Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only Syndrome

Miriam Cerván-Martín; Lara Bossini-Castillo; Andrea Guzmán-Jimenez; Rocío Rivera-Egea; Nicolás Garrido; Saturnino Luján; Gema Romeu; Samuel Santos-Ribeiro; José A. Castilla; M. Carmen Gonzalvo; Ana Clavero; F. Javier Vicente; Vicente Maldonado; Sara González-Muñoz; Inmaculada Rodríguez-Martín; Miguel Burgos; Rafael Jiménez; Maria Graça Pinto; Isabel Pereira; Joaquim Nunes; Josvany Sánchez-Curbelo; Olga López-Rodrigo; Iris Pereira-Caetano; Patricia Isabel Marques; Filipa Carvalho; Alberto Barros; Lluís Bassas; Susana Seixas; João Gonçalves; Sara Larriba; Alexandra M. Lopes; F. David Carmona; Rogelio J. Palomino-Morales

doi:10.3390/jpm12060932

Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only Syndrome

Miriam Cerván-Martín, Lara Bossini-Castillo, Andrea Guzmán-Jimenez, Rocío Rivera-Egea, Nicolás Garrido, Saturnino Luján, Gema Romeu, Samuel Santos-Ribeiro, José A. Castilla, M. Carmen Gonzalvo, Ana Clavero, F. Javier Vicente, Vicente Maldonado, Sara González-Muñoz, Inmaculada Rodríguez-Martín, Miguel Burgos, Rafael Jiménez, Maria Graça Pinto, Isabel Pereira, Joaquim NunesJosvany Sánchez-Curbelo, Olga López-Rodrigo, Iris Pereira-Caetano, Patricia Isabel Marques, Filipa Carvalho, Alberto Barros, Lluís Bassas, Susana Seixas, João Gonçalves, Sara Larriba, Alexandra M. Lopes, F. David Carmona, Rogelio J. Palomino-Morales

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Abstract

We aimed to analyze the role of the common genetic variants located in the PIN1 locus, a relevant prolyl isomerase required to control the proliferation of spermatogonial stem cells and the integrity of the blood–testis barrier, in the genetic risk of developing male infertility due to a severe spermatogenic failure (SPGF). Genotyping was performed using TaqMan genotyping assays for three PIN1 taggers (rs2287839, rs2233678 and rs62105751). The study cohort included 715 males diagnosed with SPGF and classified as suffering from non-obstructive azoospermia (NOA, n = 505) or severe oligospermia (SO, n = 210), and 1058 controls from the Iberian Peninsula. The allelic frequency differences between cases and controls were analyzed by the means of logistic regression models. A subtype specific genetic association with the subset of NOA patients classified as suffering from the Sertoli cell-only (SCO) syndrome was observed with the minor alleles showing strong risk effects for this subset (OR_addrs2287839 = 1.85 (1.17–2.93), OR_addrs2233678 = 1.62 (1.11–2.36), OR_addrs62105751 = 1.43 (1.06–1.93)). The causal variants were predicted to affect the binding of key transcription factors and to produce an altered PIN1 gene expression and isoform balance. In conclusion, common non-coding single-nucleotide polymorphisms located in PIN1 increase the genetic risk to develop SCO.

Original language	English
Article number	932
Journal	Journal of Personalized Medicine
Volume	12
Issue number	6
DOIs	https://doi.org/10.3390/jpm12060932
Publication status	Published - Jun 2022

Keywords

Male infertility
PIN1
Sertoli cell-only syndrome
Severe spermatogenic failure
Single-nucleotide polymorphism

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10.3390/jpm12060932

jpm-12-00932-v2Final published version, 2.68 MBLicence: CC BY

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Cerván-Martín, M., Bossini-Castillo, L., Guzmán-Jimenez, A., Rivera-Egea, R., Garrido, N., Luján, S., Romeu, G., Santos-Ribeiro, S., Castilla, J. A., Gonzalvo, M. C., Clavero, A., Vicente, F. J., Maldonado, V., González-Muñoz, S., Rodríguez-Martín, I., Burgos, M., Jiménez, R., Pinto, M. G., Pereira, I., ... Palomino-Morales, R. J. (2022). Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only Syndrome. Journal of Personalized Medicine, 12(6), Article 932. https://doi.org/10.3390/jpm12060932

@article{f7908626cb624760b70f6cd18ae8e42e,

title = "Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only Syndrome",

abstract = "We aimed to analyze the role of the common genetic variants located in the PIN1 locus, a relevant prolyl isomerase required to control the proliferation of spermatogonial stem cells and the integrity of the blood–testis barrier, in the genetic risk of developing male infertility due to a severe spermatogenic failure (SPGF). Genotyping was performed using TaqMan genotyping assays for three PIN1 taggers (rs2287839, rs2233678 and rs62105751). The study cohort included 715 males diagnosed with SPGF and classified as suffering from non-obstructive azoospermia (NOA, n = 505) or severe oligospermia (SO, n = 210), and 1058 controls from the Iberian Peninsula. The allelic frequency differences between cases and controls were analyzed by the means of logistic regression models. A subtype specific genetic association with the subset of NOA patients classified as suffering from the Sertoli cell-only (SCO) syndrome was observed with the minor alleles showing strong risk effects for this subset (ORaddrs2287839 = 1.85 (1.17–2.93), ORaddrs2233678 = 1.62 (1.11–2.36), ORaddrs62105751 = 1.43 (1.06–1.93)). The causal variants were predicted to affect the binding of key transcription factors and to produce an altered PIN1 gene expression and isoform balance. In conclusion, common non-coding single-nucleotide polymorphisms located in PIN1 increase the genetic risk to develop SCO.",

keywords = "Male infertility, PIN1, Sertoli cell-only syndrome, Severe spermatogenic failure, Single-nucleotide polymorphism",

author = "Miriam Cerv{\'a}n-Mart{\'i}n and Lara Bossini-Castillo and Andrea Guzm{\'a}n-Jimenez and Roc{\'i}o Rivera-Egea and Nicol{\'a}s Garrido and Saturnino Luj{\'a}n and Gema Romeu and Samuel Santos-Ribeiro and Castilla, {Jos{\'e} A.} and Gonzalvo, {M. Carmen} and Ana Clavero and Vicente, {F. Javier} and Vicente Maldonado and Sara Gonz{\'a}lez-Mu{\~n}oz and Inmaculada Rodr{\'i}guez-Mart{\'i}n and Miguel Burgos and Rafael Jim{\'e}nez and Pinto, {Maria Gra{\c c}a} and Isabel Pereira and Joaquim Nunes and Josvany S{\'a}nchez-Curbelo and Olga L{\'o}pez-Rodrigo and Iris Pereira-Caetano and Marques, {Patricia Isabel} and Filipa Carvalho and Alberto Barros and Llu{\'i}s Bassas and Susana Seixas and Jo{\~a}o Gon{\c c}alves and Sara Larriba and Lopes, {Alexandra M.} and Carmona, {F. David} and Palomino-Morales, {Rogelio J.}",

note = "Funding Information: Funding: This work was supported by the Plan Andaluz de Investigaci{\'o}n, Desarrollo e Innovaci{\'o}n (PAIDI 2020) (ref. PY20_00212, P20_00583), and the Spanish Ministry of Economy and Competitiveness through the Spanish National Plan for Scientific and Technical Research and Innovation (ref. SAF2016–78722-R, PID2020–120157RB-I00) and the Proyectos I + D + i del Programa Operativo FEDER 2020 (ref. B-CTS-584-UGR20, B-CTS-260-UGR20). FDC was supported by the “Ram{\'o}n y Cajal” program (ref. RYC-2014–16458), and LBC was supported by the Spanish Ministry of Economy and Competitiveness through the “Juan de la Cierva Incorporaci{\'o}n” program (Grant ref. IJC2018– 038026-I, funded by MCIN/AEI/10.13039/501100011033), all of them including FEDER funds. AGJ was funded by MCIN/AEI/10.13039/501100011033 and FSE “El FSE invierte en tu futuro”(grant ref. FPU20/02926). SGM was funded by a previously mentioned project (ref. PY20_00212). IPATIMUP integrates the i3S Research Unit, which is partially supported by the Portuguese Foundation for Science and Technology (FCT), financed by the European Social Funds (COMPETE-FEDER) and National Funds (projects PEstC/SAU/LA0003/2013 and POCI-01–0145-FEDER-007274). AML is funded by the Portuguese Government through FCT (IF/01262/2014). PIM is supported by the FCT post-doctoral fellowship (SFRH/BPD/120777/2016), financed from the Portuguese State Budget of the Ministry for Science, Technology and High Education and from the European Social Fund, available through the Programa Operacional do Capital Humano. ToxOmics—Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, Nova Medical School, Lisbon, is also partially supported by FCT (Projects: UID/BIM/00009/2013 and UIDB/UIDP/00009/2020). SLarriba received support from Instituto de Salud Carlos III (grant DTS18/00101], co-funded by FEDER funds/European Regional Development Fund (ERDF)—a way to build Europe), and from “Generalitat de Catalunya” (grant 2017SGR191). SLarriba is sponsored by the “Researchers Consolidation Program” from the SNS-Dpt. Salut Generalitat de Catalunya (Exp. CES09/020). This article is related to the Ph.D. Doctoral Thesis of Miriam Cerv{\'a}n-Mart{\'i}n (grant ref. BES-2017–081222 funded by MCIN/AEI/10.13039/501100011033 and FSE “El FSE invierte en tu futuro”). Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

month = jun,

doi = "10.3390/jpm12060932",

language = "English",

volume = "12",

journal = "Journal of Personalized Medicine",

issn = "2075-4426",

publisher = "MDPI - Multidisciplinary Digital Publishing Institute",

number = "6",

}

Cerván-Martín, M, Bossini-Castillo, L, Guzmán-Jimenez, A, Rivera-Egea, R, Garrido, N, Luján, S, Romeu, G, Santos-Ribeiro, S, Castilla, JA, Gonzalvo, MC, Clavero, A, Vicente, FJ, Maldonado, V, González-Muñoz, S, Rodríguez-Martín, I, Burgos, M, Jiménez, R, Pinto, MG, Pereira, I, Nunes, J, Sánchez-Curbelo, J, López-Rodrigo, O, Pereira-Caetano, I, Marques, PI, Carvalho, F, Barros, A, Bassas, L, Seixas, S, Gonçalves, J, Larriba, S, Lopes, AM, Carmona, FD & Palomino-Morales, RJ 2022, 'Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only Syndrome', Journal of Personalized Medicine, vol. 12, no. 6, 932. https://doi.org/10.3390/jpm12060932

TY - JOUR

T1 - Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only Syndrome

AU - Cerván-Martín, Miriam

AU - Bossini-Castillo, Lara

AU - Guzmán-Jimenez, Andrea

AU - Rivera-Egea, Rocío

AU - Garrido, Nicolás

AU - Luján, Saturnino

AU - Romeu, Gema

AU - Santos-Ribeiro, Samuel

AU - Castilla, José A.

AU - Gonzalvo, M. Carmen

AU - Clavero, Ana

AU - Vicente, F. Javier

AU - Maldonado, Vicente

AU - González-Muñoz, Sara

AU - Rodríguez-Martín, Inmaculada

AU - Burgos, Miguel

AU - Jiménez, Rafael

AU - Pinto, Maria Graça

AU - Pereira, Isabel

AU - Nunes, Joaquim

AU - Sánchez-Curbelo, Josvany

AU - López-Rodrigo, Olga

AU - Pereira-Caetano, Iris

AU - Marques, Patricia Isabel

AU - Carvalho, Filipa

AU - Barros, Alberto

AU - Bassas, Lluís

AU - Seixas, Susana

AU - Gonçalves, João

AU - Larriba, Sara

AU - Lopes, Alexandra M.

AU - Carmona, F. David

AU - Palomino-Morales, Rogelio J.

N1 - Funding Information: Funding: This work was supported by the Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020) (ref. PY20_00212, P20_00583), and the Spanish Ministry of Economy and Competitiveness through the Spanish National Plan for Scientific and Technical Research and Innovation (ref. SAF2016–78722-R, PID2020–120157RB-I00) and the Proyectos I + D + i del Programa Operativo FEDER 2020 (ref. B-CTS-584-UGR20, B-CTS-260-UGR20). FDC was supported by the “Ramón y Cajal” program (ref. RYC-2014–16458), and LBC was supported by the Spanish Ministry of Economy and Competitiveness through the “Juan de la Cierva Incorporación” program (Grant ref. IJC2018– 038026-I, funded by MCIN/AEI/10.13039/501100011033), all of them including FEDER funds. AGJ was funded by MCIN/AEI/10.13039/501100011033 and FSE “El FSE invierte en tu futuro”(grant ref. FPU20/02926). SGM was funded by a previously mentioned project (ref. PY20_00212). IPATIMUP integrates the i3S Research Unit, which is partially supported by the Portuguese Foundation for Science and Technology (FCT), financed by the European Social Funds (COMPETE-FEDER) and National Funds (projects PEstC/SAU/LA0003/2013 and POCI-01–0145-FEDER-007274). AML is funded by the Portuguese Government through FCT (IF/01262/2014). PIM is supported by the FCT post-doctoral fellowship (SFRH/BPD/120777/2016), financed from the Portuguese State Budget of the Ministry for Science, Technology and High Education and from the European Social Fund, available through the Programa Operacional do Capital Humano. ToxOmics—Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, Nova Medical School, Lisbon, is also partially supported by FCT (Projects: UID/BIM/00009/2013 and UIDB/UIDP/00009/2020). SLarriba received support from Instituto de Salud Carlos III (grant DTS18/00101], co-funded by FEDER funds/European Regional Development Fund (ERDF)—a way to build Europe), and from “Generalitat de Catalunya” (grant 2017SGR191). SLarriba is sponsored by the “Researchers Consolidation Program” from the SNS-Dpt. Salut Generalitat de Catalunya (Exp. CES09/020). This article is related to the Ph.D. Doctoral Thesis of Miriam Cerván-Martín (grant ref. BES-2017–081222 funded by MCIN/AEI/10.13039/501100011033 and FSE “El FSE invierte en tu futuro”). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022/6

Y1 - 2022/6

N2 - We aimed to analyze the role of the common genetic variants located in the PIN1 locus, a relevant prolyl isomerase required to control the proliferation of spermatogonial stem cells and the integrity of the blood–testis barrier, in the genetic risk of developing male infertility due to a severe spermatogenic failure (SPGF). Genotyping was performed using TaqMan genotyping assays for three PIN1 taggers (rs2287839, rs2233678 and rs62105751). The study cohort included 715 males diagnosed with SPGF and classified as suffering from non-obstructive azoospermia (NOA, n = 505) or severe oligospermia (SO, n = 210), and 1058 controls from the Iberian Peninsula. The allelic frequency differences between cases and controls were analyzed by the means of logistic regression models. A subtype specific genetic association with the subset of NOA patients classified as suffering from the Sertoli cell-only (SCO) syndrome was observed with the minor alleles showing strong risk effects for this subset (ORaddrs2287839 = 1.85 (1.17–2.93), ORaddrs2233678 = 1.62 (1.11–2.36), ORaddrs62105751 = 1.43 (1.06–1.93)). The causal variants were predicted to affect the binding of key transcription factors and to produce an altered PIN1 gene expression and isoform balance. In conclusion, common non-coding single-nucleotide polymorphisms located in PIN1 increase the genetic risk to develop SCO.

AB - We aimed to analyze the role of the common genetic variants located in the PIN1 locus, a relevant prolyl isomerase required to control the proliferation of spermatogonial stem cells and the integrity of the blood–testis barrier, in the genetic risk of developing male infertility due to a severe spermatogenic failure (SPGF). Genotyping was performed using TaqMan genotyping assays for three PIN1 taggers (rs2287839, rs2233678 and rs62105751). The study cohort included 715 males diagnosed with SPGF and classified as suffering from non-obstructive azoospermia (NOA, n = 505) or severe oligospermia (SO, n = 210), and 1058 controls from the Iberian Peninsula. The allelic frequency differences between cases and controls were analyzed by the means of logistic regression models. A subtype specific genetic association with the subset of NOA patients classified as suffering from the Sertoli cell-only (SCO) syndrome was observed with the minor alleles showing strong risk effects for this subset (ORaddrs2287839 = 1.85 (1.17–2.93), ORaddrs2233678 = 1.62 (1.11–2.36), ORaddrs62105751 = 1.43 (1.06–1.93)). The causal variants were predicted to affect the binding of key transcription factors and to produce an altered PIN1 gene expression and isoform balance. In conclusion, common non-coding single-nucleotide polymorphisms located in PIN1 increase the genetic risk to develop SCO.

KW - Male infertility

KW - PIN1

KW - Sertoli cell-only syndrome

KW - Severe spermatogenic failure

KW - Single-nucleotide polymorphism

UR - http://www.scopus.com/inward/record.url?scp=85135009656&partnerID=8YFLogxK

U2 - 10.3390/jpm12060932

DO - 10.3390/jpm12060932

M3 - Article

AN - SCOPUS:85135009656

SN - 2075-4426

VL - 12

JO - Journal of Personalized Medicine

JF - Journal of Personalized Medicine

IS - 6

M1 - 932

ER -

Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only Syndrome

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