The effect of inversion at 8p23 on BLK association with lupus in Caucasian population
To explore the potential influence of the polymorphic 8p23.1 inversion on known autoimmune susceptibility risk at or near BLK locus, we validated a new bioinformatics method that utilizes SNP data to enable accurate, high-throughput genotyping of the 8p23.1 inversion in a Caucasian population. Princ...
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| Veröffentlicht in: | PloS one 2014-12, Vol.9 (12), p.e115614 |
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| description | To explore the potential influence of the polymorphic 8p23.1 inversion on known autoimmune susceptibility risk at or near BLK locus, we validated a new bioinformatics method that utilizes SNP data to enable accurate, high-throughput genotyping of the 8p23.1 inversion in a Caucasian population.
Principal components analysis (PCA) was performed using markers inside the inversion territory followed by k-means cluster analyses on 7416 European derived and 267 HapMaP CEU and TSI samples. A logistic regression conditional analysis was performed.
Three subgroups have been identified; inversion homozygous, heterozygous and non-inversion homozygous. The status of inversion was further validated using HapMap samples that had previously undergone Fluorescence in situ hybridization (FISH) assays with a concordance rate of above 98%. Conditional analyses based on the status of inversion were performed. We found that overall association signals in the BLK region remain significant after controlling for inversion status. The proportion of lupus cases and controls (cases/controls) in each subgroup was determined to be 0.97 for the inverted homozygous group (1067 cases and 1095 controls), 1.12 for the inverted heterozygous group (1935 cases 1717 controls) and 1.36 for non-inverted subgroups (924 cases and 678 controls). After calculating the linkage disequilibrium between inversion status and lupus risk haplotype we found that the lupus risk haplotype tends to reside on non-inversion background. As a result, a new association effect between non-inversion status and lupus phenotype has been identified ((p = 8.18×10(-7), OR = 1.18, 95%CI = 1.10-1.26).
Our results demonstrate that both known lupus risk haplotype and inversion status act additively in the pathogenesis of lupus. Since inversion regulates expression of many genes in its territory, altered expression of other genes might also be involved in the development of lupus. |
| doi_str_mv | 10.1371/journal.pone.0115614 |
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Principal components analysis (PCA) was performed using markers inside the inversion territory followed by k-means cluster analyses on 7416 European derived and 267 HapMaP CEU and TSI samples. A logistic regression conditional analysis was performed.
Three subgroups have been identified; inversion homozygous, heterozygous and non-inversion homozygous. The status of inversion was further validated using HapMap samples that had previously undergone Fluorescence in situ hybridization (FISH) assays with a concordance rate of above 98%. Conditional analyses based on the status of inversion were performed. We found that overall association signals in the BLK region remain significant after controlling for inversion status. The proportion of lupus cases and controls (cases/controls) in each subgroup was determined to be 0.97 for the inverted homozygous group (1067 cases and 1095 controls), 1.12 for the inverted heterozygous group (1935 cases 1717 controls) and 1.36 for non-inverted subgroups (924 cases and 678 controls). After calculating the linkage disequilibrium between inversion status and lupus risk haplotype we found that the lupus risk haplotype tends to reside on non-inversion background. As a result, a new association effect between non-inversion status and lupus phenotype has been identified ((p = 8.18×10(-7), OR = 1.18, 95%CI = 1.10-1.26).
Our results demonstrate that both known lupus risk haplotype and inversion status act additively in the pathogenesis of lupus. Since inversion regulates expression of many genes in its territory, altered expression of other genes might also be involved in the development of lupus.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0115614</identifier><identifier>PMID: 25545785</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Autoimmune diseases ; Bioinformatics ; Biology and Life Sciences ; Case-Control Studies ; Children & youth ; Chromosomes, Human, Pair 8 - genetics ; Consent ; European Continental Ancestry Group ; Female ; Fluorescence ; Fluorescence in situ hybridization ; Gene expression ; Genes ; Genetic Loci ; Genomes ; Genomics ; Genotyping ; Haplotypes ; Homozygote ; Hospitals ; Humans ; Immunology ; Inversion ; Inversion effects ; Kinases ; Linkage disequilibrium ; Lupus ; Lupus Erythematosus, Systemic - genetics ; Male ; Medical research ; Medicine ; Medicine and Health Sciences ; Mutation ; Pathogenesis ; Polymorphism, Single Nucleotide ; Population ; Principal components analysis ; Quality control ; Regression analysis ; Research and Analysis Methods ; Rheumatoid arthritis ; Risk ; Sequence Inversion ; Single-nucleotide polymorphism ; src-Family Kinases - genetics ; Statistical analysis ; Subgroups ; Systemic lupus erythematosus ; Territory ; United States ; Warts</subject><ispartof>PloS one, 2014-12, Vol.9 (12), p.e115614</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-cc2916750f52ede9745d896cbd7013e77a29cb4092a60c05c5d8c7c7968277793</citedby><cites>FETCH-LOGICAL-c692t-cc2916750f52ede9745d896cbd7013e77a29cb4092a60c05c5d8c7c7968277793</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/PMC4278715/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278715/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25545785$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Namjou, Bahram</creatorcontrib><creatorcontrib>Ni, Yizhao</creatorcontrib><creatorcontrib>Harley, Isaac T W</creatorcontrib><creatorcontrib>Chepelev, Iouri</creatorcontrib><creatorcontrib>Cobb, Beth</creatorcontrib><creatorcontrib>Kottyan, Leah C</creatorcontrib><creatorcontrib>Gaffney, Patrick M</creatorcontrib><creatorcontrib>Guthridge, Joel M</creatorcontrib><creatorcontrib>Kaufman, Kenneth</creatorcontrib><creatorcontrib>Harley, John B</creatorcontrib><title>The effect of inversion at 8p23 on BLK association with lupus in Caucasian population</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>To explore the potential influence of the polymorphic 8p23.1 inversion on known autoimmune susceptibility risk at or near BLK locus, we validated a new bioinformatics method that utilizes SNP data to enable accurate, high-throughput genotyping of the 8p23.1 inversion in a Caucasian population.
Principal components analysis (PCA) was performed using markers inside the inversion territory followed by k-means cluster analyses on 7416 European derived and 267 HapMaP CEU and TSI samples. A logistic regression conditional analysis was performed.
Three subgroups have been identified; inversion homozygous, heterozygous and non-inversion homozygous. The status of inversion was further validated using HapMap samples that had previously undergone Fluorescence in situ hybridization (FISH) assays with a concordance rate of above 98%. Conditional analyses based on the status of inversion were performed. We found that overall association signals in the BLK region remain significant after controlling for inversion status. The proportion of lupus cases and controls (cases/controls) in each subgroup was determined to be 0.97 for the inverted homozygous group (1067 cases and 1095 controls), 1.12 for the inverted heterozygous group (1935 cases 1717 controls) and 1.36 for non-inverted subgroups (924 cases and 678 controls). After calculating the linkage disequilibrium between inversion status and lupus risk haplotype we found that the lupus risk haplotype tends to reside on non-inversion background. As a result, a new association effect between non-inversion status and lupus phenotype has been identified ((p = 8.18×10(-7), OR = 1.18, 95%CI = 1.10-1.26).
Our results demonstrate that both known lupus risk haplotype and inversion status act additively in the pathogenesis of lupus. Since inversion regulates expression of many genes in its territory, altered expression of other genes might also be involved in the development of lupus.</description><subject>Autoimmune diseases</subject><subject>Bioinformatics</subject><subject>Biology and Life Sciences</subject><subject>Case-Control Studies</subject><subject>Children & youth</subject><subject>Chromosomes, Human, Pair 8 - genetics</subject><subject>Consent</subject><subject>European Continental Ancestry Group</subject><subject>Female</subject><subject>Fluorescence</subject><subject>Fluorescence in situ hybridization</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Genetic Loci</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Genotyping</subject><subject>Haplotypes</subject><subject>Homozygote</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Immunology</subject><subject>Inversion</subject><subject>Inversion effects</subject><subject>Kinases</subject><subject>Linkage disequilibrium</subject><subject>Lupus</subject><subject>Lupus Erythematosus, Systemic - genetics</subject><subject>Male</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Mutation</subject><subject>Pathogenesis</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Population</subject><subject>Principal components analysis</subject><subject>Quality control</subject><subject>Regression analysis</subject><subject>Research and Analysis Methods</subject><subject>Rheumatoid arthritis</subject><subject>Risk</subject><subject>Sequence Inversion</subject><subject>Single-nucleotide polymorphism</subject><subject>src-Family Kinases - genetics</subject><subject>Statistical analysis</subject><subject>Subgroups</subject><subject>Systemic lupus erythematosus</subject><subject>Territory</subject><subject>United States</subject><subject>Warts</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl1rFDEUhgdRbK3-A9EBQfBi13xnciPUxY_FhYK23oazSWY3ZXYyTjJV_73Z7rTsgILkIodznvPm5PAWxXOM5phK_PY6DH0LzbwLrZsjjLnA7EFxihUlM0EQfXgUnxRPYrxGiNNKiMfFCeGccVnx0-LqcutKV9fOpDLUpW9vXB99aEtIZdURWubw_epLCTEG4yHtSz992pbN0A0x8-UCBgPRQ1t2oRuaW-Rp8aiGJrpn431WXH38cLn4PFtdfFouzlczIxRJM2OIwkJyVHPirFOScVspYdZWIkydlECUWTOkCAhkEDe5bKSRSlRESqnoWfHyoNs1IepxI1FjwVDFFZcsE8sDYQNc6673O-h_6wBe3yZCv9HQJ28ap5GtLSHCCioUq0wNFjFKLQOgjjlns9a78bVhvXPWuDb10ExEp5XWb_Um3GhGZCUxzwKvRoE-_BhcTP8YeaQ2kKfybR2ymNn5aPQ5w5ISitn-6_O_UPlYt_Mme6L2OT9peDNpyExyv9IGhhj18tvX_2cvvk_Z10fs1kGTtjE0w94HcQqyA2j6EGPv6vvNYaT3lr7bht5bWo-Wzm0vjrd-33TnYfoHoOPv0w</recordid><startdate>20141229</startdate><enddate>20141229</enddate><creator>Namjou, Bahram</creator><creator>Ni, Yizhao</creator><creator>Harley, Isaac T W</creator><creator>Chepelev, Iouri</creator><creator>Cobb, Beth</creator><creator>Kottyan, Leah C</creator><creator>Gaffney, Patrick M</creator><creator>Guthridge, Joel M</creator><creator>Kaufman, Kenneth</creator><creator>Harley, John B</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>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</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>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PIMPY</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20141229</creationdate><title>The effect of inversion at 8p23 on BLK association with lupus in Caucasian population</title><author>Namjou, Bahram ; Ni, Yizhao ; Harley, Isaac T W ; Chepelev, Iouri ; Cobb, Beth ; Kottyan, Leah C ; Gaffney, Patrick M ; Guthridge, Joel M ; Kaufman, Kenneth ; Harley, John B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-cc2916750f52ede9745d896cbd7013e77a29cb4092a60c05c5d8c7c7968277793</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Autoimmune diseases</topic><topic>Bioinformatics</topic><topic>Biology and Life Sciences</topic><topic>Case-Control Studies</topic><topic>Children & youth</topic><topic>Chromosomes, Human, Pair 8 - genetics</topic><topic>Consent</topic><topic>European Continental Ancestry Group</topic><topic>Female</topic><topic>Fluorescence</topic><topic>Fluorescence in situ hybridization</topic><topic>Gene expression</topic><topic>Genes</topic><topic>Genetic Loci</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Genotyping</topic><topic>Haplotypes</topic><topic>Homozygote</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Immunology</topic><topic>Inversion</topic><topic>Inversion effects</topic><topic>Kinases</topic><topic>Linkage disequilibrium</topic><topic>Lupus</topic><topic>Lupus Erythematosus, Systemic - genetics</topic><topic>Male</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Mutation</topic><topic>Pathogenesis</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Population</topic><topic>Principal components analysis</topic><topic>Quality control</topic><topic>Regression analysis</topic><topic>Research and Analysis Methods</topic><topic>Rheumatoid arthritis</topic><topic>Risk</topic><topic>Sequence Inversion</topic><topic>Single-nucleotide polymorphism</topic><topic>src-Family Kinases - genetics</topic><topic>Statistical analysis</topic><topic>Subgroups</topic><topic>Systemic lupus erythematosus</topic><topic>Territory</topic><topic>United States</topic><topic>Warts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Namjou, Bahram</creatorcontrib><creatorcontrib>Ni, Yizhao</creatorcontrib><creatorcontrib>Harley, Isaac T W</creatorcontrib><creatorcontrib>Chepelev, Iouri</creatorcontrib><creatorcontrib>Cobb, Beth</creatorcontrib><creatorcontrib>Kottyan, Leah C</creatorcontrib><creatorcontrib>Gaffney, Patrick M</creatorcontrib><creatorcontrib>Guthridge, Joel M</creatorcontrib><creatorcontrib>Kaufman, Kenneth</creatorcontrib><creatorcontrib>Harley, John B</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Principal components analysis (PCA) was performed using markers inside the inversion territory followed by k-means cluster analyses on 7416 European derived and 267 HapMaP CEU and TSI samples. A logistic regression conditional analysis was performed.
Three subgroups have been identified; inversion homozygous, heterozygous and non-inversion homozygous. The status of inversion was further validated using HapMap samples that had previously undergone Fluorescence in situ hybridization (FISH) assays with a concordance rate of above 98%. Conditional analyses based on the status of inversion were performed. We found that overall association signals in the BLK region remain significant after controlling for inversion status. The proportion of lupus cases and controls (cases/controls) in each subgroup was determined to be 0.97 for the inverted homozygous group (1067 cases and 1095 controls), 1.12 for the inverted heterozygous group (1935 cases 1717 controls) and 1.36 for non-inverted subgroups (924 cases and 678 controls). After calculating the linkage disequilibrium between inversion status and lupus risk haplotype we found that the lupus risk haplotype tends to reside on non-inversion background. As a result, a new association effect between non-inversion status and lupus phenotype has been identified ((p = 8.18×10(-7), OR = 1.18, 95%CI = 1.10-1.26).
Our results demonstrate that both known lupus risk haplotype and inversion status act additively in the pathogenesis of lupus. Since inversion regulates expression of many genes in its territory, altered expression of other genes might also be involved in the development of lupus.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25545785</pmid><doi>10.1371/journal.pone.0115614</doi><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-12, Vol.9 (12), p.e115614 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1640859574 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Autoimmune diseases Bioinformatics Biology and Life Sciences Case-Control Studies Children & youth Chromosomes, Human, Pair 8 - genetics Consent European Continental Ancestry Group Female Fluorescence Fluorescence in situ hybridization Gene expression Genes Genetic Loci Genomes Genomics Genotyping Haplotypes Homozygote Hospitals Humans Immunology Inversion Inversion effects Kinases Linkage disequilibrium Lupus Lupus Erythematosus, Systemic - genetics Male Medical research Medicine Medicine and Health Sciences Mutation Pathogenesis Polymorphism, Single Nucleotide Population Principal components analysis Quality control Regression analysis Research and Analysis Methods Rheumatoid arthritis Risk Sequence Inversion Single-nucleotide polymorphism src-Family Kinases - genetics Statistical analysis Subgroups Systemic lupus erythematosus Territory United States Warts |
| title | The effect of inversion at 8p23 on BLK association with lupus in Caucasian population |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-21T14%3A53%3A51IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20effect%20of%20inversion%20at%208p23%20on%20BLK%20association%20with%20lupus%20in%20Caucasian%20population&rft.jtitle=PloS%20one&rft.au=Namjou,%20Bahram&rft.date=2014-12-29&rft.volume=9&rft.issue=12&rft.spage=e115614&rft.pages=e115614-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0115614&rft_dat=%3Cgale_plos_%3EA417323149%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1640859574&rft_id=info:pmid/25545785&rft_galeid=A417323149&rft_doaj_id=oai_doaj_org_article_0dfd226d636948cfad0433d4aa3e4eed&rfr_iscdi=true |