Common genetic variation in KATNAL1 non-coding regions is involved in the susceptibility to severe phenotypes of male infertility.
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Cerván-Martín Miriam, Bossini-Castillo Lara, Guzmán-Jiménez Andrea, Rivera-Egea Rocío, Garrido Nicolás, Lujan Saturnino, Romeu Gema, Santos-Ribeiro Samuel, IVIRMA Group, Lisbon Clinical Group, 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
Аннотация
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 spermatogenic 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.