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Research Project
Understanding the basis of semen hyperviscosity and asthenozoospermia phenotypes - a systems biology approach
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Common genetic variation in KATNAL1 non-coding regions is involved in the susceptibility to severe phenotypes of male infertility
Publication . Cerván‐Martín, Miriam; Bossini‐Castillo, Lara; Guzmán‐Jiménez, Andrea; Rivera‐Egea, Rocío; Garrido, Nicolás; Lujan, Saturnino; Romeu, Gema; Santos‐Ribeiro, Samuel; Castilla, José Antonio; Gonzalvo, María del Carmen; Clavero, Ana; Maldonado, Vicente; Vicente, Francisco Javier; Burgos, Miguel; Jiménez, Rafael; González‐Muñoz, Sara; Sánchez‐Curbelo, Josvany; López‐Rodrigo, Olga; Pereira‐Caetano, Iris; Marques, Patricia Isabel; Carvalho, Filipa; Barros, Alberto; Bassas, Lluís; Seixas, Susana; Gonçalves, João; Larriba, Sara; Lopes, Alexandra Manuel; Palomino‐Morales, Rogelio Jesús; Carmona, Francisco David
Background: Previous studies in animal models evidenced that genetic mutations
of KATNAL1, resulting in dysfunction of its encoded protein, lead to male infertility
through disruption of microtubule remodelling and premature germ cell exfoliation.
Subsequent studies in humans also suggested a possible role of KATNAL1 single nucleotide polymorphisms in the development of male infertility as a consequence of
severe spermatogenic failure.
Objectives: The main objective of the present study is to evaluate the effect of the
common genetic variation of KATNAL1 in a large and phenotypically well-characterised
cohort of infertile men because of severe spermatogenic failure.
Materials and methods: A total of 715 infertile men because of severe spermato genic failure, including 210 severe oligospermia and 505 non-obstructive azoospermia
patients, as well as 1058 unaffected controls were genotyped for three KATNAL1
single-nucleotide polymorphism taggers (rs2077011, rs7338931 and rs2149971).
Case–control association analyses by logistic regression assuming different models
and in silico functional characterisation of risk variants were conducted.
Results: Genetic associations were observed between the three analysed taggers and
different severe spermatogenic failure groups. However, in all cases, the haplotype
model (rs2077011*C | rs7338931*T | rs2149971*A) better explained the observed
associations than the three risk alleles independently. This haplotype was associated
with non-obstructive azoospermia (adjusted p = 4.96E-02, odds ratio = 2.97), Sertoli cell only syndrome (adjusted p = 2.83E-02, odds ratio = 5.16) and testicular sperm
extraction unsuccessful outcomes (adjusted p = 8.99E-04, odds ratio = 6.13). The in
silico analyses indicated that the effect on severe spermatogenic failure predisposition
could be because of an alteration of the KATNAL1 splicing pattern.
Conclusions: Specific allelic combinations of KATNAL1 genetic polymorphisms may
confer a risk of developing severe male infertility phenotypes by favouring the
overrepresentation of a short non-functional transcript isoform in the testis.
Contribution of TEX15 genetic variants to the risk of developing severe non-obstructive oligozoospermia
Publication . Guzmán-Jiménez, Andrea; González-Muñoz, Sara; Cerván-Martín, Miriam; Rivera-Egea, Rocío; Garrido, Nicolás; Luján, Saturnino; Santos-Ribeiro, Samuel; Castilla, José A.; Gonzalvo, M. Carmen; Clavero, Ana; Vicente, F. Javier; Maldonado, Vicente; Villegas-Salmerón, Javier; Burgos, Miguel; Jiménez, Rafael; Pinto, Maria Graça; Pereira, Isabel; Nunes, Joaquim; Sánchez-Curbelo, Josvany; López-Rodrigo, Olga; Pereira-Caetano, Iris; Marques, Patricia Isabel; Carvalho, Filipa; Barros, Alberto; Bassas, Lluís; Seixas, Susana; Gonçalves, João; Lopes, Alexandra M.; Larriba, Sara; Palomino-Morales, Rogelio J.; Carmona, F. David; Bossini-Castillo, Lara
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.
Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility
Publication . 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. David
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-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.
Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only Syndrome
Publication . Cerván-Martín, Miriam; Bossini-Castillo, Lara; Guzmán-Jimenez, Andrea; 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; González-Muñoz, Sara; Rodríguez-Martín, Inmaculada; Burgos, Miguel; Jiménez, Rafael; Pinto, Maria Graça; Pereira, Isabel; Nunes, Joaquim; Sánchez-Curbelo, Josvany; López-Rodrigo, Olga; Pereira-Caetano, Iris; Marques, Patricia Isabel; Carvalho, Filipa; Barros, Alberto; Bassas, Lluís; Seixas, Susana; Gonçalves, João; Larriba, Sara; Lopes, Alexandra M.; Carmona, F. David; Palomino-Morales, Rogelio J.
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.
Effect and in silico characterization of genetic variants associated with severe spermatogenic disorders in a large Iberian cohort
Publication . Cerván‐Martín, Miriam; Bossini‐Castillo, Lara; Rivera‐Egea, Rocío; Garrido, Nicolás; Luján, Saturnino; Romeu, Gema; Santos‐Ribeiro, Samuel; IVIRMA Group, Lisbon Clinical Group; Castilla, José A.; Gonzalvo, María del Carmen; Clavero, Ana; Vicente, Francisco Javier; Guzmán‐Jiménez, Andrea; Burgos, Miguel; Barrionuevo, Francisco Javier; Jiménez, Rafael; Sánchez‐Curbelo, Josvany; López‐Rodrigo, Olga; Peraza, María Fernanda; Pereira‐Caetano, Iris; Marques, Patrícia Isabel; Carvalho, Filipa; Barros, Alberto; Bassas, Luís; Seixas, Susana; Gonçalves, João; Larriba, Sara; Lopes, Alexandra Manuel; Carmona, Francisco David; Palomino‐Morales, Rogelio Jesús
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.
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Fundação para a Ciência e a Tecnologia
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Funding Award Number
SFRH/BPD/120777/2016