Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms
Abdominal aortic aneurysms (AAAs) are characterized by histologic signs of chronic inflammation, destructive remodeling of extracellular matrix, and depletion of vascular smooth muscle cells. We investigated the process of extracellular matrix remodeling by performing a genetic association study wit...
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| creator | Ogata, Toru Shibamura, Hidenori Tromp, Gerard Sinha, Moumita Goddard, Katrina A.B. Sakalihasan, Natzi Limet, Raymond MacKean, Gerald L. Arthur, Claudette Sueda, Taijiro Land, Susan Kuivaniemi, Helena |
| description | Abdominal aortic aneurysms (AAAs) are characterized by histologic signs of chronic inflammation, destructive remodeling of extracellular matrix, and depletion of vascular smooth muscle cells. We investigated the process of extracellular matrix remodeling by performing a genetic association study with polymorphisms in the genes for matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and structural extracellular matrix molecules in AAA. Our hypothesis was that genetic variations in one or more of these genes contribute to greater or lesser activity of these gene products, and thereby contribute to susceptibility for developing AAAs.
DNA samples from 812 unrelated white subject (AAA, n = 387; controls, n = 425) were genotyped for 14 polymorphisms in 13 different candidate genes: MMP1(nt-1607), MMP2(nt-955), MMP3(nt-1612), MMP9(nt-1562), MMP10(nt+180), MMP12(nt-82), MMP13(nt-77), TIMP1(nt+434), TIMP1(rs2070584), TIMP2(rs2009196), TIMP3(nt-1296), TGFB1(nt-509), ELN(nt+422), and COL3A1(nt+581). Odds ratios and
P values adjusted for gender and country of origin using logistic regression and stratified by family history of AAA were calculated to test for association between genotype and disease status. Haplotype analysis was carried out for the two TIMP1 polymorphisms in male subjects.
Analyses with one polymorphism per test without interactions showed an association with the two TIMP1 gene polymorphisms (nt+434,
P = .0047; rs2070584,
P = .015) in male subjects without a family history of AAA. The association remained significant when analyzing TIMP1 haplotypes (χ
2
P = .014 and empirical
P = .009). In addition, we found a significant interaction between the polymorphism and gender for MMP10 (
P = .037) in cases without a family history of AAA, as well as between the polymorphism and country of origin for ELN (
P = .0169) and TIMP3 (
P = .0023) in cases with a family history of AAA.
These findings suggest that genetic variations in TIMP1, TIMP3, MMP10, and ELN genes may contribute to the pathogenesis of AAAs. Further work is needed to confirm the findings in an independent set of samples and to study the functional role of these variants in AAA. It is noteworthy that contrary to a previous study, we did not find an association between the MMP9 (nt-1562) polymorphism and AAA, suggesting genetic heterogeneity of the disease.
Abdominal aortic aneurysms (AAAs) are an important cardiovascular disease, but the genetic and environmental ris |
| doi_str_mv | 10.1016/j.jvs.2005.02.020 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_1249499</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0741521405002363</els_id><sourcerecordid>67920563</sourcerecordid><originalsourceid>FETCH-LOGICAL-c523t-47222e440bb01ec318446e7955ca8fe91f84804a34e71d97495b5f4bc243a41d3</originalsourceid><addsrcrecordid>eNp9kVGL1DAUhYMo7uzqD_BF8qJvHZM0aRsEQRZ3FRZ80eeQpredDGlTk7ZL_72Z6eDqi-FCAvnuuSc5CL2hZE8JLT4c98cl7hkhYk9YKvIM7SiRZVZURD5HO1JymglG-RW6jvFICKWiKl-iKyok5wUpd2i5hwEma7AetFujjdi3ePRu7X0YDzb2EdsB19Y731mjnVtxAAeLHiZs9NDYRk-AuyRyBkc9WRimiB_tdMC6bnxvkzDWPmxDYA5rEn2FXrTaRXh92W_Qz7svP26_Zg_f77_dfn7IjGD5lPGSMQack7omFExOq2QbSimE0VULkrYVrwjXOYeSNrLkUtSi5bVhPNecNvkN-rTpjnPdQ2OSt6CdGoPtdViV11b9ezPYg-r8oijjkkuZBPJNwFnoQPlQW7Wwc-P5PLtOaaNqUIwVlaJpsSp1vb-MDf7XDHFSvY0GnEsf4OeoilIyIoo8gXQDTfAxBmj_WKNEnTJWR5UyVqeMFWGpSOp5-_ebnjouoSbg3QXQMUXWBj0YG5-4QjLK5Eno48ZBSmCxEFQ0KT0DjQ1gJtV4-x8bvwER8cdg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>67920563</pqid></control><display><type>article</type><title>Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms</title><source>MEDLINE</source><source>ScienceDirect Journals (5 years ago - present)</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Ogata, Toru ; Shibamura, Hidenori ; Tromp, Gerard ; Sinha, Moumita ; Goddard, Katrina A.B. ; Sakalihasan, Natzi ; Limet, Raymond ; MacKean, Gerald L. ; Arthur, Claudette ; Sueda, Taijiro ; Land, Susan ; Kuivaniemi, Helena</creator><creatorcontrib>Ogata, Toru ; Shibamura, Hidenori ; Tromp, Gerard ; Sinha, Moumita ; Goddard, Katrina A.B. ; Sakalihasan, Natzi ; Limet, Raymond ; MacKean, Gerald L. ; Arthur, Claudette ; Sueda, Taijiro ; Land, Susan ; Kuivaniemi, Helena</creatorcontrib><description>Abdominal aortic aneurysms (AAAs) are characterized by histologic signs of chronic inflammation, destructive remodeling of extracellular matrix, and depletion of vascular smooth muscle cells. We investigated the process of extracellular matrix remodeling by performing a genetic association study with polymorphisms in the genes for matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and structural extracellular matrix molecules in AAA. Our hypothesis was that genetic variations in one or more of these genes contribute to greater or lesser activity of these gene products, and thereby contribute to susceptibility for developing AAAs.
DNA samples from 812 unrelated white subject (AAA, n = 387; controls, n = 425) were genotyped for 14 polymorphisms in 13 different candidate genes: MMP1(nt-1607), MMP2(nt-955), MMP3(nt-1612), MMP9(nt-1562), MMP10(nt+180), MMP12(nt-82), MMP13(nt-77), TIMP1(nt+434), TIMP1(rs2070584), TIMP2(rs2009196), TIMP3(nt-1296), TGFB1(nt-509), ELN(nt+422), and COL3A1(nt+581). Odds ratios and
P values adjusted for gender and country of origin using logistic regression and stratified by family history of AAA were calculated to test for association between genotype and disease status. Haplotype analysis was carried out for the two TIMP1 polymorphisms in male subjects.
Analyses with one polymorphism per test without interactions showed an association with the two TIMP1 gene polymorphisms (nt+434,
P = .0047; rs2070584,
P = .015) in male subjects without a family history of AAA. The association remained significant when analyzing TIMP1 haplotypes (χ
2
P = .014 and empirical
P = .009). In addition, we found a significant interaction between the polymorphism and gender for MMP10 (
P = .037) in cases without a family history of AAA, as well as between the polymorphism and country of origin for ELN (
P = .0169) and TIMP3 (
P = .0023) in cases with a family history of AAA.
These findings suggest that genetic variations in TIMP1, TIMP3, MMP10, and ELN genes may contribute to the pathogenesis of AAAs. Further work is needed to confirm the findings in an independent set of samples and to study the functional role of these variants in AAA. It is noteworthy that contrary to a previous study, we did not find an association between the MMP9 (nt-1562) polymorphism and AAA, suggesting genetic heterogeneity of the disease.
Abdominal aortic aneurysms (AAAs) are an important cardiovascular disease, but the genetic and environmental risk factors, which contribute to individual’s risk to develop an aneurysm, are poorly understood. Histologically, AAAs are characterized by signs of chronic inflammation, destructive remodeling of the extracellular matrix, and depletion of vascular smooth muscle cells. We hypothesized that genes involved in these events could harbor changes that make individuals more susceptible to developing aneurysms. This study identified significant genetic associations between DNA sequence changes in tissue inhibitor of metalloproteinase 1 (TIMP1), TIMP3, matrix metalloproteinase 10 (MMP10) and elastin (ELN) genes, and AAA. The results will require confirmation using an independent set of samples. After replication it is possible that these sequence changes in combination with other risk factors could be used in the future to identify individuals who are at increased risk for developing an AAA.</description><identifier>ISSN: 0741-5214</identifier><identifier>ISSN: 1097-6809</identifier><identifier>EISSN: 1097-6809</identifier><identifier>DOI: 10.1016/j.jvs.2005.02.020</identifier><identifier>PMID: 15944607</identifier><identifier>CODEN: JVSUES</identifier><language>eng</language><publisher>New York, NY: Mosby, Inc</publisher><subject>Aortic Aneurysm, Abdominal - genetics ; Biological and medical sciences ; Blood and lymphatic vessels ; Cardiology. Vascular system ; Cardiovascular & respiratory systems ; Chirurgie ; Diseases of the aorta ; Elastin - genetics ; Extracellular Matrix - genetics ; Female ; Genetic Predisposition to Disease - genetics ; Human health sciences ; Humans ; Linkage Disequilibrium ; Male ; Matrix Metalloproteinase 10 ; Medical sciences ; Metalloendopeptidases - genetics ; Polymorphism, Genetic - genetics ; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis ; Sciences de la santé humaine ; Surgery ; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases ; Systèmes cardiovasculaire & respiratoire ; Tissue Inhibitor of Metalloproteinase-1 - genetics ; Tissue Inhibitor of Metalloproteinase-3 ; Tissue Inhibitor of Metalloproteinases - genetics ; Vascular surgery: aorta, extremities, vena cava. Surgery of the lymphatic vessels</subject><ispartof>Journal of vascular surgery, 2005-06, Vol.41 (6), p.1036-1042</ispartof><rights>2005 The Society for Vascular Surgery</rights><rights>2005 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c523t-47222e440bb01ec318446e7955ca8fe91f84804a34e71d97495b5f4bc243a41d3</citedby><cites>FETCH-LOGICAL-c523t-47222e440bb01ec318446e7955ca8fe91f84804a34e71d97495b5f4bc243a41d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jvs.2005.02.020$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16921290$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15944607$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ogata, Toru</creatorcontrib><creatorcontrib>Shibamura, Hidenori</creatorcontrib><creatorcontrib>Tromp, Gerard</creatorcontrib><creatorcontrib>Sinha, Moumita</creatorcontrib><creatorcontrib>Goddard, Katrina A.B.</creatorcontrib><creatorcontrib>Sakalihasan, Natzi</creatorcontrib><creatorcontrib>Limet, Raymond</creatorcontrib><creatorcontrib>MacKean, Gerald L.</creatorcontrib><creatorcontrib>Arthur, Claudette</creatorcontrib><creatorcontrib>Sueda, Taijiro</creatorcontrib><creatorcontrib>Land, Susan</creatorcontrib><creatorcontrib>Kuivaniemi, Helena</creatorcontrib><title>Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms</title><title>Journal of vascular surgery</title><addtitle>J Vasc Surg</addtitle><description>Abdominal aortic aneurysms (AAAs) are characterized by histologic signs of chronic inflammation, destructive remodeling of extracellular matrix, and depletion of vascular smooth muscle cells. We investigated the process of extracellular matrix remodeling by performing a genetic association study with polymorphisms in the genes for matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and structural extracellular matrix molecules in AAA. Our hypothesis was that genetic variations in one or more of these genes contribute to greater or lesser activity of these gene products, and thereby contribute to susceptibility for developing AAAs.
DNA samples from 812 unrelated white subject (AAA, n = 387; controls, n = 425) were genotyped for 14 polymorphisms in 13 different candidate genes: MMP1(nt-1607), MMP2(nt-955), MMP3(nt-1612), MMP9(nt-1562), MMP10(nt+180), MMP12(nt-82), MMP13(nt-77), TIMP1(nt+434), TIMP1(rs2070584), TIMP2(rs2009196), TIMP3(nt-1296), TGFB1(nt-509), ELN(nt+422), and COL3A1(nt+581). Odds ratios and
P values adjusted for gender and country of origin using logistic regression and stratified by family history of AAA were calculated to test for association between genotype and disease status. Haplotype analysis was carried out for the two TIMP1 polymorphisms in male subjects.
Analyses with one polymorphism per test without interactions showed an association with the two TIMP1 gene polymorphisms (nt+434,
P = .0047; rs2070584,
P = .015) in male subjects without a family history of AAA. The association remained significant when analyzing TIMP1 haplotypes (χ
2
P = .014 and empirical
P = .009). In addition, we found a significant interaction between the polymorphism and gender for MMP10 (
P = .037) in cases without a family history of AAA, as well as between the polymorphism and country of origin for ELN (
P = .0169) and TIMP3 (
P = .0023) in cases with a family history of AAA.
These findings suggest that genetic variations in TIMP1, TIMP3, MMP10, and ELN genes may contribute to the pathogenesis of AAAs. Further work is needed to confirm the findings in an independent set of samples and to study the functional role of these variants in AAA. It is noteworthy that contrary to a previous study, we did not find an association between the MMP9 (nt-1562) polymorphism and AAA, suggesting genetic heterogeneity of the disease.
Abdominal aortic aneurysms (AAAs) are an important cardiovascular disease, but the genetic and environmental risk factors, which contribute to individual’s risk to develop an aneurysm, are poorly understood. Histologically, AAAs are characterized by signs of chronic inflammation, destructive remodeling of the extracellular matrix, and depletion of vascular smooth muscle cells. We hypothesized that genes involved in these events could harbor changes that make individuals more susceptible to developing aneurysms. This study identified significant genetic associations between DNA sequence changes in tissue inhibitor of metalloproteinase 1 (TIMP1), TIMP3, matrix metalloproteinase 10 (MMP10) and elastin (ELN) genes, and AAA. The results will require confirmation using an independent set of samples. After replication it is possible that these sequence changes in combination with other risk factors could be used in the future to identify individuals who are at increased risk for developing an AAA.</description><subject>Aortic Aneurysm, Abdominal - genetics</subject><subject>Biological and medical sciences</subject><subject>Blood and lymphatic vessels</subject><subject>Cardiology. Vascular system</subject><subject>Cardiovascular & respiratory systems</subject><subject>Chirurgie</subject><subject>Diseases of the aorta</subject><subject>Elastin - genetics</subject><subject>Extracellular Matrix - genetics</subject><subject>Female</subject><subject>Genetic Predisposition to Disease - genetics</subject><subject>Human health sciences</subject><subject>Humans</subject><subject>Linkage Disequilibrium</subject><subject>Male</subject><subject>Matrix Metalloproteinase 10</subject><subject>Medical sciences</subject><subject>Metalloendopeptidases - genetics</subject><subject>Polymorphism, Genetic - genetics</subject><subject>Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis</subject><subject>Sciences de la santé humaine</subject><subject>Surgery</subject><subject>Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases</subject><subject>Systèmes cardiovasculaire & respiratoire</subject><subject>Tissue Inhibitor of Metalloproteinase-1 - genetics</subject><subject>Tissue Inhibitor of Metalloproteinase-3</subject><subject>Tissue Inhibitor of Metalloproteinases - genetics</subject><subject>Vascular surgery: aorta, extremities, vena cava. Surgery of the lymphatic vessels</subject><issn>0741-5214</issn><issn>1097-6809</issn><issn>1097-6809</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kVGL1DAUhYMo7uzqD_BF8qJvHZM0aRsEQRZ3FRZ80eeQpredDGlTk7ZL_72Z6eDqi-FCAvnuuSc5CL2hZE8JLT4c98cl7hkhYk9YKvIM7SiRZVZURD5HO1JymglG-RW6jvFICKWiKl-iKyok5wUpd2i5hwEma7AetFujjdi3ePRu7X0YDzb2EdsB19Y731mjnVtxAAeLHiZs9NDYRk-AuyRyBkc9WRimiB_tdMC6bnxvkzDWPmxDYA5rEn2FXrTaRXh92W_Qz7svP26_Zg_f77_dfn7IjGD5lPGSMQack7omFExOq2QbSimE0VULkrYVrwjXOYeSNrLkUtSi5bVhPNecNvkN-rTpjnPdQ2OSt6CdGoPtdViV11b9ezPYg-r8oijjkkuZBPJNwFnoQPlQW7Wwc-P5PLtOaaNqUIwVlaJpsSp1vb-MDf7XDHFSvY0GnEsf4OeoilIyIoo8gXQDTfAxBmj_WKNEnTJWR5UyVqeMFWGpSOp5-_ebnjouoSbg3QXQMUXWBj0YG5-4QjLK5Eno48ZBSmCxEFQ0KT0DjQ1gJtV4-x8bvwER8cdg</recordid><startdate>20050601</startdate><enddate>20050601</enddate><creator>Ogata, Toru</creator><creator>Shibamura, Hidenori</creator><creator>Tromp, Gerard</creator><creator>Sinha, Moumita</creator><creator>Goddard, Katrina A.B.</creator><creator>Sakalihasan, Natzi</creator><creator>Limet, Raymond</creator><creator>MacKean, Gerald L.</creator><creator>Arthur, Claudette</creator><creator>Sueda, Taijiro</creator><creator>Land, Susan</creator><creator>Kuivaniemi, Helena</creator><general>Mosby, Inc</general><general>Elsevier</general><general>Mosby Year Book</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</scope><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>7X8</scope><scope>Q33</scope><scope>5PM</scope></search><sort><creationdate>20050601</creationdate><title>Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms</title><author>Ogata, Toru ; Shibamura, Hidenori ; Tromp, Gerard ; Sinha, Moumita ; Goddard, Katrina A.B. ; Sakalihasan, Natzi ; Limet, Raymond ; MacKean, Gerald L. ; Arthur, Claudette ; Sueda, Taijiro ; Land, Susan ; Kuivaniemi, Helena</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c523t-47222e440bb01ec318446e7955ca8fe91f84804a34e71d97495b5f4bc243a41d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Aortic Aneurysm, Abdominal - genetics</topic><topic>Biological and medical sciences</topic><topic>Blood and lymphatic vessels</topic><topic>Cardiology. Vascular system</topic><topic>Cardiovascular & respiratory systems</topic><topic>Chirurgie</topic><topic>Diseases of the aorta</topic><topic>Elastin - genetics</topic><topic>Extracellular Matrix - genetics</topic><topic>Female</topic><topic>Genetic Predisposition to Disease - genetics</topic><topic>Human health sciences</topic><topic>Humans</topic><topic>Linkage Disequilibrium</topic><topic>Male</topic><topic>Matrix Metalloproteinase 10</topic><topic>Medical sciences</topic><topic>Metalloendopeptidases - genetics</topic><topic>Polymorphism, Genetic - genetics</topic><topic>Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis</topic><topic>Sciences de la santé humaine</topic><topic>Surgery</topic><topic>Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases</topic><topic>Systèmes cardiovasculaire & respiratoire</topic><topic>Tissue Inhibitor of Metalloproteinase-1 - genetics</topic><topic>Tissue Inhibitor of Metalloproteinase-3</topic><topic>Tissue Inhibitor of Metalloproteinases - genetics</topic><topic>Vascular surgery: aorta, extremities, vena cava. Surgery of the lymphatic vessels</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ogata, Toru</creatorcontrib><creatorcontrib>Shibamura, Hidenori</creatorcontrib><creatorcontrib>Tromp, Gerard</creatorcontrib><creatorcontrib>Sinha, Moumita</creatorcontrib><creatorcontrib>Goddard, Katrina A.B.</creatorcontrib><creatorcontrib>Sakalihasan, Natzi</creatorcontrib><creatorcontrib>Limet, Raymond</creatorcontrib><creatorcontrib>MacKean, Gerald L.</creatorcontrib><creatorcontrib>Arthur, Claudette</creatorcontrib><creatorcontrib>Sueda, Taijiro</creatorcontrib><creatorcontrib>Land, Susan</creatorcontrib><creatorcontrib>Kuivaniemi, Helena</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Université de Liège - Open Repository and Bibliography (ORBI)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of vascular surgery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ogata, Toru</au><au>Shibamura, Hidenori</au><au>Tromp, Gerard</au><au>Sinha, Moumita</au><au>Goddard, Katrina A.B.</au><au>Sakalihasan, Natzi</au><au>Limet, Raymond</au><au>MacKean, Gerald L.</au><au>Arthur, Claudette</au><au>Sueda, Taijiro</au><au>Land, Susan</au><au>Kuivaniemi, Helena</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms</atitle><jtitle>Journal of vascular surgery</jtitle><addtitle>J Vasc Surg</addtitle><date>2005-06-01</date><risdate>2005</risdate><volume>41</volume><issue>6</issue><spage>1036</spage><epage>1042</epage><pages>1036-1042</pages><issn>0741-5214</issn><issn>1097-6809</issn><eissn>1097-6809</eissn><coden>JVSUES</coden><abstract>Abdominal aortic aneurysms (AAAs) are characterized by histologic signs of chronic inflammation, destructive remodeling of extracellular matrix, and depletion of vascular smooth muscle cells. We investigated the process of extracellular matrix remodeling by performing a genetic association study with polymorphisms in the genes for matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and structural extracellular matrix molecules in AAA. Our hypothesis was that genetic variations in one or more of these genes contribute to greater or lesser activity of these gene products, and thereby contribute to susceptibility for developing AAAs.
DNA samples from 812 unrelated white subject (AAA, n = 387; controls, n = 425) were genotyped for 14 polymorphisms in 13 different candidate genes: MMP1(nt-1607), MMP2(nt-955), MMP3(nt-1612), MMP9(nt-1562), MMP10(nt+180), MMP12(nt-82), MMP13(nt-77), TIMP1(nt+434), TIMP1(rs2070584), TIMP2(rs2009196), TIMP3(nt-1296), TGFB1(nt-509), ELN(nt+422), and COL3A1(nt+581). Odds ratios and
P values adjusted for gender and country of origin using logistic regression and stratified by family history of AAA were calculated to test for association between genotype and disease status. Haplotype analysis was carried out for the two TIMP1 polymorphisms in male subjects.
Analyses with one polymorphism per test without interactions showed an association with the two TIMP1 gene polymorphisms (nt+434,
P = .0047; rs2070584,
P = .015) in male subjects without a family history of AAA. The association remained significant when analyzing TIMP1 haplotypes (χ
2
P = .014 and empirical
P = .009). In addition, we found a significant interaction between the polymorphism and gender for MMP10 (
P = .037) in cases without a family history of AAA, as well as between the polymorphism and country of origin for ELN (
P = .0169) and TIMP3 (
P = .0023) in cases with a family history of AAA.
These findings suggest that genetic variations in TIMP1, TIMP3, MMP10, and ELN genes may contribute to the pathogenesis of AAAs. Further work is needed to confirm the findings in an independent set of samples and to study the functional role of these variants in AAA. It is noteworthy that contrary to a previous study, we did not find an association between the MMP9 (nt-1562) polymorphism and AAA, suggesting genetic heterogeneity of the disease.
Abdominal aortic aneurysms (AAAs) are an important cardiovascular disease, but the genetic and environmental risk factors, which contribute to individual’s risk to develop an aneurysm, are poorly understood. Histologically, AAAs are characterized by signs of chronic inflammation, destructive remodeling of the extracellular matrix, and depletion of vascular smooth muscle cells. We hypothesized that genes involved in these events could harbor changes that make individuals more susceptible to developing aneurysms. This study identified significant genetic associations between DNA sequence changes in tissue inhibitor of metalloproteinase 1 (TIMP1), TIMP3, matrix metalloproteinase 10 (MMP10) and elastin (ELN) genes, and AAA. The results will require confirmation using an independent set of samples. After replication it is possible that these sequence changes in combination with other risk factors could be used in the future to identify individuals who are at increased risk for developing an AAA.</abstract><cop>New York, NY</cop><pub>Mosby, Inc</pub><pmid>15944607</pmid><doi>10.1016/j.jvs.2005.02.020</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of vascular surgery, 2005-06, Vol.41 (6), p.1036-1042 |
| issn | 0741-5214 1097-6809 1097-6809 |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present); EZB-FREE-00999 freely available EZB journals |
| subjects | Aortic Aneurysm, Abdominal - genetics Biological and medical sciences Blood and lymphatic vessels Cardiology. Vascular system Cardiovascular & respiratory systems Chirurgie Diseases of the aorta Elastin - genetics Extracellular Matrix - genetics Female Genetic Predisposition to Disease - genetics Human health sciences Humans Linkage Disequilibrium Male Matrix Metalloproteinase 10 Medical sciences Metalloendopeptidases - genetics Polymorphism, Genetic - genetics Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis Sciences de la santé humaine Surgery Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases Systèmes cardiovasculaire & respiratoire Tissue Inhibitor of Metalloproteinase-1 - genetics Tissue Inhibitor of Metalloproteinase-3 Tissue Inhibitor of Metalloproteinases - genetics Vascular surgery: aorta, extremities, vena cava. Surgery of the lymphatic vessels |
| title | Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-05T23%3A35%3A24IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Genetic%20analysis%20of%20polymorphisms%20in%20biologically%20relevant%20candidate%20genes%20in%20patients%20with%20abdominal%20aortic%20aneurysms&rft.jtitle=Journal%20of%20vascular%20surgery&rft.au=Ogata,%20Toru&rft.date=2005-06-01&rft.volume=41&rft.issue=6&rft.spage=1036&rft.epage=1042&rft.pages=1036-1042&rft.issn=0741-5214&rft.eissn=1097-6809&rft.coden=JVSUES&rft_id=info:doi/10.1016/j.jvs.2005.02.020&rft_dat=%3Cproquest_pubme%3E67920563%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=67920563&rft_id=info:pmid/15944607&rft_els_id=S0741521405002363&rfr_iscdi=true |