Effect and in silico characterization of genetic variants associated with severe spermatogenic disorders in a large Iberian cohort.
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Infertility, Male
/ genetics
LIM Domain Proteins
/ genetics
Male
Microfilament Proteins
/ genetics
Myotonin-Protein Kinase
/ genetics
Peroxins
/ genetics
Polymorphism, Single Nucleotide
/ genetics
Portugal
Receptors, Cytoplasmic and Nuclear
/ genetics
Semen Analysis
Spain
genetic association study
impaired spermatogenesis
male infertility
non-obstructive azoospermia
severe oligospermia
Journal
Andrology
ISSN: 2047-2927
Titre abrégé: Andrology
Pays: England
ID NLM: 101585129
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
revised:
08
03
2021
received:
19
01
2021
accepted:
24
03
2021
pubmed:
31
3
2021
medline:
13
1
2022
entrez:
30
3
2021
Statut:
ppublish
Résumé
Severe spermatogenic failure (SpF) represents the most extreme manifestation of male infertility, as it decreases drastically the semen quality leading to either severe oligospermia (SO, <5 million spermatozoa/mL semen) or non-obstructive azoospermia (NOA, complete lack of spermatozoa in the ejaculate without obstructive causes). The main objective of the present study is to analyze in the Iberian population the effect of 6 single-nucleotide polymorphisms (SNPs) previously associated with NOA in Han Chinese through genome-wide association studies (GWAS) and to establish their possible functional relevance in the development of specific SpF patterns. We genotyped 674 Iberian infertile men (including 480 NOA and 194 SO patients) and 1058 matched unaffected controls for the GWAS-associated variants PRMT6-rs12097821, PEX10-rs2477686, CDC42BPA-rs3000811, IL17A-rs13206743, ABLIM1-rs7099208, and SOX5-rs10842262. Their association with SpF, SO, NOA, and different NOA phenotypes was evaluated by logistic regression models, and their functional relevance was defined by comprehensive interrogation of public resources. ABLIM1-rs7099208 was associated with SpF under both additive (OR = 0.86, p = 0.036) and dominant models (OR = 0.78, p = 0.026). The CDC42BPA-rs3000811 minor allele frequency was significantly increased in the subgroup of NOA patients showing maturation arrest (MA) of germ cells compared to the remaining NOA cases under the recessive model (OR = 4.45, p = 0.044). The PEX10-rs2477686 SNP was associated with a negative testicular sperm extraction (TESE) outcome under the additive model (OR = 1.32, p = 0.034). The analysis of functional annotations suggested that these variants affect the testis-specific expression of nearby genes and that lincRNA may play a role in SpF. Our data support the association of three previously reported NOA risk variants in Asians (ABLIM1-rs7099208, CDC42BPA-rs3000811, and PEX10-rs2477686) with different manifestations of SpF in Iberians of European descent, likely by influencing gene expression and lincRNA deregulation.
Sections du résumé
BACKGROUND
Severe spermatogenic failure (SpF) represents the most extreme manifestation of male infertility, as it decreases drastically the semen quality leading to either severe oligospermia (SO, <5 million spermatozoa/mL semen) or non-obstructive azoospermia (NOA, complete lack of spermatozoa in the ejaculate without obstructive causes).
OBJECTIVES
The main objective of the present study is to analyze in the Iberian population the effect of 6 single-nucleotide polymorphisms (SNPs) previously associated with NOA in Han Chinese through genome-wide association studies (GWAS) and to establish their possible functional relevance in the development of specific SpF patterns.
MATERIALS AND METHODS
We genotyped 674 Iberian infertile men (including 480 NOA and 194 SO patients) and 1058 matched unaffected controls for the GWAS-associated variants PRMT6-rs12097821, PEX10-rs2477686, CDC42BPA-rs3000811, IL17A-rs13206743, ABLIM1-rs7099208, and SOX5-rs10842262. Their association with SpF, SO, NOA, and different NOA phenotypes was evaluated by logistic regression models, and their functional relevance was defined by comprehensive interrogation of public resources.
RESULTS
ABLIM1-rs7099208 was associated with SpF under both additive (OR = 0.86, p = 0.036) and dominant models (OR = 0.78, p = 0.026). The CDC42BPA-rs3000811 minor allele frequency was significantly increased in the subgroup of NOA patients showing maturation arrest (MA) of germ cells compared to the remaining NOA cases under the recessive model (OR = 4.45, p = 0.044). The PEX10-rs2477686 SNP was associated with a negative testicular sperm extraction (TESE) outcome under the additive model (OR = 1.32, p = 0.034). The analysis of functional annotations suggested that these variants affect the testis-specific expression of nearby genes and that lincRNA may play a role in SpF.
CONCLUSIONS
Our data support the association of three previously reported NOA risk variants in Asians (ABLIM1-rs7099208, CDC42BPA-rs3000811, and PEX10-rs2477686) with different manifestations of SpF in Iberians of European descent, likely by influencing gene expression and lincRNA deregulation.
Substances chimiques
ABLIM1 protein, human
0
LIM Domain Proteins
0
Microfilament Proteins
0
PEX10 protein, human
0
Peroxins
0
Receptors, Cytoplasmic and Nuclear
0
CDC42BPA protein, human
EC 2.7.1.-
Myotonin-Protein Kinase
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1151-1165Investigateurs
Alberto Pacheco
(A)
Cristina González
(C)
Susana Gómez
(S)
David Amorós
(D)
Jesus Aguilar
(J)
Fernando Quintana
(F)
Carlos Calhaz-Jorge
(C)
Ana Aguiar
(A)
Joaquim Nunes
(J)
Sandra Sousa
(S)
Maria Graça Pinto
(MG)
Sónia Correia
(S)
Informations de copyright
© 2021 American Society of Andrology and European Academy of Andrology.
Références
Marston AL, Amon A. Meiosis: cell-cycle controls shuffle and deal. Nat Rev Mol Cell Biol. 2004;5(12):983-997. https://doi.org/10.1038/nrm1526
Agarwal A, Mulgund A, Hamada A, Chyatte MR. A unique view on male infertility around the globe. Reprod Biol Endocrinol. 2015;13:37. https://doi.org/10.1186/s12958-015-0032-1
Pan MM, Hockenberry MS, Kirby EW, Lipshultz LI. Male infertility diagnosis and treatment in the era of in vitro fertilization and intracytoplasmic sperm injection. The Med Clin North America. 2018;102:337-347. https://doi.org/10.1016/j.mcna.2017.10.008
Tournaye H, Krausz C, Oates RD. Concepts in diagnosis and therapy for male reproductive impairment. Lancet Diabet Endocrinol. 2017;5:554-564. https://doi.org/10.1016/S2213-8587(16)30043-2
Wosnitzer MS. Genetic evaluation of male infertility. Transl Androl Urol. 2014;3(1):17-26. https://doi.org/10.3978/j.issn.2223-4683.2014.02.04
Juul A, Almstrup K, Andersson AM, et al. Possible fetal determinants of male infertility. Nat Rev Endocrinol. 2014;10(9):553-562. https://doi.org/10.1038/nrendo.2014.97
Deruyver Y, Vanderschueren D, Van der Aa F. Outcome of microdissection TESE compared with conventional TESE in non-obstructive azoospermia: a systematic review. Andrology. 2014;2(1):20-24. https://doi.org/10.1111/j.2047-2927.2013.00148.x
Tuttelmann F, Ruckert C, Ropke A. Disorders of spermatogenesis: Perspectives for novel genetic diagnostics after 20 years of unchanged routine. Medizinische Genetik: Mitteilungsblatt des Berufsverbandes Medizinische Genetik eV. 2018;30(1):12-20. https://doi.org/10.1007/s11825-018-0181-7
Cervan-Martin M, Castilla JA, Palomino-Morales RJ, Carmona FD. Genetic landscape of nonobstructive azoospermia and new perspectives for the clinic. Journal of clinical medicine. 2020;9(2):300. https://doi.org/10.3390/jcm9020300
Krausz C, Riera-Escamilla A. Genetics of male infertility. Nat Rev Urol. 2018;15(6):369-384. https://doi.org/10.1038/s41585-018-0003-3
Hu Z, Xia Y, Guo X, et al. A genome-wide association study in Chinese men identifies three risk loci for non-obstructive azoospermia. Nat Genet. 2011;44(2):183-186. https://doi.org/10.1038/ng.1040
Hu Z, Li Z, Yu J, et al. Association analysis identifies new risk loci for non-obstructive azoospermia in Chinese men. Nat Commun. 2014;5:3857. https://doi.org/10.1038/ncomms4857
Luo M, Li Y, Guo H, et al. Protein arginine methyltransferase 6 involved in germ cell viability during spermatogenesis and down-regulated by the androgen receptor. Int J Mol Sci. 2015;16:29467-29481. https://doi.org/10.3390/ijms161226186
Chen H, Liu Z, Huang X. Drosophila models of peroxisomal biogenesis disorder: peroxins are required for spermatogenesis and very-long-chain fatty acid metabolism. Hum Mol Genet. 2010;19(3):494-505. https://doi.org/10.1093/hmg/ddp518
Daigle M, Roumaud P, Martin LJ. Expressions of Sox9, Sox5, and Sox13 transcription factors in mice testis during postnatal development. Mol Cell Biochem. 2015;407(1-2):209-221. https://doi.org/10.1007/s11010-015-2470-7
Budde LM, Wu C, Tilman C, Douglas I, Ghosh S. Regulation of IkappaBbeta expression in testis. Mol Biol Cell. 2002;13(12):4179-4194. https://doi.org/10.1091/mbc.01-07-0373
Duan YG, Yu CF, Novak N, et al. Immunodeviation towards a Th17 immune response associated with testicular damage in azoospermic men. International journal of andrology. 2011;34(6 Pt 2):e536-e545. https://doi.org/10.1111/j.1365-2605.2010.01137.x
Wong EW, Mruk DD, Cheng CY. Biology and regulation of ectoplasmic specialization, an atypical adherens junction type, in the testis. Biochem Biophys Acta. 2008;1778(3):692-708. https://doi.org/10.1016/j.bbamem.2007.11.006
Little J, Higgins JP, Ioannidis JP, et al. Strengthening the reporting of genetic association studies (STREGA): an extension of the STROBE Statement. Hum Genet. 2009;125(2):131-151. https://doi.org/10.1007/s00439-008-0592-7
World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen, 5th edn. Geneva: WHO Press; 2010.
Skol AD, Scott LJ, Abecasis GR, Boehnke M. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet. 2006;38(2):209-213. https://doi.org/10.1038/ng1706
Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. GigaScience. 2015;4:7. https://doi.org/10.1186/s13742-015-0047-8
Machiela MJ, Chanock SJ. LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics. 2015;31(21):3555-3557. https://doi.org/10.1093/bioinformatics/btv402
Davis CA, Hitz BC, Sloan CA, et al. The Encyclopedia of DNA elements (ENCODE): data portal update. Nucleic Acids Res. 2018;46(D1):D794-D801. https://doi.org/10.1093/nar/gkx1081
Dayem Ullah AZ, Oscanoa J, Wang J, Nagano A, Lemoine NR, Chelala C. SNPnexus: assessing the functional relevance of genetic variation to facilitate the promise of precision medicine. Nucleic Acids Res. 2018;46(W1):W109-W113. https://doi.org/10.1093/nar/gky399
Ward LD, Kellis M. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Res. 2016;44(D1):D877-D881. https://doi.org/10.1093/nar/gkv1340
Kumar S, Ambrosini G, Bucher P. SNP2TFBS - a database of regulatory SNPs affecting predicted transcription factor binding site affinity. Nucleic Acids Res. 2017;45(D1):D139-D144. https://doi.org/10.1093/nar/gkw1064
Kundaje A, Meuleman W, Ernst J, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518(7539):317-330. https://doi.org/10.1038/nature14248
Boyle AP, Hong EL, Hariharan M, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012;22(9):1790-1797. https://doi.org/10.1101/gr.137323.112
Durinck S, Spellman PT, Birney E, Huber W. Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt. Nat Protoc. 2009;4(8):1184-1191. https://doi.org/10.1038/nprot.2009.97
Cervan-Martin M, Suazo-Sanchez MI, Rivera-Egea R, et al. Intronic variation of the SOHLH2 gene confers risk to male reproductive impairment. Fertil Steril. 2020;114:398-406. https://doi.org/10.1016/j.fertnstert.2020.02.115
Auton A, Brooks LD, Durbin RM, et al. A global reference for human genetic variation. Nature. 2015;526:68-74. https://doi.org/10.1038/nature15393
Hu G, Schones DE, Cui K, et al. Regulation of nucleosome landscape and transcription factor targeting at tissue-specific enhancers by BRG1. Genome Res. 2011;21(10):1650-1658. https://doi.org/10.1101/gr.121145.111
Gnessi L, Scarselli F, Minasi MG, et al. Testicular histopathology, semen analysis and FSH, predictive value of sperm retrieval: supportive counseling in case of reoperation after testicular sperm extraction (TESE). BMC urology. 2018;18:63. https://doi.org/10.1016/j.fertnstert.2020.02.115
Gu X, Li H, Chen X, et al. PEX10, SIRPA-SIRPG, and SOX5 gene polymorphisms are strongly associated with nonobstructive azoospermia susceptibility. J Assist Reprod Genet. 2019;36(4):759-768. https://doi.org/10.1007/s10815-019-01417-w
Sato Y, Jinam T, Iwamoto T, et al. Replication study and meta-analysis of human nonobstructive azoospermia in Japanese populations. Biol Reprod. 2013;88(4):87. https://doi.org/10.1095/biolreprod.112.106377
Tu W, Liu Y, Shen Y, et al. Genome-wide Loci linked to non-obstructive azoospermia susceptibility may be independent of reduced sperm production in males with normozoospermia. Biol Reprod. 2015;92(2):41. https://doi.org/10.1095/biolreprod.114.125237
Zou S, Li Z, Wang Y, et al. Association study between polymorphisms of PRMT6, PEX10, SOX5, and nonobstructive azoospermia in the Han Chinese population. Biol Reprod. 2014;90(5):96. https://doi.org/10.1095/biolreprod.113.116541
Liu SY, Zhang CJ, Peng HY, et al. Strong association of SLC1A1 and DPF3 gene variants with idiopathic male infertility in Han Chinese. Asian J Androl. 2017;19(4):486-492. https://doi.org/10.4103/1008-682X.178850
Molinari E, Bar H, Pyle AM, Patrizio P. Transcriptome analysis of human cumulus cells reveals hypoxia as the main determinant of follicular senescence. Mol Hum Reprod. 2016;22(8):866-876. https://doi.org/10.1093/molehr/gaw038
Ransohoff JD, Wei Y, Khavari PA. The functions and unique features of long intergenic non-coding RNA. Nat Rev Mol Cell Biol. 2018;19(3):143-157. https://doi.org/10.1038/nrm.2017.104
Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell. 2013;154(1):26-46. https://doi.org/10.1016/j.cell.2013.06.020
Lu M, Tian H, Cao YX, et al. Downregulation of miR-320a/383-sponge-like long non-coding RNA NLC1-C (narcolepsy candidate-region 1 genes) is associated with male infertility and promotes testicular embryonal carcinoma cell proliferation. Cell Death Dis. 2015;6:e1960. https://doi.org/10.1038/cddis.2015.267
Wen K, Yang L, Xiong T, et al. Critical roles of long noncoding RNAs in Drosophila spermatogenesis. Genome Res. 2016;26(9):1233-1244. https://doi.org/10.1101/gr.199547.115
Zhang C, Gao L, Xu EY. LncRNA, a new component of expanding RNA-protein regulatory network important for animal sperm development. Semin Cell Dev Biol. 2016;59:110-117. https://doi.org/10.1016/j.semcdb.2016.06.013
Zhang X, Zhang P, Song D, et al. Expression profiles and characteristics of human lncRNA in normal and asthenozoospermia spermdagger. Biol Reprod. 2019;100(4):982-993. https://doi.org/10.1093/biolre/ioy253
Winge SB, Dalgaard MD, Jensen JM, et al. Transcriptome profiling of fetal Klinefelter testis tissue reveals a possible involvement of long non-coding RNAs in gonocyte maturation. Hum Mol Genet. 2018;27(3):430-439. https://doi.org/10.1093/hmg/ddx411
Unbekandt M, Olson MF. The actin-myosin regulatory MRCK kinases: regulation, biological functions and associations with human cancer. J Mol Med (Berl). 2014;92:217-225. https://doi.org/10.1007/s00109-014-1133-6
Zhang Y, Qian J, Wu M, et al. A susceptibility locus rs7099208 is associated with non-obstructive azoospermia via reduction in the expression of FAM160B1. Journal of biomedical research. 2015;29(6):491-500. https://doi.org/10.7555/JBR.29.20150034
Vloeberghs V, Verheyen G, Haentjens P, Goossens A, Polyzos NP, Tournaye H. How successful is TESE-ICSI in couples with non-obstructive azoospermia? Hum Reprod. 2015;30:1790-1796. https://doi.org/10.1093/humrep/dev139