Coronary Heart Disease in Systemic Lupus Erythematosus Is Associated With Interferon Regulatory Factor-8 Gene Variants
BACKGROUND—Patients with systemic lupus erythematosus have increased morbidity and mortality in coronary heart disease (CHD). We asked whether there was a genetic influence on CHD in systemic lupus erythematosus. METHODS AND RESULTS—The association between single-nucleotide polymorphisms (SNPs) and...
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| Veröffentlicht in: | Circulation. Cardiovascular genetics 2013-06, Vol.6 (3), p.255-263 |
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| creator | Leonard, Dag Svenungsson, Elisabet Sandling, Johanna K Berggren, Olof Jönsen, Andreas Bengtsson, Christine Wang, Chuan Jensen-Urstad, Kerstin Granstam, Sven-Olof Bengtsson, Anders A Gustafsson, Johanna T Gunnarsson, Iva Rantapää-Dahlqvist, Solbritt Nordmark, Gunnel Eloranta, Maija-Leena Syvänen, Ann-Christine Rönnblom, Lars |
| description | BACKGROUND—Patients with systemic lupus erythematosus have increased morbidity and mortality in coronary heart disease (CHD). We asked whether there was a genetic influence on CHD in systemic lupus erythematosus.
METHODS AND RESULTS—The association between single-nucleotide polymorphisms (SNPs) and CHD in 2 populations of patients with systemic lupus erythematosus was assessed. Patients were genotyped on a custom 12k Illumina Array. The allele frequencies were compared between patients with (n=66) and without (n=509) CHD. We found 61 SNPs with an association (P |
| doi_str_mv | 10.1161/CIRCGENETICS.113.000044 |
| format | Article |
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METHODS AND RESULTS—The association between single-nucleotide polymorphisms (SNPs) and CHD in 2 populations of patients with systemic lupus erythematosus was assessed. Patients were genotyped on a custom 12k Illumina Array. The allele frequencies were compared between patients with (n=66) and without (n=509) CHD. We found 61 SNPs with an association (P<0.01) to CHD, with the strongest association for 3 SNPs located in the interferon regulatory factor-8 (IRF8) gene. Comparison of the allele frequencies of these 61 SNPs in patients with (n=27) and without (n=212) CHD in the second study population revealed that 2 SNPs, rs925994 and rs10514610 in IRF8 (linkage disequilibrium, r=0.84), were associated with CHD in both study populations. Meta-analysis of the SNP rs925994 gave an odds ratio of 3.6 (2.1–6.3), P value 1.9×10. The identified IRF8 allele remained as a risk factor for CHD after adjustment for traditional CHD risk factors. The IRF8 risk allele was associated with the presence of carotid plaques (P<0.001) and increased intima-media thickness (P=0.01). By electrophoretic mobility shift assays, we show weaker binding of protein to the risk allele of the highly linked SNP rs11117415, and by flow cytometry, a reduced frequency of circulating B cells was detected in patients with the IRF8 risk allele.
CONCLUSIONS—There is a considerable genetic component for CHD in systemic lupus erythematosus, with IRF8 as a strong susceptibility locus.</description><identifier>ISSN: 1942-325X</identifier><identifier>ISSN: 1942-3268</identifier><identifier>EISSN: 1942-3268</identifier><identifier>DOI: 10.1161/CIRCGENETICS.113.000044</identifier><identifier>PMID: 23661672</identifier><language>eng</language><publisher>United States: American Heart Association, Inc</publisher><subject>Adult ; Aged ; cardiovascular disease ; carotid intima-media thickness ; Clinical Medicine ; coronary ; coronary disease ; Coronary Disease - genetics ; disease ; European Continental Ancestry Group - genetics ; Female ; genes ; Genetic Predisposition to Disease ; Genetic Variation ; Humans ; interferon regulatory factor-8 ; Interferon Regulatory Factors - genetics ; Klinisk medicin ; lupus erythematosus ; Lupus Erythematosus, Systemic - genetics ; Male ; Medical and Health Sciences ; Medicin och hälsovetenskap ; Middle Aged ; Molecular Medicine ; Molekylär medicin ; myocardial ischemia ; Polymorphism, Single Nucleotide ; Reumatologi och inflammation ; Rheumatology and Autoimmunity ; Sweden ; systemic ; Young Adult</subject><ispartof>Circulation. Cardiovascular genetics, 2013-06, Vol.6 (3), p.255-263</ispartof><rights>2013 American Heart Association, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6385-9cd8e30a4e9c65352d263d0ceca78d98ed337b2841d47ef8596b8d3cd74537863</citedby><cites>FETCH-LOGICAL-c6385-9cd8e30a4e9c65352d263d0ceca78d98ed337b2841d47ef8596b8d3cd74537863</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3687,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23661672$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-78965$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttps://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-202415$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttps://lup.lub.lu.se/record/3983160$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:126879530$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Leonard, Dag</creatorcontrib><creatorcontrib>Svenungsson, Elisabet</creatorcontrib><creatorcontrib>Sandling, Johanna K</creatorcontrib><creatorcontrib>Berggren, Olof</creatorcontrib><creatorcontrib>Jönsen, Andreas</creatorcontrib><creatorcontrib>Bengtsson, Christine</creatorcontrib><creatorcontrib>Wang, Chuan</creatorcontrib><creatorcontrib>Jensen-Urstad, Kerstin</creatorcontrib><creatorcontrib>Granstam, Sven-Olof</creatorcontrib><creatorcontrib>Bengtsson, Anders A</creatorcontrib><creatorcontrib>Gustafsson, Johanna T</creatorcontrib><creatorcontrib>Gunnarsson, Iva</creatorcontrib><creatorcontrib>Rantapää-Dahlqvist, Solbritt</creatorcontrib><creatorcontrib>Nordmark, Gunnel</creatorcontrib><creatorcontrib>Eloranta, Maija-Leena</creatorcontrib><creatorcontrib>Syvänen, Ann-Christine</creatorcontrib><creatorcontrib>Rönnblom, Lars</creatorcontrib><title>Coronary Heart Disease in Systemic Lupus Erythematosus Is Associated With Interferon Regulatory Factor-8 Gene Variants</title><title>Circulation. Cardiovascular genetics</title><addtitle>Circ Cardiovasc Genet</addtitle><description>BACKGROUND—Patients with systemic lupus erythematosus have increased morbidity and mortality in coronary heart disease (CHD). We asked whether there was a genetic influence on CHD in systemic lupus erythematosus.
METHODS AND RESULTS—The association between single-nucleotide polymorphisms (SNPs) and CHD in 2 populations of patients with systemic lupus erythematosus was assessed. Patients were genotyped on a custom 12k Illumina Array. The allele frequencies were compared between patients with (n=66) and without (n=509) CHD. We found 61 SNPs with an association (P<0.01) to CHD, with the strongest association for 3 SNPs located in the interferon regulatory factor-8 (IRF8) gene. Comparison of the allele frequencies of these 61 SNPs in patients with (n=27) and without (n=212) CHD in the second study population revealed that 2 SNPs, rs925994 and rs10514610 in IRF8 (linkage disequilibrium, r=0.84), were associated with CHD in both study populations. Meta-analysis of the SNP rs925994 gave an odds ratio of 3.6 (2.1–6.3), P value 1.9×10. The identified IRF8 allele remained as a risk factor for CHD after adjustment for traditional CHD risk factors. The IRF8 risk allele was associated with the presence of carotid plaques (P<0.001) and increased intima-media thickness (P=0.01). By electrophoretic mobility shift assays, we show weaker binding of protein to the risk allele of the highly linked SNP rs11117415, and by flow cytometry, a reduced frequency of circulating B cells was detected in patients with the IRF8 risk allele.
CONCLUSIONS—There is a considerable genetic component for CHD in systemic lupus erythematosus, with IRF8 as a strong susceptibility locus.</description><subject>Adult</subject><subject>Aged</subject><subject>cardiovascular disease</subject><subject>carotid intima-media thickness</subject><subject>Clinical Medicine</subject><subject>coronary</subject><subject>coronary disease</subject><subject>Coronary Disease - genetics</subject><subject>disease</subject><subject>European Continental Ancestry Group - genetics</subject><subject>Female</subject><subject>genes</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetic Variation</subject><subject>Humans</subject><subject>interferon regulatory factor-8</subject><subject>Interferon Regulatory Factors - genetics</subject><subject>Klinisk medicin</subject><subject>lupus erythematosus</subject><subject>Lupus Erythematosus, Systemic - genetics</subject><subject>Male</subject><subject>Medical and Health Sciences</subject><subject>Medicin och hälsovetenskap</subject><subject>Middle Aged</subject><subject>Molecular Medicine</subject><subject>Molekylär medicin</subject><subject>myocardial ischemia</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Reumatologi och inflammation</subject><subject>Rheumatology and Autoimmunity</subject><subject>Sweden</subject><subject>systemic</subject><subject>Young Adult</subject><issn>1942-325X</issn><issn>1942-3268</issn><issn>1942-3268</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkktvEzEUhUcIREvgL8AsWTDF78eymqZppAikthR2lsdz0wydRxjPEOXfc6OkgU0kLFm-vvrOsWyfJPlAyQWlin7O57f5bPplej_P77DDLwgOIV4k59QKlnGmzMtjLX-cJW9i_EmIEpyr18kZ40pRpdl58jvv-q71_Ta9Ad8P6VUVwUdIqza928YBmiqki3E9xnTab4cVNH7oIu7mMb2MsQuVH6BMv1fDKp23A_RLQLv0Fh7HGkm0vfYB18ykM2ghffB95dshvk1eLX0d4d1hnSTfrqf3-U22-Dqb55eLLChuZGZDaYATL8AGJblkJVO8JAGC16a0BkrOdcGMoKXQsDTSqsKUPJRaSK6N4pMk2_vGDazHwq37qsHLus5X7tB6wgqcZFZyi7w9ya_7rvwrehZSfGqNWoLaxUltPa5xFjh3GuuNFEsuXaEL7wQY7YrCSqeJD5oza8pCoN2nk3ZX1cOl6_pHN46OESao_E-8GZ02Vu3wj3scb_VrhDi4pooB6tq30I3RUa4JZcxiYCaJ3qOh72LsYXn0psTt0uj-TSN2uNunEZXvD4eMRQPlUfccPwTEHth0NYYnPtXjBnq3Al8PK0co_q6wOmNYEYWe2c5Y8j_k6u6J</recordid><startdate>201306</startdate><enddate>201306</enddate><creator>Leonard, Dag</creator><creator>Svenungsson, Elisabet</creator><creator>Sandling, Johanna K</creator><creator>Berggren, Olof</creator><creator>Jönsen, Andreas</creator><creator>Bengtsson, Christine</creator><creator>Wang, Chuan</creator><creator>Jensen-Urstad, Kerstin</creator><creator>Granstam, Sven-Olof</creator><creator>Bengtsson, Anders A</creator><creator>Gustafsson, Johanna T</creator><creator>Gunnarsson, Iva</creator><creator>Rantapää-Dahlqvist, Solbritt</creator><creator>Nordmark, Gunnel</creator><creator>Eloranta, Maija-Leena</creator><creator>Syvänen, Ann-Christine</creator><creator>Rönnblom, Lars</creator><general>American Heart Association, Inc</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>7X8</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D93</scope><scope>DF2</scope><scope>D95</scope></search><sort><creationdate>201306</creationdate><title>Coronary Heart Disease in Systemic Lupus Erythematosus Is Associated With Interferon Regulatory Factor-8 Gene Variants</title><author>Leonard, Dag ; Svenungsson, Elisabet ; Sandling, Johanna K ; Berggren, Olof ; Jönsen, Andreas ; Bengtsson, Christine ; Wang, Chuan ; Jensen-Urstad, Kerstin ; Granstam, Sven-Olof ; Bengtsson, Anders A ; Gustafsson, Johanna T ; Gunnarsson, Iva ; Rantapää-Dahlqvist, Solbritt ; Nordmark, Gunnel ; Eloranta, Maija-Leena ; Syvänen, Ann-Christine ; Rönnblom, Lars</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6385-9cd8e30a4e9c65352d263d0ceca78d98ed337b2841d47ef8596b8d3cd74537863</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adult</topic><topic>Aged</topic><topic>cardiovascular disease</topic><topic>carotid intima-media thickness</topic><topic>Clinical Medicine</topic><topic>coronary</topic><topic>coronary disease</topic><topic>Coronary Disease - genetics</topic><topic>disease</topic><topic>European Continental Ancestry Group - genetics</topic><topic>Female</topic><topic>genes</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetic Variation</topic><topic>Humans</topic><topic>interferon regulatory factor-8</topic><topic>Interferon Regulatory Factors - genetics</topic><topic>Klinisk medicin</topic><topic>lupus erythematosus</topic><topic>Lupus Erythematosus, Systemic - genetics</topic><topic>Male</topic><topic>Medical and Health Sciences</topic><topic>Medicin och hälsovetenskap</topic><topic>Middle Aged</topic><topic>Molecular Medicine</topic><topic>Molekylär medicin</topic><topic>myocardial ischemia</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Reumatologi och inflammation</topic><topic>Rheumatology and Autoimmunity</topic><topic>Sweden</topic><topic>systemic</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Leonard, Dag</creatorcontrib><creatorcontrib>Svenungsson, Elisabet</creatorcontrib><creatorcontrib>Sandling, Johanna K</creatorcontrib><creatorcontrib>Berggren, Olof</creatorcontrib><creatorcontrib>Jönsen, Andreas</creatorcontrib><creatorcontrib>Bengtsson, Christine</creatorcontrib><creatorcontrib>Wang, Chuan</creatorcontrib><creatorcontrib>Jensen-Urstad, Kerstin</creatorcontrib><creatorcontrib>Granstam, Sven-Olof</creatorcontrib><creatorcontrib>Bengtsson, Anders A</creatorcontrib><creatorcontrib>Gustafsson, Johanna T</creatorcontrib><creatorcontrib>Gunnarsson, Iva</creatorcontrib><creatorcontrib>Rantapää-Dahlqvist, Solbritt</creatorcontrib><creatorcontrib>Nordmark, Gunnel</creatorcontrib><creatorcontrib>Eloranta, Maija-Leena</creatorcontrib><creatorcontrib>Syvänen, Ann-Christine</creatorcontrib><creatorcontrib>Rönnblom, Lars</creatorcontrib><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>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Umeå universitet</collection><collection>SWEPUB Uppsala universitet</collection><collection>SWEPUB Lunds universitet</collection><jtitle>Circulation. Cardiovascular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Leonard, Dag</au><au>Svenungsson, Elisabet</au><au>Sandling, Johanna K</au><au>Berggren, Olof</au><au>Jönsen, Andreas</au><au>Bengtsson, Christine</au><au>Wang, Chuan</au><au>Jensen-Urstad, Kerstin</au><au>Granstam, Sven-Olof</au><au>Bengtsson, Anders A</au><au>Gustafsson, Johanna T</au><au>Gunnarsson, Iva</au><au>Rantapää-Dahlqvist, Solbritt</au><au>Nordmark, Gunnel</au><au>Eloranta, Maija-Leena</au><au>Syvänen, Ann-Christine</au><au>Rönnblom, Lars</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Coronary Heart Disease in Systemic Lupus Erythematosus Is Associated With Interferon Regulatory Factor-8 Gene Variants</atitle><jtitle>Circulation. Cardiovascular genetics</jtitle><addtitle>Circ Cardiovasc Genet</addtitle><date>2013-06</date><risdate>2013</risdate><volume>6</volume><issue>3</issue><spage>255</spage><epage>263</epage><pages>255-263</pages><issn>1942-325X</issn><issn>1942-3268</issn><eissn>1942-3268</eissn><abstract>BACKGROUND—Patients with systemic lupus erythematosus have increased morbidity and mortality in coronary heart disease (CHD). We asked whether there was a genetic influence on CHD in systemic lupus erythematosus.
METHODS AND RESULTS—The association between single-nucleotide polymorphisms (SNPs) and CHD in 2 populations of patients with systemic lupus erythematosus was assessed. Patients were genotyped on a custom 12k Illumina Array. The allele frequencies were compared between patients with (n=66) and without (n=509) CHD. We found 61 SNPs with an association (P<0.01) to CHD, with the strongest association for 3 SNPs located in the interferon regulatory factor-8 (IRF8) gene. Comparison of the allele frequencies of these 61 SNPs in patients with (n=27) and without (n=212) CHD in the second study population revealed that 2 SNPs, rs925994 and rs10514610 in IRF8 (linkage disequilibrium, r=0.84), were associated with CHD in both study populations. Meta-analysis of the SNP rs925994 gave an odds ratio of 3.6 (2.1–6.3), P value 1.9×10. The identified IRF8 allele remained as a risk factor for CHD after adjustment for traditional CHD risk factors. The IRF8 risk allele was associated with the presence of carotid plaques (P<0.001) and increased intima-media thickness (P=0.01). By electrophoretic mobility shift assays, we show weaker binding of protein to the risk allele of the highly linked SNP rs11117415, and by flow cytometry, a reduced frequency of circulating B cells was detected in patients with the IRF8 risk allele.
CONCLUSIONS—There is a considerable genetic component for CHD in systemic lupus erythematosus, with IRF8 as a strong susceptibility locus.</abstract><cop>United States</cop><pub>American Heart Association, Inc</pub><pmid>23661672</pmid><doi>10.1161/CIRCGENETICS.113.000044</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Circulation. Cardiovascular genetics, 2013-06, Vol.6 (3), p.255-263 |
| issn | 1942-325X 1942-3268 1942-3268 |
| language | eng |
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| source | MEDLINE; American Heart Association Journals |
| subjects | Adult Aged cardiovascular disease carotid intima-media thickness Clinical Medicine coronary coronary disease Coronary Disease - genetics disease European Continental Ancestry Group - genetics Female genes Genetic Predisposition to Disease Genetic Variation Humans interferon regulatory factor-8 Interferon Regulatory Factors - genetics Klinisk medicin lupus erythematosus Lupus Erythematosus, Systemic - genetics Male Medical and Health Sciences Medicin och hälsovetenskap Middle Aged Molecular Medicine Molekylär medicin myocardial ischemia Polymorphism, Single Nucleotide Reumatologi och inflammation Rheumatology and Autoimmunity Sweden systemic Young Adult |
| title | Coronary Heart Disease in Systemic Lupus Erythematosus Is Associated With Interferon Regulatory Factor-8 Gene Variants |
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