Contribution of TEX15 genetic variants to the risk of developing severe non-obstructive oligozoospermia

Andrea Guzmán-Jiménez; Sara González-Muñoz; Miriam Cerván-Martín; Rocío Rivera-Egea; Nicolás Garrido; Saturnino Luján; Samuel Santos-Ribeiro; José A Castilla; M Carmen Gonzalvo; Ana Clavero; F Javier Vicente; Vicente Maldonado; Javier Villegas-Salmerón; 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; Alexandra M Lopes; Sara Larriba; Rogelio J Palomino-Morales; F David Carmona; Lara Bossini-Castillo; IVIRMA Group; Lisbon Clinical Group

doi:10.3389/fcell.2022.1089782

Contribution of TEX15 genetic variants to the risk of developing severe non-obstructive oligozoospermia

Front Cell Dev Biol. 2022 Dec 15:10:1089782. doi: 10.3389/fcell.2022.1089782. eCollection 2022.

Authors

Andrea Guzmán-Jiménez^{1

2}, Sara González-Muñoz^{1

2}, Miriam Cerván-Martín^{1

2}, Rocío Rivera-Egea^{3

4}, Nicolás Garrido^{4

5}, Saturnino Luján⁵, Samuel Santos-Ribeiro^{6

7}, José A Castilla^{2

8

9}, M Carmen Gonzalvo^{2

8}, Ana Clavero^{2

8}, F Javier Vicente^{2

10}, Vicente Maldonado¹¹, Javier Villegas-Salmerón¹, Miguel Burgos¹, Rafael Jiménez¹, Maria Graça Pinto¹², Isabel Pereira¹³, Joaquim Nunes¹³, Josvany Sánchez-Curbelo¹⁴, Olga López-Rodrigo¹⁴, Iris Pereira-Caetano¹⁵, Patricia Isabel Marques^{16

17}, Filipa Carvalho^{16

18}, Alberto Barros^{16

18}, Lluís Bassas¹⁴, Susana Seixas^{16

17}, João Gonçalves^{16

19}, Alexandra M Lopes^{16

20}, Sara Larriba²¹, Rogelio J Palomino-Morales^{2

22}, F David Carmona^{1

2}, Lara Bossini-Castillo^{1

2}; IVIRMA Group; Lisbon Clinical Group

Affiliations

¹ Departamento de Genética e Instituto de Biotecnología, Centro de Investigación Biomédica (CIBM), Universidad de Granada, Granada, Spain.
² Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain.
³ Andrology Laboratory and Sperm Bank, IVIRMA Valencia, Valencia, Spain.
⁴ IVI Foundation, Health Research Institute La Fe, Valencia, Spain.
⁵ Servicio de Urología. Hospital Universitari i Politecnic La Fe e Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain.
⁶ IVI-RMA Lisbon, Lisbon, Portugal.
⁷ Department of Obstetrics and Gynecology, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
⁸ Unidad de Reproducción, UGC Obstetricia y Ginecología, HU Virgen de Las Nieves, Granada, Spain.
⁹ CEIFER Biobanco-GAMETIA, Granada, Spain.
¹⁰ UGC de Urología, HU Virgen de las Nieves, Granada, Spain.
¹¹ UGC de Obstetricia y Ginecología, Complejo Hospitalario de Jaén, Jaén, Spain.
¹² Centro de Medicina Reprodutiva, Maternidade Alfredo da Costa, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal.
¹³ Departamento de Obstetrícia, Ginecologia e Medicina da Reprodução, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Lisboa, Portugal.
¹⁴ Laboratory of Seminology and Embryology, Andrology Service-Fundació Puigvert, Barcelona, Spain.
¹⁵ Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisbon, Portugal.
¹⁶ i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
¹⁷ Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
¹⁸ Serviço de Genética, Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal.
¹⁹ ToxOmics-Centro de Toxicogenómica e Saúde Humana, Nova Medical School, Lisbon, Portugal.
²⁰ CGPP-IBMC-Centro de Genética Preditiva e Preventiva, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
²¹ Human Molecular Genetics Group, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
²² Departamento de Bioquímica y Biología Molecular I, Universidad de Granada, Granada, Spain.

Abstract

Background: Severe spermatogenic failure (SPGF) represents one of the most relevant causes of male infertility. This pathological condition can lead to extreme abnormalities in the seminal sperm count, such as severe oligozoospermia (SO) or non-obstructive azoospermia (NOA). Most cases of SPGF have an unknown aetiology, and it is known that this idiopathic form of male infertility represents a complex condition. In this study, we aimed to evaluate whether common genetic variation in TEX15, which encodes a key player in spermatogenesis, is involved in the susceptibility to idiopathic SPGF. Materials and Methods: We designed a genetic association study comprising a total of 727 SPGF cases (including 527 NOA and 200 SO) and 1,058 unaffected men from the Iberian Peninsula. Following a tagging strategy, three tag single-nucleotide polymorphisms (SNPs) of TEX15 (rs1362912, rs323342, and rs323346) were selected for genotyping using TaqMan probes. Case-control association tests were then performed by logistic regression models. In silico analyses were also carried out to shed light into the putative functional implications of the studied variants. Results: A significant increase in TEX15-rs1362912 minor allele frequency (MAF) was observed in the group of SO patients (MAF = 0.0842) compared to either the control cohort (MAF = 0.0468, OR = 1.90, p = 7.47E-03) or the NOA group (MAF = 0.0472, OR = 1.83, p = 1.23E-02). The genotype distribution of the SO population was also different from those of both control (p = 1.14E-02) and NOA groups (p = 4.33-02). The analysis of functional annotations of the human genome suggested that the effect of the SO-associated TEX15 variants is likely exerted by alteration of the binding affinity of crucial transcription factors for spermatogenesis. Conclusion: Our results suggest that common variation in TEX15 is involved in the genetic predisposition to SO, thus supporting the notion of idiopathic SPGF as a complex trait.

Keywords: TEX15; association study; oligozoospermia; polymorphisms; spermatogenesis.

Copyright © 2022 Guzmán-Jiménez, González-Muñoz, Cerván-Martín, Rivera-Egea, Garrido, Luján, Santos-Ribeiro, Castilla, Gonzalvo, Clavero, Vicente, Maldonado, Villegas-Salmerón, Burgos, Jiménez, Pinto, Pereira, Nunes, Sánchez-Curbelo, López-Rodrigo, Pereira-Caetano, Marques, Carvalho, Barros, Bassas, Seixas, Gonçalves, Lopes, Larriba, Palomino-Morales, Carmona, Bossini-Castillo, IVIRMA Group and Lisbon Clinical Group.