Browsing by Author "Calhaz-Jorge, Carlos"
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- Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertilityPublication . Cerván-Martín, Miriam; Tüttelmann, Frank; Lopes, Alexandra M.; Bossini-Castillo, Lara; Rivera-Egea, Rocío; Garrido, Nicolás; Lujan, Saturnino; Romeu, Gema; Santos-Ribeiro, Samuel; Castilla, José A.; Carmen Gonzalvo, M.; Clavero, Ana; Maldonado, Vicente; Vicente, F. Javier; González-Muñoz, Sara; Guzmán-Jiménez, Andrea; Burgos, Miguel; Jiménez, Rafael; Pacheco, Alberto; González, Cristina; Gómez, Susana; Amorós, David; Aguilar, Jesus; Quintana, Fernando; Calhaz-Jorge, Carlos; Aguiar, Ana; Nunes, Joaquim; Sousa, Sandra; Pereira, Isabel; Pinto, Maria Graça; Correia, Sónia; Sánchez-Curbelo, Josvany; López-Rodrigo, Olga; Martín, Javier; Pereira-Caetano, Iris; Marques, Patricia I.; Carvalho, Filipa; Barros, Alberto; Gromoll, Jörg; Bassas, Lluís; Seixas, Susana; Gonçalves, João; Larriba, Sara; Kliesch, Sabine; Palomino-Morales, Rogelio J.; Carmona, F. DavidWe 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-DRβ1 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.
- Incorrect DNA methylation of the DAZL promoter CpG island associates with defective human spermPublication . Navarro-Costa, Paulo; Nogueira, Paulo; Carvalho, Marta; Leal, Fernanda; Cordeiro, Inês; Calhaz-Jorge, Carlos; Gonçalves, João; Plancha, Carlos E.Background: Successful gametogenesis requires the establishment of an appropriate epigenetic state in developing germ cells. Nevertheless, an association between abnormal spermatogenesis and epigenetic disturbances in germline-specific genes remains to be demonstrated. Methods: In this study, the DNA methylation pattern of the promoter CpG island (CGI) of two germline regulator genes—DAZL and DAZ, was characterized by bisulphite genomic sequencing in quality-fractioned ejaculated sperm populations from normozoospermic (NZ) and oligoasthenoteratozoospermic (OAT) men. Results: OAT patients display increased methylation defects in the DAZL promoter CGI when compared with NZ controls. Such differences are recorded when analyzing sperm fractions enriched either in normal or defective germ cells (P , 0.001 in both cases). Significant differences in DNA methylation profiles are also observable when comparing the qualitatively distinct germ cell fractions inside the NZ and OAT groups (P ¼ 0.003 and P ¼ 0.007, respectively). Contrastingly, the unmethylation pattern of the DAZ promoter CGI remains correctly established in all experimental groups. Conclusions: An association between disrupted DNA methylation of a key spermatogenesis gene and abnormal human sperm is described here for the first time. These results suggest that incorrect epigenetic marks in germline genes may be correlated with male gametogenic defects.
- Intronic variation of the SOHLH2 gene confers risk to male reproductive impairmentPublication . Cerván-Martín, Miriam; Suazo-Sánchez, M. Irene; Rivera-Egea, Rocío; Garrido, Nicolás; Luján, Saturnino; Romeu, Gema; Santos-Ribeiro, Samuel; Castilla, José A.; Gonzalvo, M. Carmen; Clavero, Ana; Vicente, F. Javier; Maldonado, Vicente; Burgos, Miguel; Barrionuevo, Francisco J.; Jiménez, Rafael; Sánchez-Curbelo, Josvany; López-Rodrigo, Olga; Peraza, M. Fernanda; Pereira-Caetano, Iris; Marques, Patricia I.; Carvalho, Filipa; Barros, Alberto; Bassas, Lluís; Seixas, Susana; Gonçalves, João; Larriba, Sara; Lopes, Alexandra M.; Palomino-Morales, Rogelio J.; Carmona, F. David; Calhaz-Jorge, Carlos; Aguiar, Ana; Nunes, Joaquim; Sousa, Sandra; Graça Pinto, Maria; Correia, Sónia; Pacheco, Alberto; González, Cristina; Gómez, Susana; Amorós, David; Aguilar, Jesús; Quintana, FernandoObjective: To evaluate whether SOHLH2 intronic variation contributes to the genetic predisposition to male infertility traits, including severe oligospermia (SO) and different nonobstructive azoospermia (NOA) clinical phenotypes. Design: Genetic association study. Setting: Not applicable. Patient(s): Five hundred five cases (455 infertile patients diagnosed with NOA and 50 with SO) and 1,050 healthy controls from Spain and Portugal. Intervention(s): None. Main outcome measure(s): Genomic DNA extraction from peripheral blood mononuclear cells, genotyping of the SOHLH2 polymorphisms rs1328626 and rs6563386 using the TaqMan allelic discrimination technology, case-control association analyses using logistic regression models, and exploration of functional annotations in publicly available databases. Result(s): Evidence of association was observed for both rs6563386 with SO and rs1328626 with unsuccessful sperm retrieval after testicular sperm extraction (TESE-) in the context of NOA. A dominant effect of the minor alleles was suggested in both associations, either when the subset of patients with the manifestation were compared against the control group (rs6563386/SO: P=.021, odds ratio [OR] = 0.51; rs1328626/TESE-: P=.066, OR = 1.46) or against the group of patients without the manifestation (rs6563386/SO: P=.014, OR = 0.46; rs1328626/TESE-: P=.012, OR = 2.43). The haplotype tests suggested a combined effect of both polymorphisms. In silico analyses evidenced that this effect could be due to alteration of the isoform population. Conclusion(s): Our data suggest that intronic variation of SOHLH2 is associated with spermatogenic failure. The genetic effect is likely caused by different haplotypes of rs6563386 and rs1328626, which may predispose to SO or TESE- depending on the specific allelic combination.