biomedical, PsyBrain Inc, and RID Ventures LLC and reported receiving royalties through Massachusetts General Hospital from Concordant Rater Systems (now Bracket/Medco). N Perroud received honoraria for participating in expert panels from pharmaceutical companies including Lundbeck. G Bondolfi is a member of a national advisory board for Bristol–Myer Squibb and Pfizer and has received research funding from GlaxoSmithKline, Wyeth–Lederle, Bristol–Myers Squibb and Sanofi Aventis. M O'Donovan's department received £2000 in lieu of an honorarium to M O'Donovan from Lilly as a result of his participation in sponsored symposia in 2012. Those symposia were unrelated to the contents of this manuscript. The other authors declare no conflict of interest.

Funding Information:
The NEWMEDS study was funded by the Innovative Medicine Initiative Joint Undertaking (IMI-JU) under grant agreement n° 115008 of which resources are composed of European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA) in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013). EFPIA members Pfizer, Glaxo Smith Kline, and F. Hoffmann La-Roche have contributed work and samples to the project presented here. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Funding Information:
The PGRN-AMPS dataset used for the analyses described in this manuscript was obtained from dbGaP (study accession phs000670.v1.p1). PGRN-AMPS was supported, in part, by NIH grants RO1 GM28157, U19 GM61388 (The Pharmacogenomics Research Network), U01 HG005137, R01 CA138461, P20 1P20AA017830-01 (The Mayo Clinic Center for Individualized Treatment of Alcohol Dependence), and a PhRMA Foundation Center of Excellence in Clinical Pharmacology Award.

Funding Information:
The GENDEP project was supported by a European Commission Framework 6 grant (contract reference: LSHB-CT-2003-503428). The Medical Research Council, United Kingdom, and GlaxoSmithKline (G0701420) provided support for genotyping.

Funding Information:
We thank the NIMH for providing access to data on the STAR-D sample. We also thank the authors of previous publications in this dataset, and foremost, we thank the patients and their families who agreed to be enrolled in the study. Data and biomaterials were obtained from the limited access datasets distributed from the NIH-supported ‘‘Sequenced Treatment Alternatives to Relieve Depression’’ (STAR*D). The study was supported by NIMH Contract No. N01MH90003 to the University of Texas Southwestern Medical Center. The ClinicalTrials.gov identifier is NCT00021528 .

Funding Information:
Dr Rudolf Uher is supported by the Canada Research Chairs Program.

Funding Information:
The GENDEP project was supported by a European Commission Framework 6 grant (contract reference: LSHB-CT-2003-503428). The Medical Research Council, United Kingdom, and GlaxoSmithKline (G0701420) provided support for genotyping.

Publisher Copyright:
© 2018 Elsevier B.V. and ECNP

ASJC Scopus Subject Areas

Pharmacology
Neurology
Clinical Neurology
Psychiatry and Mental health
Biological Psychiatry
Pharmacology (medical)

PubMed: MeSH publication types

Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.euroneuro.2018.05.009

Cite this

Fabbri, C., Tansey, K. E., Perlis, R. H., Hauser, J., Henigsberg, N., Maier, W., Mors, O., Placentino, A., Rietschel, M., Souery, D., Breen, G., Curtis, C., Lee, S. H., Newhouse, S., Patel, H., O'Donovan, M., Lewis, G., Jenkins, G., Weinshilboum, R. M., ... Lewis, C. M. (2018). Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: Meta-analysis of data from genome-wide association studies. European Neuropsychopharmacology, 28(8), 945-954. https://doi.org/10.1016/j.euroneuro.2018.05.009

Fabbri, C, Tansey, KE, Perlis, RH, Hauser, J, Henigsberg, N, Maier, W, Mors, O, Placentino, A, Rietschel, M, Souery, D, Breen, G, Curtis, C, Lee, SH, Newhouse, S, Patel, H, O'Donovan, M, Lewis, G, Jenkins, G, Weinshilboum, RM, Farmer, A, Aitchison, KJ, Craig, I, McGuffin, P, Schruers, K, Biernacka, JM, Uher, R & Lewis, CM 2018, 'Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: Meta-analysis of data from genome-wide association studies', European Neuropsychopharmacology, vol. 28, no. 8, pp. 945-954. https://doi.org/10.1016/j.euroneuro.2018.05.009

@article{94ad5f92754c4693ae278bb10ae5e905,

title = "Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: Meta-analysis of data from genome-wide association studies",

abstract = "Cytochrome (CYP) P450 enzymes have a primary role in antidepressant metabolism and variants in these polymorphic genes are targets for pharmacogenetic investigation. This is the first meta-analysis to investigate how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects. CYP2C19 metabolic phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most common CYP2C19 functional polymorphisms (rs4244285 and rs12248560) in Caucasians. These polymorphisms were genotyped or imputed from genome-wide data in four samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod, PGRN-AMPS). Treatment efficacy was assessed by standardized percentage symptom improvement and by remission. Side effect data were available at weeks 2–4, 6 and 9 in three samples. A fixed-effects meta-analysis was performed using EM as the reference group. Analysis of 2558 patients for efficacy and 2037 patients for side effects showed that PMs had higher symptom improvement (SMD = 0.43, CI = 0.19–0.66) and higher remission rates (OR = 1.55, CI = 1.23–1.96) compared to EMs. At weeks 2–4, PMs showed higher risk of gastro-intestinal (OR = 1.26, CI = 1.08–1.47), neurological (OR = 1.28, CI = 1.07–1.53) and sexual side effects (OR = 1.52, CI = 1.23–1.87; week 6 values were similar). No difference was seen at week 9 or in total side effect burden. PMs did not have higher risk of dropout at week 4 compared to EMs. Antidepressant dose was not different among CYP2C19 groups. CYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs being relatively rare among Caucasians (∼2%).",

author = "Chiara Fabbri and Tansey, {Katherine E.} and Perlis, {Roy H.} and Joanna Hauser and Neven Henigsberg and Wolfgang Maier and Ole Mors and Anna Placentino and Marcella Rietschel and Daniel Souery and Gerome Breen and Charles Curtis and Lee, {Sang Hyuk} and Stephen Newhouse and Hamel Patel and Michael O'Donovan and Glyn Lewis and Gregory Jenkins and Weinshilboum, {Richard M.} and Anne Farmer and Aitchison, {Katherine J.} and Ian Craig and Peter McGuffin and Koen Schruers and Biernacka, {Joanna M.} and Rudolf Uher and Lewis, {Cathryn M.}",

note = "Funding Information: N Henigsberg participated in clinical trials sponsored by pharmaceutical companies including GlaxoSmithKline and Lundbeck. D Souery is serving in national advisory boards or consulting for Janssen, TEVA, Glaxo Smith Kline. His center is receiving unrestricted financial support from Lundbeck and Fondation Ren{\'e} de Spoellberghe. W Maier, KJ Aitchison, AE Farmer and P McGuffin have received consultancy fees and honoraria for participating in expert panels from pharmaceutical companies including Lundbeck and GlaxoSmithKline and Roche Diagnostics. Dr Perlis reported serving on scientific advisory boards or consulting for Genomind LLC, Healthrageous, Pfizer, Perfect Health, Proteus Biomedical, PsyBrain Inc, and RID Ventures LLC and reported receiving royalties through Massachusetts General Hospital from Concordant Rater Systems (now Bracket/Medco). N Perroud received honoraria for participating in expert panels from pharmaceutical companies including Lundbeck. G Bondolfi is a member of a national advisory board for Bristol–Myer Squibb and Pfizer and has received research funding from GlaxoSmithKline, Wyeth–Lederle, Bristol–Myers Squibb and Sanofi Aventis. M O'Donovan's department received £2000 in lieu of an honorarium to M O'Donovan from Lilly as a result of his participation in sponsored symposia in 2012. Those symposia were unrelated to the contents of this manuscript. The other authors declare no conflict of interest. Funding Information: The NEWMEDS study was funded by the Innovative Medicine Initiative Joint Undertaking (IMI-JU) under grant agreement n° 115008 of which resources are composed of European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA) in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013). EFPIA members Pfizer, Glaxo Smith Kline, and F. Hoffmann La-Roche have contributed work and samples to the project presented here. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: The PGRN-AMPS dataset used for the analyses described in this manuscript was obtained from dbGaP (study accession phs000670.v1.p1). PGRN-AMPS was supported, in part, by NIH grants RO1 GM28157, U19 GM61388 (The Pharmacogenomics Research Network), U01 HG005137, R01 CA138461, P20 1P20AA017830-01 (The Mayo Clinic Center for Individualized Treatment of Alcohol Dependence), and a PhRMA Foundation Center of Excellence in Clinical Pharmacology Award. Funding Information: The GENDEP project was supported by a European Commission Framework 6 grant (contract reference: LSHB-CT-2003-503428). The Medical Research Council, United Kingdom, and GlaxoSmithKline (G0701420) provided support for genotyping. Funding Information: We thank the NIMH for providing access to data on the STAR-D sample. We also thank the authors of previous publications in this dataset, and foremost, we thank the patients and their families who agreed to be enrolled in the study. Data and biomaterials were obtained from the limited access datasets distributed from the NIH-supported {\textquoteleft}{\textquoteleft}Sequenced Treatment Alternatives to Relieve Depression{\textquoteright}{\textquoteright} (STAR*D). The study was supported by NIMH Contract No. N01MH90003 to the University of Texas Southwestern Medical Center. The ClinicalTrials.gov identifier is NCT00021528 . Funding Information: Dr Rudolf Uher is supported by the Canada Research Chairs Program. Funding Information: The GENDEP project was supported by a European Commission Framework 6 grant (contract reference: LSHB-CT-2003-503428). The Medical Research Council, United Kingdom, and GlaxoSmithKline (G0701420) provided support for genotyping. Publisher Copyright: {\textcopyright} 2018 Elsevier B.V. and ECNP",

year = "2018",

month = aug,

doi = "10.1016/j.euroneuro.2018.05.009",

language = "English",

volume = "28",

pages = "945--954",

journal = "European Neuropsychopharmacology",

issn = "0924-977X",

publisher = "Elsevier",

number = "8",

}

TY - JOUR

T1 - Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects

T2 - Meta-analysis of data from genome-wide association studies

AU - Fabbri, Chiara

AU - Tansey, Katherine E.

AU - Perlis, Roy H.

AU - Hauser, Joanna

AU - Henigsberg, Neven

AU - Maier, Wolfgang

AU - Mors, Ole

AU - Placentino, Anna

AU - Rietschel, Marcella

AU - Souery, Daniel

AU - Breen, Gerome

AU - Curtis, Charles

AU - Lee, Sang Hyuk

AU - Newhouse, Stephen

AU - Patel, Hamel

AU - O'Donovan, Michael

AU - Lewis, Glyn

AU - Jenkins, Gregory

AU - Weinshilboum, Richard M.

AU - Farmer, Anne

AU - Aitchison, Katherine J.

AU - Craig, Ian

AU - McGuffin, Peter

AU - Schruers, Koen

AU - Biernacka, Joanna M.

AU - Uher, Rudolf

AU - Lewis, Cathryn M.

N1 - Funding Information: N Henigsberg participated in clinical trials sponsored by pharmaceutical companies including GlaxoSmithKline and Lundbeck. D Souery is serving in national advisory boards or consulting for Janssen, TEVA, Glaxo Smith Kline. His center is receiving unrestricted financial support from Lundbeck and Fondation René de Spoellberghe. W Maier, KJ Aitchison, AE Farmer and P McGuffin have received consultancy fees and honoraria for participating in expert panels from pharmaceutical companies including Lundbeck and GlaxoSmithKline and Roche Diagnostics. Dr Perlis reported serving on scientific advisory boards or consulting for Genomind LLC, Healthrageous, Pfizer, Perfect Health, Proteus Biomedical, PsyBrain Inc, and RID Ventures LLC and reported receiving royalties through Massachusetts General Hospital from Concordant Rater Systems (now Bracket/Medco). N Perroud received honoraria for participating in expert panels from pharmaceutical companies including Lundbeck. G Bondolfi is a member of a national advisory board for Bristol–Myer Squibb and Pfizer and has received research funding from GlaxoSmithKline, Wyeth–Lederle, Bristol–Myers Squibb and Sanofi Aventis. M O'Donovan's department received £2000 in lieu of an honorarium to M O'Donovan from Lilly as a result of his participation in sponsored symposia in 2012. Those symposia were unrelated to the contents of this manuscript. The other authors declare no conflict of interest. Funding Information: The NEWMEDS study was funded by the Innovative Medicine Initiative Joint Undertaking (IMI-JU) under grant agreement n° 115008 of which resources are composed of European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA) in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013). EFPIA members Pfizer, Glaxo Smith Kline, and F. Hoffmann La-Roche have contributed work and samples to the project presented here. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: The PGRN-AMPS dataset used for the analyses described in this manuscript was obtained from dbGaP (study accession phs000670.v1.p1). PGRN-AMPS was supported, in part, by NIH grants RO1 GM28157, U19 GM61388 (The Pharmacogenomics Research Network), U01 HG005137, R01 CA138461, P20 1P20AA017830-01 (The Mayo Clinic Center for Individualized Treatment of Alcohol Dependence), and a PhRMA Foundation Center of Excellence in Clinical Pharmacology Award. Funding Information: The GENDEP project was supported by a European Commission Framework 6 grant (contract reference: LSHB-CT-2003-503428). The Medical Research Council, United Kingdom, and GlaxoSmithKline (G0701420) provided support for genotyping. Funding Information: We thank the NIMH for providing access to data on the STAR-D sample. We also thank the authors of previous publications in this dataset, and foremost, we thank the patients and their families who agreed to be enrolled in the study. Data and biomaterials were obtained from the limited access datasets distributed from the NIH-supported ‘‘Sequenced Treatment Alternatives to Relieve Depression’’ (STAR*D). The study was supported by NIMH Contract No. N01MH90003 to the University of Texas Southwestern Medical Center. The ClinicalTrials.gov identifier is NCT00021528 . Funding Information: Dr Rudolf Uher is supported by the Canada Research Chairs Program. Funding Information: The GENDEP project was supported by a European Commission Framework 6 grant (contract reference: LSHB-CT-2003-503428). The Medical Research Council, United Kingdom, and GlaxoSmithKline (G0701420) provided support for genotyping. Publisher Copyright: © 2018 Elsevier B.V. and ECNP

PY - 2018/8

Y1 - 2018/8

N2 - Cytochrome (CYP) P450 enzymes have a primary role in antidepressant metabolism and variants in these polymorphic genes are targets for pharmacogenetic investigation. This is the first meta-analysis to investigate how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects. CYP2C19 metabolic phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most common CYP2C19 functional polymorphisms (rs4244285 and rs12248560) in Caucasians. These polymorphisms were genotyped or imputed from genome-wide data in four samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod, PGRN-AMPS). Treatment efficacy was assessed by standardized percentage symptom improvement and by remission. Side effect data were available at weeks 2–4, 6 and 9 in three samples. A fixed-effects meta-analysis was performed using EM as the reference group. Analysis of 2558 patients for efficacy and 2037 patients for side effects showed that PMs had higher symptom improvement (SMD = 0.43, CI = 0.19–0.66) and higher remission rates (OR = 1.55, CI = 1.23–1.96) compared to EMs. At weeks 2–4, PMs showed higher risk of gastro-intestinal (OR = 1.26, CI = 1.08–1.47), neurological (OR = 1.28, CI = 1.07–1.53) and sexual side effects (OR = 1.52, CI = 1.23–1.87; week 6 values were similar). No difference was seen at week 9 or in total side effect burden. PMs did not have higher risk of dropout at week 4 compared to EMs. Antidepressant dose was not different among CYP2C19 groups. CYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs being relatively rare among Caucasians (∼2%).

AB - Cytochrome (CYP) P450 enzymes have a primary role in antidepressant metabolism and variants in these polymorphic genes are targets for pharmacogenetic investigation. This is the first meta-analysis to investigate how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects. CYP2C19 metabolic phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most common CYP2C19 functional polymorphisms (rs4244285 and rs12248560) in Caucasians. These polymorphisms were genotyped or imputed from genome-wide data in four samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod, PGRN-AMPS). Treatment efficacy was assessed by standardized percentage symptom improvement and by remission. Side effect data were available at weeks 2–4, 6 and 9 in three samples. A fixed-effects meta-analysis was performed using EM as the reference group. Analysis of 2558 patients for efficacy and 2037 patients for side effects showed that PMs had higher symptom improvement (SMD = 0.43, CI = 0.19–0.66) and higher remission rates (OR = 1.55, CI = 1.23–1.96) compared to EMs. At weeks 2–4, PMs showed higher risk of gastro-intestinal (OR = 1.26, CI = 1.08–1.47), neurological (OR = 1.28, CI = 1.07–1.53) and sexual side effects (OR = 1.52, CI = 1.23–1.87; week 6 values were similar). No difference was seen at week 9 or in total side effect burden. PMs did not have higher risk of dropout at week 4 compared to EMs. Antidepressant dose was not different among CYP2C19 groups. CYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs being relatively rare among Caucasians (∼2%).

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Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: Meta-analysis of data from genome-wide association studies

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

UN SDGs

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