Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility

Cerván-Martín, Miriam; Tüttelmann, Frank; Bossini‐Castillo, Lara; Rivera‐Egea, Rocío; Garrido, Nicolás; Lujan, Saturnino; Magraner, G. Romeu; Santos-Ribeiro, Samuel; Castilla, J.A.; Gonzálvo, M. Carmen; Clavero, Ana; Maldonado, Vicente; Vicente, F.J.; González-Muñoz, Sara; Guzmán-Jiménez, Andrea; Burgos, Miguel; Jiménez, Rafael; Pacheco, A.; González, Cristina; Gómez, Susana; Amorós, David; Aguilar, J.; Quintana, Fernando; Calhaz‐Jorge, Carlos; Aguiar, A. Pedro; Nunes, Joaquim; Sousa, Sandra Maria Zákia Lian; Pereira, Ivana Cardoso; Pinto, Maria Graça; Correia, Sónia; Sánchez‐Curbelo, Josvany; López-Rodrigo, Olga; Martín, Javier; Pereira‐Caetano, Iris; Marques, Patrícia; Carvalho, Filipa; Barros, Alberto; Gromoll, Jörg; Bassas, Lluís; Seixas, Susana; Gonçalves, João; Larriba, Sara; Kliesch, Sabine; Palomino-Morales, Rogelio; Carmona, F. David

doi:10.1038/s42003-022-04192-0

Cited by 3 publications

(2 citation statements)

References 99 publications

(105 reference statements)

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“…There are several limitations to our study, in that our SEM model does not consider scenarios with: (i) maternal and fetal interactions or incompatibility 17 , 18 ; (ii) individual low-frequency alleles; (iii) non-classical HLA genes in MHC region: (iv) linkage disequilibrium or potential interactions between different HLA loci; (v) the possibility of dominance, epistasis, gene-environment or gene-gene interactions; (vi) potential non-transmitted paternal genetic effects on offspring BW; (vii) direct causal path between own (maternal) BW and offspring BW; and (viii) the influence of HLA-associated infertility. 49 , 50 Furthermore, UKB only has self-reported BW and does not provide gestational age for adjustment. We have discussed these limitations in Supplementary Note 12 (available as Supplementary data at IJE online) and further investigated some important assumptions ( Supplementary Notes 3, 10 and 11 ; Supplementary Figures S7–8 ; Supplementary Table S10 , available as Supplementary data at IJE online).…”

Section: Discussionmentioning

confidence: 99%

Partitioning genetic effects on birthweight at classical human leukocyte antigen loci into maternal and fetal components, using structural equation modelling

Wang,

Warrington,

Evans

2023

International Journal of Epidemiology

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Background Single nucleotide polymorphisms in the human leukocyte antigen (HLA) region in both maternal and fetal genomes have been robustly associated with birthweight (BW) in previous genetic association studies. However, no study to date has partitioned the association between BW and classical HLA alleles into maternal and fetal components. Methods We used structural equation modelling (SEM) to estimate the maternal and fetal effects of classical HLA alleles on BW. Our SEM leverages the data structure of the UK Biobank (UKB), which includes ∼270 000 participants’ own BW and/or the BW of their firstborn child. Results We show via simulation that our model yields asymptotically unbiased estimates of the maternal and fetal allelic effects on BW and appropriate type I error rates, in contrast to simple regression models. Asymptotic power calculations show that we have sufficient power to detect moderate-sized maternal or fetal allelic effects of common HLA alleles on BW in the UKB. Applying our SEM to imputed classical HLA alleles and own and offspring BW from the UKB replicated the previously reported association at the HLA-C locus and revealed strong evidence for maternal (HLA-A*03:01, B*35:01, B*39:06, P <0.001) and fetal allelic effects (HLA-B*39:06, P <0.001) of non-HLA-C alleles on BW. Conclusions Our model yields asymptotically unbiased estimates, appropriate type I error rates and appreciable power to estimate maternal and fetal effects on BW. These novel allelic associations between BW and classical HLA alleles provide insight into the immunogenetics of fetal growth in utero.

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Section: Discussionmentioning

confidence: 99%

Partitioning genetic effects on birthweight at classical human leukocyte antigen loci into maternal and fetal components, using structural equation modelling

Wang,

Warrington,

Evans

2023

International Journal of Epidemiology

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“…Furthermore, the heterogeneity of azoospermia poses a challenge, as different subtypes may require tailored approaches [11]. Patient selection and individualized treatment strategies are crucial for success.…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cell Therapy for Azoospermia: Navigating Differentiation Challenges and Charting Future Frontiers in Male Fertility Treatment

Rahmanifar

2024

WKMJ

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This minireview explores the current landscape of stem cell therapy for azoospermia, focusing on the potential and challenges associated with Mesenchymal Stem Cells (MSCs). The discussion encompasses the precise regulation of MSC differentiation, safety considerations, and ethical implications. Recent advancements in optimizing differentiation protocols, improving engraftment efficiency, and ongoing clinical trials are highlighted. Despite the hurdles, MSCs emerge as a promising avenue for male infertility treatment. The conclusion emphasizes the necessity for continued research and clinical trials to unlock the full potential of MSC therapy in addressing the complexities of azoospermia.

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Changes in environmental exposures over decades may influence the genetic architecture of severe spermatogenic failure

Cerván-Martín,

González-Muñoz,

Guzmán-Jiménez

et al. 2024

Human Reproduction

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STUDY QUESTION Do the genetic determinants of idiopathic severe spermatogenic failure (SPGF) differ between generations? SUMMARY ANSWER Our data support that the genetic component of idiopathic SPGF is impacted by dynamic changes in environmental exposures over decades. WHAT IS KNOWN ALREADY The idiopathic form of SPGF has a multifactorial etiology wherein an interaction between genetic, epigenetic, and environmental factors leads to the disease onset and progression. At the genetic level, genome-wide association studies (GWASs) allow the analysis of millions of genetic variants across the genome in a hypothesis-free manner, as a valuable tool for identifying susceptibility risk loci. However, little is known about the specific role of non-genetic factors and their influence on the genetic determinants in this type of conditions. STUDY DESIGN, SIZE, DURATION Case-control genetic association analyses were performed including a total of 912 SPGF cases and 1360 unaffected controls. PARTICIPANTS/MATERIALS, SETTING, METHODS All participants had European ancestry (Iberian and German). SPGF cases were diagnosed during the last decade either with idiopathic non-obstructive azoospermia (n = 547) or with idiopathic non-obstructive oligozoospermia (n = 365). Case-control genetic association analyses were performed by logistic regression models considering the generation as a covariate and by in silico functional characterization of the susceptibility genomic regions. MAIN RESULTS AND THE ROLE OF CHANCE This analysis revealed 13 novel genetic association signals with SPGF, with eight of them being independent. The observed associations were mostly explained by the interaction between each lead variant and the age-group. Additionally, we established links between these loci and diverse non-genetic factors, such as toxic or dietary habits, respiratory disorders, and autoimmune diseases, which might potentially influence the genetic architecture of idiopathic SPGF. LARGE SCALE DATA GWAS data are available from the authors upon reasonable request. LIMITATIONS, REASONS FOR CAUTION Additional independent studies involving large cohorts in ethnically diverse populations are warranted to confirm our findings. WIDER IMPLICATIONS OF THE FINDINGS Overall, this study proposes an innovative strategy to achieve a more precise understanding of conditions such as SPGF by considering the interactions between a variable exposome through different generations and genetic predisposition to complex diseases. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the “Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020)” (ref. PY20_00212, P20_00583), the Spanish Ministry of Economy and Competitiveness through the Spanish National Plan for Scientific and Technical Research and Innovation (ref. PID2020-120157RB-I00 funded by MCIN/ AEI/10.13039/501100011033), and the ‘Proyectos I+D+i del Programa Operativo FEDER 2020’ (ref. B-CTS-584-UGR20). ToxOmics-Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, is also partially supported by the Portuguese Foundation for Science and Technology (Projects: UIDB/00009/2020; UIDP/00009/2020). The authors declare no competing interests. TRIAL REGISTRATION NUMBER N/A.

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Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility

Cited by 3 publications

References 99 publications

Partitioning genetic effects on birthweight at classical human leukocyte antigen loci into maternal and fetal components, using structural equation modelling

Partitioning genetic effects on birthweight at classical human leukocyte antigen loci into maternal and fetal components, using structural equation modelling

Mesenchymal Stem Cell Therapy for Azoospermia: Navigating Differentiation Challenges and Charting Future Frontiers in Male Fertility Treatment

Changes in environmental exposures over decades may influence the genetic architecture of severe spermatogenic failure

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