Vitamin D Represses Retinoic Acid-Dependent Transactivation of the Retinoic Acid Receptor-ß2 Promoter: The AF-2 Domain of the Vitamin D Receptor Is Required for Transrepression

10 pages, 8 figures.Retinoic acid (RA)-dependent activation of the RA receptor ß2 (RARß2) gene in embryonal carcinoma cells is mediated by binding of retinoid receptor heterodimers (RAR/RXR) to a RA response element (RARE) located closely to the TATA box. We have analyzed the effect of vitamin D on the response of the RARß2 promoter to RA in pituitary GH4C1 cells that coexpress receptors for retinoids and vitamin D. Incubation with vitamin D markedly reduced the response to RA caused by transcriptional interference of the vitamin D receptor (VDR) on the RARE. This DNA element binds VDR/RXR heterodimers with high affinity, and these inactive heterodimers can displace active RAR/RXR from the RARE. Overexpression of RXR in GH4C1 cells, as well as incubation with BMS649 (a RXR-specific ligand), increased the inhibitory effect of vitamin D, suggesting that the VDR/RXR heterodimer is the repressive species and that titration of RXR is not responsible for this inhibition. Although DNA binding could be required for full potency of the inhibitory activity of VDR, it is not absolutely required because a truncated receptor (VDR {Delta}1–111), lacking the DNA binding domain, also displays repressor activity. Furthermore, the ability to mediate transrepression by vitamin D was strongly decreased when a mutant VDR in which the last 12 C-terminal aminoacids have been deleted (VDR {Delta}AF-2) was used. Because this region contains the domain responsible for ligand-dependent recruitment of coactivators, titration of common coactivators for VDR and RAR could be involved in the inhibitory effect of vitamin D. In agreement with this hypothesis, overexpression of E1A, which can act as a RARß2 promoter-specific coactivator, significantly reversed repression by vitamin D.This work was supported by Grants PM94–0094 and PM97–0135 from the Direccion General de Enseñanza Superior e Investigación Científica.Peer reviewe

Retinoic acid protects human breast cancer cells against etoposide-induced apoptosis by NF-kappaB-dependent but cIAP2-independent mechanisms

<p>Abstract</p> <p>Background</p> <p>Retinoids, through their cognate nuclear receptors, exert potent effects on cell growth, differentiation and apoptosis, and have significant promise for cancer therapy and chemoprevention. These ligands can determine the ultimate fate of target cells by stimulating or repressing gene expression directly, or indirectly through crosstalking with other signal transducers.</p> <p>Results</p> <p>Using different breast cancer cell models, we show here that depending on the cellular context retinoids can signal either towards cell death or cell survival. Indeed, retinoids can induce the expression of pro-apoptotic (i.e. TRAIL, TNF-Related Apoptosis-Inducing Ligand, Apo2L/TNFSF10) and anti-apoptotic (i.e. cIAP2, inhibitor of apoptosis protein-2) genes. Promoter mapping, gel retardation and chromatin immunoprecipitation assays revealed that retinoids induce the expression of this gene mainly through crosstalk with NF-kappaB. Supporting this crosstalk, the activation of NF-kappaB by retinoids in T47D cells antagonizes the apoptosis triggered by the chemotherapeutic drugs etoposide, camptothecin or doxorubicin. Notably apoptosis induced by death ligands (i.e. TRAIL or antiFAS) is not antagonized by retinoids. That knockdown of cIAP2 expression by small interfering RNA does not alter the inhibition of etoposide-induced apoptosis by retinoids in T47D cells reveals that stimulation of cIAP2 expression is not the cause of their anti-apoptotic action. However, ectopic overexpression of a NF-kappaB repressor increases apoptosis by retinoids moderately and abrogates almost completely the retinoid-dependent inhibition of etoposide-induced apoptosis. Our data exclude cIAP2 and suggest that retinoids target other regulator(s) of the NF-kappaB signaling pathway to induce resistance to etoposide on certain breast cancer cells.</p> <p>Conclusions</p> <p>This study shows an important role for the NF-kappaB pathway in retinoic acid signaling and retinoic acid-mediated resistance to cancer therapy-mediated apoptosis in breast cancer cells, independently of cIAP2. Our data support the use of NF-kappaB pathway activation as a marker for screening that will help to develop novel retinoids, or retinoid-based combination therapies with improved efficacy.</p

Synergy between RA and TLR3 promotes type I IFN-dependent apoptosis through upregulation of TRAIL pathway in breast cancer cells

This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License.Due to its ability to regulate the growth, differentiation and apoptosis of cancer cells, retinoic acid (RA) is considered a signaling molecule with promising therapeutic potential in oncology. In this study, we show that RA is able to induce the intrinsic ability of breast cancer cells to recognize double-stranded RNA (dsRNA) through the upregulation of Toll-like receptor 3 (TLR3) expression. RA, co-administered with the dsRNA mimicker polyinosinic–polycytidylic acid (poly(I:C)), synergizes to mount a specific response program able to sense dsRNA through the concurrent upregulation of TLR3, the dsRNA helicases melanoma differentiation-associated antigen-5 (MDA-5) and RA-inducible gene-1 (RIG-1), and the dsRNA-activated protein kinase (PKR) expression, leading breast cancer cells to specifically express downstream transcriptional targets of dsRNA sensors, such as interferon-β (IFNβ), interleukin-8 (IL-8), chemokine (C-C motif) ligand 5 (CCL5), and C-X-C motif Chemokine 10 (CXCL10). A TLR3-dependent apoptotic program is also induced by RA and poly(I:C) co-treatment that correlates with the induction of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and contributes to block breast cancer cell proliferation. The mechanisms of apoptosis induced by RA/poly(I:C) in breast cancer cells involve type I IFN autocrine signaling, caspase-8 and caspase-3 activation, as well as TRAIL signaling. Our results reveal important links among RA, TLR3 and TRAIL and highlight the combined use of RA and poly(I:C) as a potential effective tumor therapy by improving the apoptotic response of cancer cells with low sensitivity to the action of synthetic dsRNA.This work was supported by funds from the MICINN (SAF2007-63634 and SAF2010-21195), CSIC (201120E105), and Fundación Médica Mutua Madrileña (2005 0584). ARBV was supported by funds from the MICINN. AMJ-L is a recipient of a grant from the Spanish MICINN (Ramón y Cajal Program).Peer reviewe

Targeting Innate Immunity with dsRNA-Conjugated Mesoporous Silica Nanoparticles Promotes Antitumor Effects on Breast Cancer Cells

The authors describe herein a Toll-like receptor 3 (TLR3) targeting delivery system based on mesoporous silica nanoparticles capped with the synthetic double stranded RNA polyinosinic-polycytidylic acid (poly(I:C)) for controlled cargo delivery in SK-BR-3 breast carcinoma cells. The authors' results show that poly(I:C)-conjugated nanoparticles efficiently targeted breast cancer cells due to dsRNA-TLR3 interaction. Such interaction also triggered apoptotic pathways in SK-BR-3, significantly decreasing cells viability. Poly(I:C) cytotoxic effect in breast carcinoma cells was enhanced by loading nanoparticles' mesopores with the anthracyclinic antibiotic doxorubicin, a commonly used chemotherapeutic agent.We thank the Spanish Government (projects SAF2010-21195 and MAT2012-38429-C04-01) and the Generalitat Valenciana (project PROMETEOII/2014/047) for support. A.U. and C.G. are grateful to the Ministry of Education, Culture and Sport for their doctoral fellowships. We thank J. M. Cosgaya and M. J. Latasa for helpful discussions.Ultimo, A.; Giménez Morales, C.; Bartovsky, P.; Aznar, E.; Sancenón Galarza, F.; Marcos Martínez, MD.; Amoros Del Toro, PJ.... (2016). Targeting Innate Immunity with dsRNA-Conjugated Mesoporous Silica Nanoparticles Promotes Antitumor Effects on Breast Cancer Cells. Chemistry - A European Journal. 22(5):1582-1586. https://doi.org/10.1002/chem.201504629S15821586225Torre, L. A., Bray, F., Siegel, R. L., Ferlay, J., Lortet-Tieulent, J., & Jemal, A. (2015). Global cancer statistics, 2012. CA: A Cancer Journal for Clinicians, 65(2), 87-108. doi:10.3322/caac.21262McGuire, A., Brown, J., Malone, C., McLaughlin, R., & Kerin, M. (2015). Effects of Age on the Detection and Management of Breast Cancer. Cancers, 7(2), 908-929. doi:10.3390/cancers7020815Stier, S., Maletzki, C., Klier, U., & Linnebacher, M. (2013). Combinations of TLR Ligands: A Promising Approach in Cancer Immunotherapy. 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V., Sancenón, F., Marcos, M. D., Martínez-Máñez, R., … Amorós, P. (2011). Finely Tuned Temperature-Controlled Cargo Release Using Paraffin-Capped Mesoporous Silica Nanoparticles. Angewandte Chemie International Edition, 50(47), 11172-11175. doi:10.1002/anie.201102756Aznar, E., Mondragón, L., Ros-Lis, J. V., Sancenón, F., Marcos, M. D., Martínez-Máñez, R., … Amorós, P. (2011). Finely Tuned Temperature-Controlled Cargo Release Using Paraffin-Capped Mesoporous Silica Nanoparticles. Angewandte Chemie, 123(47), 11368-11371. doi:10.1002/ange.201102756Bringas, E., Köysüren, Ö., Quach, D. V., Mahmoudi, M., Aznar, E., Roehling, J. D., … Stroeve, P. (2012). Triggered release in lipid bilayer-capped mesoporous silica nanoparticles containing SPION using an alternating magnetic field. Chemical Communications, 48(45), 5647. doi:10.1039/c2cc31563gFu, Q., Rao, G. V. R., Ista, L. K., Wu, Y., Andrzejewski, B. P., Sklar, L. A., … López, G. P. (2003). Control of Molecular Transport Through Stimuli-Responsive Ordered Mesoporous Materials. Advanced Materials, 15(15), 1262-1266. doi:10.1002/adma.200305165Bernardos, A., Mondragón, L., Aznar, E., Marcos, M. D., Martínez-Máñez, R., Sancenón, F., … Amorós, P. (2010). Enzyme-Responsive Intracellular Controlled Release Using Nanometric Silica Mesoporous Supports Capped with «Saccharides». ACS Nano, 4(11), 6353-6368. doi:10.1021/nn101499dCliment, E., Bernardos, A., Martínez-Máñez, R., Maquieira, A., Marcos, M. D., Pastor-Navarro, N., … Amorós, P. (2009). Controlled Delivery Systems Using Antibody-Capped Mesoporous Nanocontainers. Journal of the American Chemical Society, 131(39), 14075-14080. doi:10.1021/ja904456dPark, C., Kim, H., Kim, S., & Kim, C. (2009). Enzyme Responsive Nanocontainers with Cyclodextrin Gatekeepers and Synergistic Effects in Release of Guests. Journal of the American Chemical Society, 131(46), 16614-16615. doi:10.1021/ja9061085Patel, K., Angelos, S., Dichtel, W. 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Usual Dietary Intake, Nutritional Adequacy and Food Sources of Calcium, Phosphorus, Magnesium and Vitamin D of Spanish Children Aged One to <10 Years. Findings from the EsNuPI Study

Bone problems in the population begin to be establish in childhood. The present study aims to assess the usual calcium, phosphorus, magnesium, and vitamin D intakes, along with the food sources of these nutrients, in Spanish children participating in the EsNuPI (Estudio Nutricional en Población Infantil Española) study. Two 24 h dietary recalls were applied to 1448 children (1 to <10 years) divided into two sub-samples: one reference sample (RS) of the general population [n = 707] and another sample which exclusively included children consuming enriched or fortified milks, here called “adapted milks” (AMS) [n = 741]. Estimation of the usual intake shows that nutrient intake increased with age for all nutrients except vitamin D. Using as reference the Dietary Reference Values from the European Food Safety Authority (EFSA), calcium and magnesium intakes were found to be below the average requirement (AR) and adequate intake (AI), respectively, in a considerable percentage of children. Furthermore, phosphorus exceeded the AI in 100% of individuals and vitamin D was lower than the AI in almost all children studied. The results were very similar when considering only plausible reporters. When analyzing the food sources of the nutrients studied, milk and dairy products contributed the most to calcium, phosphorus, magnesium, and vitamin D. Other sources of calcium were cereals and vegetables; for phosphorus: meat, meat products, and cereals; for magnesium: cereals and fruits; and, for vitamin D: fish and eggs. These results highlight the desirability of improving the intake concerning these nutrients, which are involved in bone and metabolic health in children. The AMS group appeared to contribute better to the adequacy of those nutrients than the RS group, but both still need further improvement. Of special interest are the results of vitamin D intakes, which were significantly higher in the AMS group (although still below the AI), independent of ageThis research was funded by Instituto Puleva de Nutrición (IPN)S

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

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.Plan Andaluz de Investigacion, Desarrollo e Innovacion (PAIDI 2020) PY20_00212 P20_00583Spanish Ministry of Economy and Competitiveness through the Spanish National Plan for Scientific and Technical Research and Innovation SAF2016-78722-R PID2020-120157RB-I00Proyectos I + D + i del Programa Operativo FEDER 2020 B-CTS-584-UGR20 B-CTS-260-UGR20Spanish Government RYC-2014-16458Spanish Ministry of Economy and Competitiveness through the "Juan de la Cierva Incorporacion" program (MCIN/AEI) IJC2018038026-IEuropean CommissionMCIN/AEIFSE "El FSE invierte en tu futuro" FPU20/02926 BES-2017-081222Portuguese Foundation for Science and Technology (FCT) - European Social Funds (COMPETE-FEDER) Portuguese Foundation for Science and Technology IF/01262/2014FCT from the Portuguese State Budget of the Ministry for Science, Technology and High Education SFRH/BPD/120777/2016European Social Fund through the Programa Operacional do Capital HumanoPortuguese Foundation for Science and Technology European Commission UID/BIM/00009/2013 UIDB/UIDP/00009/2020Instituto de Salud Carlos III (FEDER funds/European Regional Development Fund (ERDF)-a way to build Europe) DTS18/00101Generalitat de Catalunya 2017SGR191SNS-Dpt. Salut Generalitat de Catalunya CES09/020 MCIN/AEI BES-2017-081222 PEstC/SAU/LA0003/2013 POCI-01-0145-FEDER-00727

Usual dietary intake, nutritional adequacy and food sources of calcium, phosphorus, magnesium and vitamin D of spanish children aged one to dagger

Bone problems in the population begin to be establish in childhood. The present study aims to assess the usual calcium, phosphorus, magnesium, and vitamin D intakes, along with the food sources of these nutrients, in Spanish children participating in the EsNuPI (Estudio Nutricional en Población Infantil Española) study. Two 24 h dietary recalls were applied to 1448 children (1 to <10 years) divided into two sub-samples: one reference sample (RS) of the general population [n = 707] and another sample which exclusively included children consuming enriched or fortified milks, here called “adapted milks” (AMS) [n = 741]. Estimation of the usual intake shows that nutrient intake increased with age for all nutrients except vitamin D. Using as reference the Dietary Reference Values from the European Food Safety Authority (EFSA), calcium and magnesium intakes were found to be below the average requirement (AR) and adequate intake (AI), respectively, in a considerable percentage of children. Furthermore, phosphorus exceeded the AI in 100% of individuals and vitamin D was lower than the AI in almost all children studied. The results were very similar when considering only plausible reporters. When analyzing the food sources of the nutrients studied, milk and dairy products contributed the most to calcium, phosphorus, magnesium, and vitamin D. Other sources of calcium were cereals and vegetables; for phosphorus: meat, meat products, and cereals; for magnesium: cereals and fruits; and, for vitamin D: fish and eggs. These results highlight the desirability of improving the intake concerning these nutrients, which are involved in bone and metabolic health in children. The AMS group appeared to contribute better to the adequacy of those nutrients than the RS group, but both still need further improvement. Of special interest are the results of vitamin D intakes, which were significantly higher in the AMS group (although still below the AI), independent of age

Evaluation of male fertility-associated loci in a european population of patients with severe spermatogenic impairment

Funding: This work was supported by the Spanish Ministry of Economy and Competitiveness through the Spanish State Plan for Scientific and Technical Research and Innovation (ref. SAF2016-78722-R), the “Ramón y Cajal” program (ref. RYC-2014-16458), and the “Juan de la Cierva Incorporación” program (ref. IJC2018-038026-I), which include FEDER funds. SLa received support from the Spanish Ministry of Science and Innovation (grants FIS-ISCIII DTS18/00101, co-funded by FEDER funds/European Regional Development Fund (ERDF)-a way to build Europe-), and from Generalitat de Catalunya (grant 2017SGR191). AG-J was recipient of a grant from the “Plan Propio” program of the University of Granada (“Becas de Iniciación a la Investigación para estudiantes de Grado”, conv.2019). SLa is sponsored by the “Researchers Consolidation Program” from the SNS-Dpt. Salut Generalitat de Catalunya (Exp. CES09/020). JG was partially funded by FCT/MCTES, through national funds attributed to Center for Toxicogenomics and Human Health—ToxOmics (UIDB/00009/2020). 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. AML is funded by the Portuguese Government through FCT (IF/01262/2014). IPATIMUP integrates the i3S Research Unit, which is partially supported by FCT in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274).Infertility is a growing concern in developed societies. Two extreme phenotypes of male infertility are non-obstructive azoospermia (NOA) and severe oligospermia (SO), which are characterized by severe spermatogenic failure (SpF). We designed a genetic association study comprising 725 Iberian infertile men as a consequence of SpF and 1058 unaffected controls to evaluate whether five single-nucleotide polymorphisms (SNPs), previously associated with reduced fertility in Hutterites, are also involved in the genetic susceptibility to idiopathic SpF and specific clinical entities. A significant difference in the allele frequencies of USP8-rs7174015 was observed under the recessive model between the NOA group and both the control group (p = 0.0226, OR = 1.33) and the SO group (p = 0.0048, OR = 1.78). Other genetic associations for EPSTI1-rs12870438 and PSAT1-rs7867029 with SO and between TUSC1-rs10966811 and testicular sperm extraction (TESE) success in the context of NOA were observed. In silico analysis of functional annotations demonstrated cis-eQTL effects of such SNPs likely due to the modification of binding motif sites for relevant transcription factors of the spermatogenic process. The findings reported here shed light on the molecular mechanisms leading to severe phenotypes of idiopathic male infertility, and may help to better understand the contribution of the common genetic variation to the development of these conditions.publishersversionpublishe

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

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

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

Lisbon clinical group co-authors and IVIRMA group co-authors Ana Aguiar, (Unidade de Medicina da Reproducao, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal); Carlos Calhaz-Jorge, (Unidade de Medicina da Reproducao, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal); Joaquim Nunes, (Unidade de Medicina da Reproducao, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal); Sandra Sousa (Unidade de Medicina da Reproducao, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal), and Sónia Correia (Centro de Medicina Reprodutiva, Maternidade Alfredo da Costa, Centro Hospitalar Lisboa Central, Lisboa, Portugal); Maria Graça Pinto(Centro de Medicina Reprodutiva, Maternidade Alfredo da Costa, Centro Hospitalar Lisboa Central, Lisboa, Portugal). Alberto Pacheco, (IVIRMA Madrid, Spain); Cristina González, (IVIRMA Sevilla, Spain); Susana Gómez, (IVIRMA Lisboa, Portugal); David Amorós, (IVIRMA Barcelona, Spain); Jesús Aguilar, (IVIRMA Vigo, Spain); Fernando Quintana, (IVIRMA Bilbao, Spain).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.This work was supported by the Spanish Ministry of Science and Innovation through the Spanish National Plan for Scientific and Technical Research and Innovation (PID 2020-120157RB-I00) and the Andalusian Government through the research projects of “Plan Andaluz de Investigacion, Desarrollo e Innovacion (PAIDI 2020)” (ref. PY20_00212) and “Programa Operativo FEDER 2020” (ref. B-CTS-584-UGR20). LB-C was supported by the Spanish Ministry of Science and Innovation through the “Juan de la Cierva Incorporacion” program (Grant ref. IJC 2018-038026- I, funded by MCIN/AEI/10.13039/501100011033), which includes FEDER funds. AG-J was funded by MCIN/AEI/ 10.13039/501100011033 and FSE “El FSE invierte en tu futuro” (grant ref. FPU20/02926). 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). PM 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 (UID/BIM/00009/2016 and UIDB/00009/2020). SL 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). SL 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 AG-J.info:eu-repo/semantics/publishedVersio