Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility
Por:
Cervan-Martin, M, Tuttelmann, F, Lopes, AM, Bossini-Castillo, L, Rivera-Egea, R, Garrido, N, Lujan, S, Romeu, G, Santos-Ribeiro, S, Castilla, JA, Gonzalvo, MC, Clavero, A, Maldonado, V, Vicente, FJ, Gonzalez-Munoz, S, Guzman-Jimenez, A, Burgos, M, Jimenez, R, Pacheco, A, Gonzalez, C, Gomez, S, Amoros, D, Aguilar, J, Quintana, F, Calhaz-Jorge, C, Aguiar, A, Nunes, J, Sousa, S, Pereira, I, Pinto, MG, Correia, S, Sanchez-Curbelo, J, Lopez-Rodrigo, O, Martin, J, Pereira-Caetano, I, Marques, PI, Carvalho, F, Barros, A, Gromoll, J, Bassas, L, Seixas, S, Goncalves, J, Larriba, S, Kliesch, S, Palomino-Morales, RJ, Carmona, FD
Publicada:
10 nov 2022
Resumen:
We conducted a genome-wide association study in a large population of infertile men due to unexplained spermatogenic failure (SPGF). More than seven million genetic variants were analysed in 1,274 SPGF cases and 1,951 unaffected controls from two independent European cohorts. Two genomic regions were associated with the most severe histological pattern of SPGF, defined by Sertoli cell-only (SCO) phenotype, namely the MHC class II gene HLA-DRB1 (rs1136759, P = 1.32E-08, OR = 1.80) and an upstream locus of VRK1 (rs115054029, P = 4.24E-08, OR = 3.14), which encodes a protein kinase involved in the regulation of spermatogenesis. The SCO-associated rs1136759 allele (G) determines a serine in the position 13 of the HLA-DR beta 1 molecule located in the antigen-binding pocket. Overall, our data support the notion of unexplained SPGF as a complex trait influenced by common variation in the genome, with the SCO phenotype likely representing an immune-mediated condition.
A GWAS in a large case-control cohort of European ancestry identifies two genomic regions, the MHC class II gene HLA-DRB1 and an upstream locus of VRK1, that are associated with the most severe phenotype of spermatogenic failure.
Filiaciones:
Cervan-Martin, M:
Univ Granada, Ctr Invest Biomed CIBM, Dept Genet, Granada, Spain
Univ Granada, Ctr Invest Biomed CIBM, Inst Biotecnol, Granada, Spain
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
Tuttelmann, F:
Univ Munster, Inst Reprod Genet, Munster, Germany
Lopes, AM:
Univ Porto I3S, Inst Invest & Inovacao Saude, Porto, Portugal
Univ Porto IPATIMUP, Inst Mol Pathol & Immunol, Porto, Portugal
Univ Porto, Inst Cell & Mol Biol, Ctr Predict & Prevent Genet, Porto, Portugal
Bossini-Castillo, L:
Univ Granada, Ctr Invest Biomed CIBM, Dept Genet, Granada, Spain
Univ Granada, Ctr Invest Biomed CIBM, Inst Biotecnol, Granada, Spain
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
Rivera-Egea, R:
IVI RMA Valencia, Androl Lab, Valencia, Spain
IVI RMA Valencia, Sperm Bank, Valencia, Spain
IVI Fdn, Hlth Res Inst La Fe, Valencia, Spain
Garrido, N:
IVI Fdn, Hlth Res Inst La Fe, Valencia, Spain
Hosp Univ & Politecn La Fe, Serv Urol, Valencia, Spain
Inst Invest Sanitaria La Fe IIS La Fe, Valencia, Spain
Lujan, S:
Hosp Univ & Politecn La Fe, Serv Urol, Valencia, Spain
Inst Invest Sanitaria La Fe IIS La Fe, Valencia, Spain
Romeu, G:
Hosp Univ & Politecn La Fe, Serv Urol, Valencia, Spain
Inst Invest Sanitaria La Fe IIS La Fe, Valencia, Spain
Santos-Ribeiro, S:
IVI RMA Lisbon, Lisbon, Portugal
Univ Lisbon, Fac Med, Dept Obstet & Gynecol, Lisbon, Portugal
Castilla, JA:
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
HU Virgen de las Nieves, Unidad Reprod, UGC Obstet & Ginecol, Granada, Spain
CEIFER Biobanco GAMETIA, Granada, Spain
Gonzalvo, MC:
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
HU Virgen de las Nieves, Unidad Reprod, UGC Obstet & Ginecol, Granada, Spain
Clavero, A:
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
HU Virgen de las Nieves, Unidad Reprod, UGC Obstet & Ginecol, Granada, Spain
Maldonado, V:
Complejo Hosp Jaen, UGC Obstet & Ginecol, Jaen, Spain
Vicente, FJ:
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
HU Virgen de las Nieves, UGC Urol, Granada, Spain
Gonzalez-Munoz, S:
Univ Granada, Ctr Invest Biomed CIBM, Dept Genet, Granada, Spain
Univ Granada, Ctr Invest Biomed CIBM, Inst Biotecnol, Granada, Spain
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
Guzman-Jimenez, A:
Univ Granada, Ctr Invest Biomed CIBM, Dept Genet, Granada, Spain
Univ Granada, Ctr Invest Biomed CIBM, Inst Biotecnol, Granada, Spain
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
Burgos, M:
Univ Granada, Ctr Invest Biomed CIBM, Dept Genet, Granada, Spain
Univ Granada, Ctr Invest Biomed CIBM, Inst Biotecnol, Granada, Spain
Jimenez, R:
Univ Granada, Ctr Invest Biomed CIBM, Dept Genet, Granada, Spain
Univ Granada, Ctr Invest Biomed CIBM, Inst Biotecnol, Granada, Spain
Pacheco, A:
IVI Fdn, Hlth Res Inst La Fe, Valencia, Spain
Univ Alfonso X El Sabio, Fac CC Salud, Madrid, Spain
Gonzalez, C:
IVI Fdn, Hlth Res Inst La Fe, Valencia, Spain
Gomez, S:
IVI Fdn, Hlth Res Inst La Fe, Valencia, Spain
Amoros, D:
IVI Fdn, Hlth Res Inst La Fe, Valencia, Spain
Aguilar, J:
IVI Fdn, Hlth Res Inst La Fe, Valencia, Spain
Quintana, F:
IVI Fdn, Hlth Res Inst La Fe, Valencia, Spain
Calhaz-Jorge, C:
Ctr Hosp Univ Lisboa Norte, Hosp Santa Maria, Unidade Med Reprod, Dept Obstet Ginecol & Med Reprod, Lisbon, Portugal
Aguiar, A:
Ctr Hosp Univ Lisboa Norte, Hosp Santa Maria, Unidade Med Reprod, Dept Obstet Ginecol & Med Reprod, Lisbon, Portugal
Nunes, J:
Ctr Hosp Univ Lisboa Norte, Hosp Santa Maria, Unidade Med Reprod, Dept Obstet Ginecol & Med Reprod, Lisbon, Portugal
Sousa, S:
Ctr Hosp Univ Lisboa Norte, Hosp Santa Maria, Unidade Med Reprod, Dept Obstet Ginecol & Med Reprod, Lisbon, Portugal
Pereira, I:
Ctr Hosp Univ Lisboa Norte, Hosp Santa Maria, Unidade Med Reprod, Dept Obstet Ginecol & Med Reprod, Lisbon, Portugal
Pinto, MG:
Ctr Hosp Univ Lisboa Cent, Ctr Med Reprod, Maternidade Dr Alfredo Costa, Lisbon, Portugal
Correia, S:
Ctr Hosp Univ Lisboa Cent, Ctr Med Reprod, Maternidade Dr Alfredo Costa, Lisbon, Portugal
Sanchez-Curbelo, J:
Fundacio Puigvert, Androl Serv, Lab Seminol & Embryol, Barcelona, Spain
Lopez-Rodrigo, O:
Fundacio Puigvert, Androl Serv, Lab Seminol & Embryol, Barcelona, Spain
Martin, J:
PTS Granada, IPBLN CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain
Pereira-Caetano, I:
Inst Nacl Saude Dr Ricardo Jorge, Dept Genet Humana, Lisbon, Portugal
Marques, PI:
Univ Porto I3S, Inst Invest & Inovacao Saude, Porto, Portugal
Univ Porto IPATIMUP, Inst Mol Pathol & Immunol, Porto, Portugal
Carvalho, F:
Univ Porto I3S, Inst Invest & Inovacao Saude, Porto, Portugal
Univ Porto, Fac Med, Dept Patol, Serv Genet, Porto, Portugal
Barros, A:
Univ Porto I3S, Inst Invest & Inovacao Saude, Porto, Portugal
Univ Porto, Fac Med, Dept Patol, Serv Genet, Porto, Portugal
Gromoll, J:
Univ Munster, Inst Reprod & Regenerat Biol, Ctr Reprod Med & Androl, Univ Clin, Munster, Germany
Bassas, L:
Fundacio Puigvert, Androl Serv, Lab Seminol & Embryol, Barcelona, Spain
Seixas, S:
Univ Porto I3S, Inst Invest & Inovacao Saude, Porto, Portugal
Univ Porto IPATIMUP, Inst Mol Pathol & Immunol, Porto, Portugal
Goncalves, J:
Inst Nacl Saude Dr Ricardo Jorge, Dept Genet Humana, Lisbon, Portugal
Nova Med Sch, ToxOm Ctr Toxicogenom & Saude Humana, Lisbon, Portugal
Larriba, S:
Hosp Llobregat, Human Mol Genet Grp, Bellvitge Biomed Res Inst IDIBELL, Barcelona, Spain
Kliesch, S:
Univ Hosp Munster, Ctr Reprod Med & Androl, Dept Clin & Surg Androl, Munster, Germany
Palomino-Morales, RJ:
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
Univ Granada, Dept Bioquim & Biol Mol 1, Granada, Spain
Carmona, FD:
Univ Granada, Ctr Invest Biomed CIBM, Dept Genet, Granada, Spain
Univ Granada, Ctr Invest Biomed CIBM, Inst Biotecnol, Granada, Spain
Inst Invest Biosanitaria Ibs Granada, Granada, Spain
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