869f01b34b1b395b6043fcaca89484ac 272143.pdf 65b93d5139a14c0bff9143ae8b576ccd6c90361a 272143.pdf 3902cd60b65e5763b1cfa198443e65e4b8903326e590c4e3367c973b18fbf731 272143.pdf Title: Evaluation of Male Fertility-Associated Loci in a European Population of Patients with Severe Spermatogenic Impairment Subject: 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. Keywords: SNPs; genetic association analysis; impaired spermatogenesis; non-obstructive azoospermia; severe oligospermia; infertility Author: Miriam Cerván-Martín, Lara Bossini-Castillo, Rocío Rivera-Egea, Nicolás Garrido, Saturnino Luján, Gema Romeu, Samuel Santos-Ribeiro, IVIRMA Group, Lisbon Clinical Group, José A. Castilla, M. Carmen Gonzalvo, Ana Clavero, F. Javier Vicente, Andrea Guzmán-Jiménez, Cláudia Costa, Inés Llinares-Burguet, Chiranan Khantham, Miguel Burgos, Francisco J. Barrionuevo, Rafael Jiménez, Josvany Sánchez-Curbelo, Olga López-Rodrigo, M. Fernanda Peraza, Iris Pereira-Caetano, Patricia I. Marques, Filipa Carvalho, Alberto Barros, Lluís Bassas, Susana Seixas, João Gonçalves, Sara Larriba, Alexandra M. Lopes, Rogelio J. Palomino-Morales and F. David Carmona Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Jan 12 02:45:34 2021 CET ModDate: Tue Jan 12 03:04:52 2021 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 19 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1591561 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- YVDGZO+VnURWPalladioL Type 1 Custom yes yes no 10 0 FTTCKH+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 NIJRQV+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 QDFNJH+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 OJYKSJ+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 UIJACC+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 36 0 BSDWLC+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 39 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 61 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 65 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 69 0 AUVDFL+URWPalladioL-BoldItal Type 1 Custom yes yes no 93 0 DZGEEV+CMBSY10 Type 1 Builtin yes yes no 100 0 OIACBC+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 123 0 OIACBE+PalatinoLinotype TrueType WinAnsi yes yes no 126 0 OIACCF+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 129 0 OIACBC+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 139 0 OIACBE+PalatinoLinotype TrueType WinAnsi yes yes no 142 0 OIACCF+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 145 0 DVCMRV+CMSY10 Type 1 Builtin yes yes no 153 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-04-04 02:33:52 CEST RepresentationInformation: 272143.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-04-03 13:36:20 CEST Size: 1591561 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 382 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Study Design and Study Population Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: SNP Selection and Genotyping Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Statistical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: In Silico Characterization of Associated Variants Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Children: Item: Title: Susceptibility to Non-Obstructive Azoospermia and Specific Histological Manifestations Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Susceptibility to Severe Oligospermia Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Evaluation of Functional Annotations Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Info: Title: Evaluation of Male Fertility-Associated Loci in a European Population of Patients with Severe Spermatogenic Impairment Author: Miriam Cerván-Martín, Lara Bossini-Castillo, Rocío Rivera-Egea, Nicolás Garrido, Saturnino Luján, Gema Romeu, Samuel Santos-Ribeiro, IVIRMA Group, Lisbon Clinical Group, José A. Castilla, M. Carmen Gonzalvo, Ana Clavero, F. Javier Vicente, Andrea Guzmán-Jiménez, Cláudia Costa, Inés Llinares-Burguet, Chiranan Khantham, Miguel Burgos, Francisco J. Barrionuevo, Rafael Jiménez, Josvany Sánchez-Curbelo, Olga López-Rodrigo, M. Fernanda Peraza, Iris Pereira-Caetano, Patricia I. Marques, Filipa Carvalho, Alberto Barros, Lluís Bassas, Susana Seixas, João Gonçalves, Sara Larriba, Alexandra M. Lopes, Rogelio J. Palomino-Morales and F. David Carmona Subject: 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. Keywords: SNPs; genetic association analysis; impaired spermatogenesis; non-obstructive azoospermia; severe oligospermia; infertility Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Jan 12 02:45:34 CET 2021 ModDate: Tue Jan 12 03:04:52 CET 2021 ID: 0xdb63819af966595876a5e22aeb096d0e, 0xdb63819af966595876a5e22aeb096d0e Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: NIJRQV+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 231 FontDescriptor: FontName: NIJRQV+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: DZGEEV+CMBSY10 FontSubset: true FirstChar: 0 LastChar: 2 FontDescriptor: FontName: DZGEEV+CMBSY10 Flags: Symbolic FontBBox: -26, -940, 1332, 825 FontFile: true Font: BaseFont: QDFNJH+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 237 FontDescriptor: FontName: QDFNJH+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 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