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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| 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. |
| doi_str_mv | 10.1371/journal.pgen.0040026 |
| format | Article |
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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.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.0040026</identifier><identifier>PMID: 18266473</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>ADP Ribose Transferases - genetics ; ADP Ribose Transferases - metabolism ; Adult ; Alleles ; Azoospermia - classification ; Azoospermia - enzymology ; Azoospermia - genetics ; Case-Control Studies ; Defects ; Female ; Gene expression ; Gene Expression Profiling ; Genetic Predisposition to Disease ; Genetics ; Genetics and Genomics ; Genomes ; GPI-Linked Proteins ; Haplotypes ; Homo (Human) ; Humans ; Infertility ; Linkage Disequilibrium ; Male ; Mammals ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Methods ; Middle Aged ; Oligonucleotide Array Sequence Analysis ; Ontology ; Polymorphism, Single Nucleotide ; Pregnancy ; Primates ; Reproductive technologies ; Reverse Transcriptase Polymerase Chain Reaction ; Sperm ; Spermatogenesis - genetics ; Statistical analysis ; Studies ; Testis - enzymology ; Urology</subject><ispartof>PLoS genetics, 2008-02, Vol.4 (2), p.e26-e26</ispartof><rights>COPYRIGHT 2008 Public Library of Science</rights><rights>2008 Okada et al. 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 credited: Okada H, Tajima A, Shichiri K, Tanaka A, Tanaka K, et al. (2008) Genome-Wide Expression of Azoospermia Testes Demonstrates a Specific Profile and Implicates ART3 in Genetic Susceptibility. PLoS Genet 4(2): e26. doi:10.1371/journal.pgen.0040026</rights><rights>2008 Okada et al. 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c790t-5a62aa6d1b9eae0a986332ab3ff8dd030cc7891a0c1b5900bf40377e531b1e013</citedby><cites>FETCH-LOGICAL-c790t-5a62aa6d1b9eae0a986332ab3ff8dd030cc7891a0c1b5900bf40377e531b1e013</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2233677/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2233677/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2101,2927,23865,27923,27924,53790,53792,79471,79472</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18266473$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Dermitzakis, Emmanouil T</contributor><creatorcontrib>Okada, Hiroyuki</creatorcontrib><creatorcontrib>Tajima, Atsushi</creatorcontrib><creatorcontrib>Shichiri, Kazuyoshi</creatorcontrib><creatorcontrib>Tanaka, Atsushi</creatorcontrib><creatorcontrib>Tanaka, Kenichi</creatorcontrib><creatorcontrib>Inoue, Ituro</creatorcontrib><title>Genome-wide expression of azoospermia testes demonstrates a specific profile and implicates ART3 in genetic susceptibility</title><title>PLoS genetics</title><addtitle>PLoS Genet</addtitle><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.</description><subject>ADP Ribose Transferases - genetics</subject><subject>ADP Ribose Transferases - metabolism</subject><subject>Adult</subject><subject>Alleles</subject><subject>Azoospermia - classification</subject><subject>Azoospermia - enzymology</subject><subject>Azoospermia - genetics</subject><subject>Case-Control Studies</subject><subject>Defects</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetics</subject><subject>Genetics and Genomics</subject><subject>Genomes</subject><subject>GPI-Linked Proteins</subject><subject>Haplotypes</subject><subject>Homo (Human)</subject><subject>Humans</subject><subject>Infertility</subject><subject>Linkage Disequilibrium</subject><subject>Male</subject><subject>Mammals</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Methods</subject><subject>Middle Aged</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Ontology</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Pregnancy</subject><subject>Primates</subject><subject>Reproductive technologies</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Sperm</subject><subject>Spermatogenesis - genetics</subject><subject>Statistical analysis</subject><subject>Studies</subject><subject>Testis - enzymology</subject><subject>Urology</subject><issn>1553-7404</issn><issn>1553-7390</issn><issn>1553-7404</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqVk11r1TAYx4sobk6_gWhBGHhxjnlpm_ZGOAydB4aDOb0NSfr0nIw06ZJWt316052qp7ILpYW-5Pf_53nJkyQvMVpiyvC7Kzd4K8yy24BdIpQhRIpHySHOc7pgGcoe770fJM9CuEKI5mXFniYHuCRFkTF6mNydgnUtLH7oGlK46TyEoJ1NXZOKO-dCB77VIu0hxDutoXU29F6MHyKNq0o3WqWdd402kApbp7rtjFb3xOrikqbapjFC6CMWhqCg67XURve3z5MnjTABXkzPo-Trxw-XJ58WZ-en65PV2UKxCvWLXBREiKLGsgIBSFRlQSkRkjZNWdeIIqVYWWGBFJZ5hZBsMkQZg5xiiQFhepS83vl2xgU-lS1wTDHNSpJRFon1jqiduOKd163wt9wJze9_OL_hwscEDPCCNrmkRJYCsqhmUgHUBUMES1lXTEWv99Nug2yhVmBjuczMdL5i9ZZv3HdOCKUFG4M5ngy8ux5i3XmrY9mMERbcEHhRYUJJMeb15i_w4dwmaiNi-No2Lu6qRku-IohQjCuaR2r5ABWv2HGtnIWxvXPB25kgMj3c9BsxhMDXXy7-g_387-z5tzl7vMduQZh-G5wZ-niAwxzMdqDyLgQPze92YMTHYfpVOT4OE5-GKcpe7bfyj2iaHvoTCnAamA</recordid><startdate>20080201</startdate><enddate>20080201</enddate><creator>Okada, Hiroyuki</creator><creator>Tajima, Atsushi</creator><creator>Shichiri, Kazuyoshi</creator><creator>Tanaka, Atsushi</creator><creator>Tanaka, Kenichi</creator><creator>Inoue, Ituro</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20080201</creationdate><title>Genome-wide expression of azoospermia testes demonstrates a specific profile and implicates ART3 in genetic susceptibility</title><author>Okada, Hiroyuki ; Tajima, Atsushi ; Shichiri, Kazuyoshi ; Tanaka, Atsushi ; Tanaka, Kenichi ; Inoue, Ituro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c790t-5a62aa6d1b9eae0a986332ab3ff8dd030cc7891a0c1b5900bf40377e531b1e013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>ADP Ribose Transferases - genetics</topic><topic>ADP Ribose Transferases - metabolism</topic><topic>Adult</topic><topic>Alleles</topic><topic>Azoospermia - classification</topic><topic>Azoospermia - enzymology</topic><topic>Azoospermia - genetics</topic><topic>Case-Control Studies</topic><topic>Defects</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetics</topic><topic>Genetics and Genomics</topic><topic>Genomes</topic><topic>GPI-Linked Proteins</topic><topic>Haplotypes</topic><topic>Homo (Human)</topic><topic>Humans</topic><topic>Infertility</topic><topic>Linkage Disequilibrium</topic><topic>Male</topic><topic>Mammals</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Methods</topic><topic>Middle Aged</topic><topic>Oligonucleotide Array Sequence Analysis</topic><topic>Ontology</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Pregnancy</topic><topic>Primates</topic><topic>Reproductive technologies</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Sperm</topic><topic>Spermatogenesis - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Okada, Hiroyuki</au><au>Tajima, Atsushi</au><au>Shichiri, Kazuyoshi</au><au>Tanaka, Atsushi</au><au>Tanaka, Kenichi</au><au>Inoue, Ituro</au><au>Dermitzakis, Emmanouil T</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genome-wide expression of azoospermia testes demonstrates a specific profile and implicates ART3 in genetic susceptibility</atitle><jtitle>PLoS genetics</jtitle><addtitle>PLoS Genet</addtitle><date>2008-02-01</date><risdate>2008</risdate><volume>4</volume><issue>2</issue><spage>e26</spage><epage>e26</epage><pages>e26-e26</pages><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><abstract>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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>18266473</pmid><doi>10.1371/journal.pgen.0040026</doi><oa>free_for_read</oa></addata></record> |
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| subjects | ADP Ribose Transferases - genetics ADP Ribose Transferases - metabolism Adult Alleles Azoospermia - classification Azoospermia - enzymology Azoospermia - genetics Case-Control Studies Defects Female Gene expression Gene Expression Profiling Genetic Predisposition to Disease Genetics Genetics and Genomics Genomes GPI-Linked Proteins Haplotypes Homo (Human) Humans Infertility Linkage Disequilibrium Male Mammals Membrane Proteins - genetics Membrane Proteins - metabolism Methods Middle Aged Oligonucleotide Array Sequence Analysis Ontology Polymorphism, Single Nucleotide Pregnancy Primates Reproductive technologies Reverse Transcriptase Polymerase Chain Reaction Sperm Spermatogenesis - genetics Statistical analysis Studies Testis - enzymology Urology |
| title | Genome-wide expression of azoospermia testes demonstrates a specific profile and implicates ART3 in genetic susceptibility |
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