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Genome-Wide Expression of Azoospermia Testes Demonstrates a Specific Profile and Implicates ART3 in Genetic Susceptibility

Infertility affects about one in six couples attempting pregnancy, with the man responsible in approximately half of the cases. Because the pathophysiology underlying azoospermia is not elucidated, most male infertility is diagnosed as idiopathic. Genome-wide gene expression analyses with microarray...

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Autores principales: Okada, Hiroyuki, Tajima, Atsushi, Shichiri, Kazuyoshi, Tanaka, Atsushi, Tanaka, Kenichi, Inoue, Ituro
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2233677/
https://www.ncbi.nlm.nih.gov/pubmed/18266473
http://dx.doi.org/10.1371/journal.pgen.0040026
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author Okada, Hiroyuki
Tajima, Atsushi
Shichiri, Kazuyoshi
Tanaka, Atsushi
Tanaka, Kenichi
Inoue, Ituro
author_facet Okada, Hiroyuki
Tajima, Atsushi
Shichiri, Kazuyoshi
Tanaka, Atsushi
Tanaka, Kenichi
Inoue, Ituro
author_sort Okada, Hiroyuki
collection PubMed
description Infertility affects about one in six couples attempting pregnancy, with the man responsible in approximately half of the cases. Because the pathophysiology underlying azoospermia is not elucidated, most male infertility is diagnosed as idiopathic. Genome-wide gene expression analyses with microarray on testis specimens from 47 non-obstructive azoospermia (NOA) and 11 obstructive azoospermia (OA) patients were performed, and 2,611 transcripts that preferentially included genes relevant to gametogenesis and reproduction according to Gene Ontology classification were found to be differentially expressed. Using a set of 945 of the 2,611 transcripts without missing data, NOA was further categorized into three classes using the non-negative matrix factorization method. Two of the three subclasses were different from the OA group in Johnsen's score, FSH level, and/or LH level, while there were no significant differences between the other subclass and the OA group. In addition, the 52 genes showing high statistical difference between NOA subclasses (p < 0.01 with Tukey's post hoc test) were subjected to allelic association analyses to identify genetic susceptibilities. After two rounds of screening, SNPs of the ADP-ribosyltransferase 3 gene (ART3) were associated with NOA with highest significance with ART3-SNP25 (rs6836703; p = 0.0025) in 442 NOA patients and 475 fertile men. Haplotypes with five SNPs were constructed, and the most common haplotype was found to be under-represented in patients (NOA 26.6% versus control 35.3%, p = 0.000073). Individuals having the most common haplotype showed an elevated level of testosterone, suggesting a protective effect of the haplotype on spermatogenesis. Thus, genome-wide gene expression analyses were used to identify genes involved in the pathogenesis of NOA, and ART3 was subsequently identified as a susceptibility gene for NOA. These findings clarify the molecular pathophysiology of NOA and suggest a novel therapeutic target in the treatment of NOA.
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spelling pubmed-22336772008-02-08 Genome-Wide Expression of Azoospermia Testes Demonstrates a Specific Profile and Implicates ART3 in Genetic Susceptibility Okada, Hiroyuki Tajima, Atsushi Shichiri, Kazuyoshi Tanaka, Atsushi Tanaka, Kenichi Inoue, Ituro PLoS Genet Research Article Infertility affects about one in six couples attempting pregnancy, with the man responsible in approximately half of the cases. Because the pathophysiology underlying azoospermia is not elucidated, most male infertility is diagnosed as idiopathic. Genome-wide gene expression analyses with microarray on testis specimens from 47 non-obstructive azoospermia (NOA) and 11 obstructive azoospermia (OA) patients were performed, and 2,611 transcripts that preferentially included genes relevant to gametogenesis and reproduction according to Gene Ontology classification were found to be differentially expressed. Using a set of 945 of the 2,611 transcripts without missing data, NOA was further categorized into three classes using the non-negative matrix factorization method. Two of the three subclasses were different from the OA group in Johnsen's score, FSH level, and/or LH level, while there were no significant differences between the other subclass and the OA group. In addition, the 52 genes showing high statistical difference between NOA subclasses (p < 0.01 with Tukey's post hoc test) were subjected to allelic association analyses to identify genetic susceptibilities. After two rounds of screening, SNPs of the ADP-ribosyltransferase 3 gene (ART3) were associated with NOA with highest significance with ART3-SNP25 (rs6836703; p = 0.0025) in 442 NOA patients and 475 fertile men. Haplotypes with five SNPs were constructed, and the most common haplotype was found to be under-represented in patients (NOA 26.6% versus control 35.3%, p = 0.000073). Individuals having the most common haplotype showed an elevated level of testosterone, suggesting a protective effect of the haplotype on spermatogenesis. Thus, genome-wide gene expression analyses were used to identify genes involved in the pathogenesis of NOA, and ART3 was subsequently identified as a susceptibility gene for NOA. These findings clarify the molecular pathophysiology of NOA and suggest a novel therapeutic target in the treatment of NOA. Public Library of Science 2008-02-08 /pmc/articles/PMC2233677/ /pubmed/18266473 http://dx.doi.org/10.1371/journal.pgen.0040026 Text en © 2008 Okada et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Okada, Hiroyuki
Tajima, Atsushi
Shichiri, Kazuyoshi
Tanaka, Atsushi
Tanaka, Kenichi
Inoue, Ituro
Genome-Wide Expression of Azoospermia Testes Demonstrates a Specific Profile and Implicates ART3 in Genetic Susceptibility
title Genome-Wide Expression of Azoospermia Testes Demonstrates a Specific Profile and Implicates ART3 in Genetic Susceptibility
title_full Genome-Wide Expression of Azoospermia Testes Demonstrates a Specific Profile and Implicates ART3 in Genetic Susceptibility
title_fullStr Genome-Wide Expression of Azoospermia Testes Demonstrates a Specific Profile and Implicates ART3 in Genetic Susceptibility
title_full_unstemmed Genome-Wide Expression of Azoospermia Testes Demonstrates a Specific Profile and Implicates ART3 in Genetic Susceptibility
title_short Genome-Wide Expression of Azoospermia Testes Demonstrates a Specific Profile and Implicates ART3 in Genetic Susceptibility
title_sort genome-wide expression of azoospermia testes demonstrates a specific profile and implicates art3 in genetic susceptibility
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2233677/
https://www.ncbi.nlm.nih.gov/pubmed/18266473
http://dx.doi.org/10.1371/journal.pgen.0040026
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