P-536 Common variation in the PIN1 locus increases the genetic risk to suffer from Sertoli Cell Only syndrome

Abstract Study question Are the common genetic variants located in the PIN1 region associated with human male infertility due to severe spermatogenic failure (SPGF)? Summary answer PIN1 gene polymorphisms may play a relevant role in the development of Sertoli Cell Only syndrome (SCO), the most extreme form of SPGF. What is known already PIN1 is a relevant prolyl isomerase in humans, that catalyzes cis/trans isomerization of peptide bonds. It has a central role in cell cycle progression and cancer, and it has been linked to the immune system promoting inflammation and reactive-oxygen species. Pin1 gene is highly expressed in adult mice testes, particularly in spermatogonia and Sertoli cells, and it is required to control the proliferation of spermatogonial stem cells. Additionally, it controls the integrity of the blood-testis barrier, helping to maintain the immune privilege of the testis. Nevertheless, mutations in PIN1 have not yet been described in human male infertility cases. Study design, size, duration A genetic association study was performed including samples from 715 men diagnosed with SPGF and classified as suffering from non-obstructive azoospermia (NOA, n = 505) or severe oligospermia (SO, n = 210), and 1,058 matched unaffected male controls from the Iberian Peninsula (Spain and Portugal). Allelic association on SPGF susceptibility were evaluated by testing three PIN1 single nucleotide polymorphisms (SNPs; rs2287839, rs2233678, and rs62105751), which tagged most of the common genetic variation present in this locus. Participants/materials, setting, methods Participants signed an informed written consent approved by the ethical committees of each participating center. SO and NOA were clinically defined according to the guidelines of the World Health Organization. Genomic DNA from blood samples was genotyped using TaqMan assays and statistical analyses were carried out by the means of logistic regression models. An in silico functional prioritization of the associated variants and their linked polymorphisms was also performed. Main results and the role of chance A subtype-specific genetic association with the subset of NOA patients classified as suffering from SCO was identified for the three analyzed genetic variants under the additive model (rs2287839: P = 1.94E-02, rs2233678: P = 1.94E-02, rs62105751: P = 1.94E-02). The minor alleles showed strong risk effects for this subset (rs2287839: OR = 1.85 [1.17-2.93], rs2233678: OR = 1.62 [1.11-2.36], rs62105751: OR = 1.43 [1.06-1.93]). Dependence analysis showed that all associated variants tagged the same signal. The variants underlying the identified association signal were prioritized based on their functional impact on the PIN1 locus, being rs3810166 the most likely candidate for functionality. The minor allele of such variant (G) is in linkage disequilibrium with the observed rs2287839-G risk allele and it is predicted to affect both gene expression and isoform balance of PIN1. The rs3810166 SNP likely influences the binding affinity of both HDAC2 and NRSF transcription factors, which are involved in cell cycle progression and transcription, respectively. Moreover, the tagged variants rs28802413 and rs10425775 were also predicted to alter the binding of significant transcription factors of the spermatogenic process, such as SIN3A and NANOG. Limitations, reasons for caution Although the overall statistical power of the study cohort was appropriate to detect the expected effects, the sample sizes in the subtype analyses were considerably lower, which may influence the obtained results. Further analyses including a larger SCO cohort should be performed to confirm our findings. Wider implications of the findings The obtained results shed light into the genetic contribution of common variation to male infertility, which may contribute to design a future panel of genetic markers to predict the testicular sperm extraction outcome, avoiding surgical interventions in NOA cases in which the probability of spermatozoa finding is much reduced. Trial registration number Not applicable