Cargando…

Analysis of positional candidate genes in the AAA1 susceptibility locus for abdominal aortic aneurysms on chromosome 19

BACKGROUND: Abdominal aortic aneurysm (AAA) is a complex disorder with multiple genetic risk factors. Using affected relative pair linkage analysis, we previously identified an AAA susceptibility locus on chromosome 19q13. This locus has been designated as the AAA1 susceptibility locus in the Online...

Descripción completa

Detalles Bibliográficos
Autores principales: Lillvis, John H, Kyo, Yoshiki, Tromp, Gerard, Lenk, Guy M, Li, Ming, Lu, Qing, Igo, Robert P, Sakalihasan, Natzi, Ferrell, Robert E, Schworer, Charles M, Gatalica, Zoran, Land, Susan, Kuivaniemi, Helena
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037298/
https://www.ncbi.nlm.nih.gov/pubmed/21247474
http://dx.doi.org/10.1186/1471-2350-12-14
_version_ 1782197966902132736
author Lillvis, John H
Kyo, Yoshiki
Tromp, Gerard
Lenk, Guy M
Li, Ming
Lu, Qing
Igo, Robert P
Sakalihasan, Natzi
Ferrell, Robert E
Schworer, Charles M
Gatalica, Zoran
Land, Susan
Kuivaniemi, Helena
author_facet Lillvis, John H
Kyo, Yoshiki
Tromp, Gerard
Lenk, Guy M
Li, Ming
Lu, Qing
Igo, Robert P
Sakalihasan, Natzi
Ferrell, Robert E
Schworer, Charles M
Gatalica, Zoran
Land, Susan
Kuivaniemi, Helena
author_sort Lillvis, John H
collection PubMed
description BACKGROUND: Abdominal aortic aneurysm (AAA) is a complex disorder with multiple genetic risk factors. Using affected relative pair linkage analysis, we previously identified an AAA susceptibility locus on chromosome 19q13. This locus has been designated as the AAA1 susceptibility locus in the Online Mendelian Inheritance in Man (OMIM) database. METHODS: Nine candidate genes were selected from the AAA1 locus based on their function, as well as mRNA expression levels in the aorta. A sample of 394 cases and 419 controls was genotyped for 41 SNPs located in or around the selected nine candidate genes using the Illumina GoldenGate platform. Single marker and haplotype analyses were performed. Three genes (CEBPG, PEPD and CD22) were selected for DNA sequencing based on the association study results, and exonic regions were analyzed. Immunohistochemical staining of aortic tissue sections from AAA and control individuals was carried out for the CD22 and PEPD proteins with specific antibodies. RESULTS: Several SNPs were nominally associated with AAA (p < 0.05). The SNPs with most significant p-values were located near the CCAAT enhancer binding protein (CEBPG), peptidase D (PEPD), and CD22. Haplotype analysis found a nominally associated 5-SNP haplotype in the CEBPG/PEPD locus, as well as a nominally associated 2-SNP haplotype in the CD22 locus. DNA sequencing of the coding regions revealed no variation in CEBPG. Seven sequence variants were identified in PEPD, including three not present in the NCBI SNP (dbSNP) database. Sequencing of all 14 exons of CD22 identified 20 sequence variants, five of which were in the coding region and six were in the 3'-untranslated region. Five variants were not present in dbSNP. Immunohistochemical staining for CD22 revealed protein expression in lymphocytes present in the aneurysmal aortic wall only and no detectable expression in control aorta. PEPD protein was expressed in fibroblasts and myofibroblasts in the media-adventitia border in both aneurysmal and non-aneurysmal tissue samples. CONCLUSIONS: Association testing of the functional positional candidate genes on the AAA1 locus on chromosome 19q13 demonstrated nominal association in three genes. PEPD and CD22 were considered the most promising candidate genes for altering AAA risk, based on gene function, association evidence, gene expression, and protein expression.
format Text
id pubmed-3037298
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-30372982011-02-11 Analysis of positional candidate genes in the AAA1 susceptibility locus for abdominal aortic aneurysms on chromosome 19 Lillvis, John H Kyo, Yoshiki Tromp, Gerard Lenk, Guy M Li, Ming Lu, Qing Igo, Robert P Sakalihasan, Natzi Ferrell, Robert E Schworer, Charles M Gatalica, Zoran Land, Susan Kuivaniemi, Helena BMC Med Genet Research Article BACKGROUND: Abdominal aortic aneurysm (AAA) is a complex disorder with multiple genetic risk factors. Using affected relative pair linkage analysis, we previously identified an AAA susceptibility locus on chromosome 19q13. This locus has been designated as the AAA1 susceptibility locus in the Online Mendelian Inheritance in Man (OMIM) database. METHODS: Nine candidate genes were selected from the AAA1 locus based on their function, as well as mRNA expression levels in the aorta. A sample of 394 cases and 419 controls was genotyped for 41 SNPs located in or around the selected nine candidate genes using the Illumina GoldenGate platform. Single marker and haplotype analyses were performed. Three genes (CEBPG, PEPD and CD22) were selected for DNA sequencing based on the association study results, and exonic regions were analyzed. Immunohistochemical staining of aortic tissue sections from AAA and control individuals was carried out for the CD22 and PEPD proteins with specific antibodies. RESULTS: Several SNPs were nominally associated with AAA (p < 0.05). The SNPs with most significant p-values were located near the CCAAT enhancer binding protein (CEBPG), peptidase D (PEPD), and CD22. Haplotype analysis found a nominally associated 5-SNP haplotype in the CEBPG/PEPD locus, as well as a nominally associated 2-SNP haplotype in the CD22 locus. DNA sequencing of the coding regions revealed no variation in CEBPG. Seven sequence variants were identified in PEPD, including three not present in the NCBI SNP (dbSNP) database. Sequencing of all 14 exons of CD22 identified 20 sequence variants, five of which were in the coding region and six were in the 3'-untranslated region. Five variants were not present in dbSNP. Immunohistochemical staining for CD22 revealed protein expression in lymphocytes present in the aneurysmal aortic wall only and no detectable expression in control aorta. PEPD protein was expressed in fibroblasts and myofibroblasts in the media-adventitia border in both aneurysmal and non-aneurysmal tissue samples. CONCLUSIONS: Association testing of the functional positional candidate genes on the AAA1 locus on chromosome 19q13 demonstrated nominal association in three genes. PEPD and CD22 were considered the most promising candidate genes for altering AAA risk, based on gene function, association evidence, gene expression, and protein expression. BioMed Central 2011-01-19 /pmc/articles/PMC3037298/ /pubmed/21247474 http://dx.doi.org/10.1186/1471-2350-12-14 Text en Copyright ©2011 Lillvis et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Lillvis, John H
Kyo, Yoshiki
Tromp, Gerard
Lenk, Guy M
Li, Ming
Lu, Qing
Igo, Robert P
Sakalihasan, Natzi
Ferrell, Robert E
Schworer, Charles M
Gatalica, Zoran
Land, Susan
Kuivaniemi, Helena
Analysis of positional candidate genes in the AAA1 susceptibility locus for abdominal aortic aneurysms on chromosome 19
title Analysis of positional candidate genes in the AAA1 susceptibility locus for abdominal aortic aneurysms on chromosome 19
title_full Analysis of positional candidate genes in the AAA1 susceptibility locus for abdominal aortic aneurysms on chromosome 19
title_fullStr Analysis of positional candidate genes in the AAA1 susceptibility locus for abdominal aortic aneurysms on chromosome 19
title_full_unstemmed Analysis of positional candidate genes in the AAA1 susceptibility locus for abdominal aortic aneurysms on chromosome 19
title_short Analysis of positional candidate genes in the AAA1 susceptibility locus for abdominal aortic aneurysms on chromosome 19
title_sort analysis of positional candidate genes in the aaa1 susceptibility locus for abdominal aortic aneurysms on chromosome 19
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037298/
https://www.ncbi.nlm.nih.gov/pubmed/21247474
http://dx.doi.org/10.1186/1471-2350-12-14
work_keys_str_mv AT lillvisjohnh analysisofpositionalcandidategenesintheaaa1susceptibilitylocusforabdominalaorticaneurysmsonchromosome19
AT kyoyoshiki analysisofpositionalcandidategenesintheaaa1susceptibilitylocusforabdominalaorticaneurysmsonchromosome19
AT trompgerard analysisofpositionalcandidategenesintheaaa1susceptibilitylocusforabdominalaorticaneurysmsonchromosome19
AT lenkguym analysisofpositionalcandidategenesintheaaa1susceptibilitylocusforabdominalaorticaneurysmsonchromosome19
AT liming analysisofpositionalcandidategenesintheaaa1susceptibilitylocusforabdominalaorticaneurysmsonchromosome19
AT luqing analysisofpositionalcandidategenesintheaaa1susceptibilitylocusforabdominalaorticaneurysmsonchromosome19
AT igorobertp analysisofpositionalcandidategenesintheaaa1susceptibilitylocusforabdominalaorticaneurysmsonchromosome19
AT sakalihasannatzi analysisofpositionalcandidategenesintheaaa1susceptibilitylocusforabdominalaorticaneurysmsonchromosome19
AT ferrellroberte analysisofpositionalcandidategenesintheaaa1susceptibilitylocusforabdominalaorticaneurysmsonchromosome19
AT schworercharlesm analysisofpositionalcandidategenesintheaaa1susceptibilitylocusforabdominalaorticaneurysmsonchromosome19
AT gatalicazoran analysisofpositionalcandidategenesintheaaa1susceptibilitylocusforabdominalaorticaneurysmsonchromosome19
AT landsusan analysisofpositionalcandidategenesintheaaa1susceptibilitylocusforabdominalaorticaneurysmsonchromosome19
AT kuivaniemihelena analysisofpositionalcandidategenesintheaaa1susceptibilitylocusforabdominalaorticaneurysmsonchromosome19