Joint effect of insulin signaling genes on cardiovascular events and on whole body and endothelial insulin resistance
Abstract Objective Insulin resistance (IR) and cardiovascular disease (CVD) share a common soil. We investigated the combined role of single nucleotide polymorphisms (SNPs) affecting insulin signaling ( ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on CVD, age at myocardial i...
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| creator | Bacci, Simonetta Prudente, Sabrina Copetti, Massimiliano Spoto, Belinda Rizza, Stefano Baratta, Roberto Di Pietro, Natalia Morini, Eleonora Di Paola, Rosa Testa, Alessandra Mallamaci, Francesca Tripepi, Giovanni Zhang, Yuan-Yuan Mercuri, Luana Di Silvestre, Sara Lauro, Renato Malatino, Lorenzo Consoli, Agostino Pellegrini, Fabio Pandolfi, Assunta Frittitta, Lucia Zoccali, Carmine Federici, Massimo Doria, Alessandro Trischitta, Vincenzo |
| description | Abstract Objective Insulin resistance (IR) and cardiovascular disease (CVD) share a common soil. We investigated the combined role of single nucleotide polymorphisms (SNPs) affecting insulin signaling ( ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on CVD, age at myocardial infarction (MI), in vivo insulin sensitivity and in vitro insulin-stimulated nitric oxide synthase (NOS) activity. Design and setting 1. We first studied, incident cardiovascular events (a composite endpoint comprising myocardial infarction-MI, stroke and cardiovascular death) in 733 patients (2186 person-years, 175 events). 2. In a replication attempt, age at MI was tested in 331 individuals. 3. OGTT-derived insulin sensitivity index (ISI) was assessed in 829 individuals with fasting glucose |
| doi_str_mv | 10.1016/j.atherosclerosis.2012.10.035 |
| format | Article |
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We investigated the combined role of single nucleotide polymorphisms (SNPs) affecting insulin signaling ( ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on CVD, age at myocardial infarction (MI), in vivo insulin sensitivity and in vitro insulin-stimulated nitric oxide synthase (NOS) activity. Design and setting 1. We first studied, incident cardiovascular events (a composite endpoint comprising myocardial infarction-MI, stroke and cardiovascular death) in 733 patients (2186 person-years, 175 events). 2. In a replication attempt, age at MI was tested in 331 individuals. 3. OGTT-derived insulin sensitivity index (ISI) was assessed in 829 individuals with fasting glucose <126 mg/dl. 4. NOS activity was measured in 40 strains of human vein endothelial cells (HUVECs). Results 1. Risk variants jointly predicted cardiovascular events (HR = 1.181; p = 0.0009) and, when added to clinical risk factors, significantly improved survival C-statistics; they also allowed a significantly correct reclassification (by net reclassification index) in the whole sample (135/733 individuals) and, even more, in obese patients (116/204 individuals). 2. Risk variants were jointly associated with age at MI ( p = 0.006). 3. A significant association was also observed with ISI ( p = 0.02). 4. Finally, risk variants were jointly associated with insulin-stimulated NOS activity in HUVECs ( p = 0.009). Conclusions Insulin signaling genes variants jointly affect cardiovascular disease, very likely by promoting whole body and endothelium-specific insulin resistance. Further studies are needed to address whether their genotyping help identify very high-risk patients who need specific and/or more aggressive preventive strategies.</description><identifier>ISSN: 0021-9150</identifier><identifier>EISSN: 1879-1484</identifier><identifier>DOI: 10.1016/j.atherosclerosis.2012.10.035</identifier><identifier>PMID: 23107043</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ireland Ltd</publisher><subject>Atherosclerosis (general aspects, experimental research) ; Biological and medical sciences ; Blood and lymphatic vessels ; Cardiology. Vascular system ; Cardiovascular ; Cardiovascular Diseases - genetics ; Cardiovascular system ; Cells, Cultured ; Cross-Sectional Studies ; Endothelial Cells - metabolism ; Endothelium, Vascular - metabolism ; Female ; Genetic susceptibility ; Humans ; Insulin - genetics ; Insulin dependent endothelial function ; Insulin Resistance - genetics ; Insulin sensitivity ; Male ; Medical sciences ; Nonsynonymous polymorphism ; Pharmacology. Drug treatments ; Prospective Studies ; Signal Transduction - genetics ; Vasodilator agents. Cerebral vasodilators</subject><ispartof>Atherosclerosis, 2013-01, Vol.226 (1), p.140-145</ispartof><rights>Elsevier Ireland Ltd</rights><rights>2012 Elsevier Ireland Ltd</rights><rights>2014 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.</rights><rights>2012 Elsevier Ireland Ltd. All rights reserved. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c584t-22c003ab552644b8a8c4713df4dcfb8294ffd90c432cb63c6f2b594dc6039f583</citedby><cites>FETCH-LOGICAL-c584t-22c003ab552644b8a8c4713df4dcfb8294ffd90c432cb63c6f2b594dc6039f583</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.atherosclerosis.2012.10.035$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26830752$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23107043$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bacci, Simonetta</creatorcontrib><creatorcontrib>Prudente, Sabrina</creatorcontrib><creatorcontrib>Copetti, Massimiliano</creatorcontrib><creatorcontrib>Spoto, Belinda</creatorcontrib><creatorcontrib>Rizza, Stefano</creatorcontrib><creatorcontrib>Baratta, Roberto</creatorcontrib><creatorcontrib>Di Pietro, Natalia</creatorcontrib><creatorcontrib>Morini, Eleonora</creatorcontrib><creatorcontrib>Di Paola, Rosa</creatorcontrib><creatorcontrib>Testa, Alessandra</creatorcontrib><creatorcontrib>Mallamaci, Francesca</creatorcontrib><creatorcontrib>Tripepi, Giovanni</creatorcontrib><creatorcontrib>Zhang, Yuan-Yuan</creatorcontrib><creatorcontrib>Mercuri, Luana</creatorcontrib><creatorcontrib>Di Silvestre, Sara</creatorcontrib><creatorcontrib>Lauro, Renato</creatorcontrib><creatorcontrib>Malatino, Lorenzo</creatorcontrib><creatorcontrib>Consoli, Agostino</creatorcontrib><creatorcontrib>Pellegrini, Fabio</creatorcontrib><creatorcontrib>Pandolfi, Assunta</creatorcontrib><creatorcontrib>Frittitta, Lucia</creatorcontrib><creatorcontrib>Zoccali, Carmine</creatorcontrib><creatorcontrib>Federici, Massimo</creatorcontrib><creatorcontrib>Doria, Alessandro</creatorcontrib><creatorcontrib>Trischitta, Vincenzo</creatorcontrib><title>Joint effect of insulin signaling genes on cardiovascular events and on whole body and endothelial insulin resistance</title><title>Atherosclerosis</title><addtitle>Atherosclerosis</addtitle><description>Abstract Objective Insulin resistance (IR) and cardiovascular disease (CVD) share a common soil. We investigated the combined role of single nucleotide polymorphisms (SNPs) affecting insulin signaling ( ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on CVD, age at myocardial infarction (MI), in vivo insulin sensitivity and in vitro insulin-stimulated nitric oxide synthase (NOS) activity. Design and setting 1. We first studied, incident cardiovascular events (a composite endpoint comprising myocardial infarction-MI, stroke and cardiovascular death) in 733 patients (2186 person-years, 175 events). 2. In a replication attempt, age at MI was tested in 331 individuals. 3. OGTT-derived insulin sensitivity index (ISI) was assessed in 829 individuals with fasting glucose <126 mg/dl. 4. NOS activity was measured in 40 strains of human vein endothelial cells (HUVECs). Results 1. Risk variants jointly predicted cardiovascular events (HR = 1.181; p = 0.0009) and, when added to clinical risk factors, significantly improved survival C-statistics; they also allowed a significantly correct reclassification (by net reclassification index) in the whole sample (135/733 individuals) and, even more, in obese patients (116/204 individuals). 2. Risk variants were jointly associated with age at MI ( p = 0.006). 3. A significant association was also observed with ISI ( p = 0.02). 4. Finally, risk variants were jointly associated with insulin-stimulated NOS activity in HUVECs ( p = 0.009). Conclusions Insulin signaling genes variants jointly affect cardiovascular disease, very likely by promoting whole body and endothelium-specific insulin resistance. Further studies are needed to address whether their genotyping help identify very high-risk patients who need specific and/or more aggressive preventive strategies.</description><subject>Atherosclerosis (general aspects, experimental research)</subject><subject>Biological and medical sciences</subject><subject>Blood and lymphatic vessels</subject><subject>Cardiology. Vascular system</subject><subject>Cardiovascular</subject><subject>Cardiovascular Diseases - genetics</subject><subject>Cardiovascular system</subject><subject>Cells, Cultured</subject><subject>Cross-Sectional Studies</subject><subject>Endothelial Cells - metabolism</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Female</subject><subject>Genetic susceptibility</subject><subject>Humans</subject><subject>Insulin - genetics</subject><subject>Insulin dependent endothelial function</subject><subject>Insulin Resistance - genetics</subject><subject>Insulin sensitivity</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Nonsynonymous polymorphism</subject><subject>Pharmacology. Drug treatments</subject><subject>Prospective Studies</subject><subject>Signal Transduction - genetics</subject><subject>Vasodilator agents. Cerebral vasodilators</subject><issn>0021-9150</issn><issn>1879-1484</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNUsuOEzEQHCEQGxZ-Ac1lJS4J7ce8DqyEVrCAVuIAnC2Pp504OPZizwTl7-khIYI9cbEtV7m63NVFccVgxYDVr7crPW4wxWz8vLq84sA4YSsQ1aNiwdqmWzLZysfFAoCzZccquCie5bwFANmw9mlxwQWDBqRYFNOn6MJYorVoxjLa0oU8eRfK7NZB02FdrjFgLmMojU6Di3udzeR1KnGPYcylDsMM_txEj2Ufh8PvGwxDJJ_eaX-WTEh2Rx0MPi-eWO0zvjjtl8W39---3nxY3n2-_Xjz9m5pqlaOS84NgNB9VfFayr7VraEPiMHKwdi-5Z20dujASMFNXwtTW95XHYE1iM5Wrbgsro-691O_w8GQ4aS9uk9up9NBRe3Uv0hwG7WOeyUq3jWyIYFXJ4EUf0yYR7Vz2aD3OmCcsmK8EbKSwCqivjlSDcWSE9pzGQZqjk5t1YPo1BzdDFN09P7l317Pr_9kRYSrE4ES0N4m6iRpnHl1K6CpOPFujzykzu4dJpWNQ-r64BKFrIbo_tvS9QMlQzk6Kv4dD5i3cUo0I9QFlbkC9WWet3ncGAdoWNeKX9IJ2as</recordid><startdate>20130101</startdate><enddate>20130101</enddate><creator>Bacci, Simonetta</creator><creator>Prudente, Sabrina</creator><creator>Copetti, Massimiliano</creator><creator>Spoto, Belinda</creator><creator>Rizza, Stefano</creator><creator>Baratta, Roberto</creator><creator>Di Pietro, Natalia</creator><creator>Morini, Eleonora</creator><creator>Di Paola, Rosa</creator><creator>Testa, Alessandra</creator><creator>Mallamaci, Francesca</creator><creator>Tripepi, Giovanni</creator><creator>Zhang, Yuan-Yuan</creator><creator>Mercuri, Luana</creator><creator>Di Silvestre, Sara</creator><creator>Lauro, Renato</creator><creator>Malatino, Lorenzo</creator><creator>Consoli, Agostino</creator><creator>Pellegrini, Fabio</creator><creator>Pandolfi, Assunta</creator><creator>Frittitta, Lucia</creator><creator>Zoccali, Carmine</creator><creator>Federici, Massimo</creator><creator>Doria, Alessandro</creator><creator>Trischitta, Vincenzo</creator><general>Elsevier Ireland Ltd</general><general>Elsevier</general><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>5PM</scope></search><sort><creationdate>20130101</creationdate><title>Joint effect of insulin signaling genes on cardiovascular events and on whole body and endothelial insulin resistance</title><author>Bacci, Simonetta ; Prudente, Sabrina ; Copetti, Massimiliano ; Spoto, Belinda ; Rizza, Stefano ; Baratta, Roberto ; Di Pietro, Natalia ; Morini, Eleonora ; Di Paola, Rosa ; Testa, Alessandra ; Mallamaci, Francesca ; Tripepi, Giovanni ; Zhang, Yuan-Yuan ; Mercuri, Luana ; Di Silvestre, Sara ; Lauro, Renato ; Malatino, Lorenzo ; Consoli, Agostino ; Pellegrini, Fabio ; Pandolfi, Assunta ; Frittitta, Lucia ; Zoccali, Carmine ; Federici, Massimo ; Doria, Alessandro ; Trischitta, Vincenzo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c584t-22c003ab552644b8a8c4713df4dcfb8294ffd90c432cb63c6f2b594dc6039f583</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Atherosclerosis (general aspects, experimental research)</topic><topic>Biological and medical sciences</topic><topic>Blood and lymphatic vessels</topic><topic>Cardiology. Vascular system</topic><topic>Cardiovascular</topic><topic>Cardiovascular Diseases - genetics</topic><topic>Cardiovascular system</topic><topic>Cells, Cultured</topic><topic>Cross-Sectional Studies</topic><topic>Endothelial Cells - metabolism</topic><topic>Endothelium, Vascular - metabolism</topic><topic>Female</topic><topic>Genetic susceptibility</topic><topic>Humans</topic><topic>Insulin - genetics</topic><topic>Insulin dependent endothelial function</topic><topic>Insulin Resistance - genetics</topic><topic>Insulin sensitivity</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Nonsynonymous polymorphism</topic><topic>Pharmacology. Drug treatments</topic><topic>Prospective Studies</topic><topic>Signal Transduction - genetics</topic><topic>Vasodilator agents. Cerebral vasodilators</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bacci, Simonetta</creatorcontrib><creatorcontrib>Prudente, Sabrina</creatorcontrib><creatorcontrib>Copetti, Massimiliano</creatorcontrib><creatorcontrib>Spoto, Belinda</creatorcontrib><creatorcontrib>Rizza, Stefano</creatorcontrib><creatorcontrib>Baratta, Roberto</creatorcontrib><creatorcontrib>Di Pietro, Natalia</creatorcontrib><creatorcontrib>Morini, Eleonora</creatorcontrib><creatorcontrib>Di Paola, Rosa</creatorcontrib><creatorcontrib>Testa, Alessandra</creatorcontrib><creatorcontrib>Mallamaci, Francesca</creatorcontrib><creatorcontrib>Tripepi, Giovanni</creatorcontrib><creatorcontrib>Zhang, Yuan-Yuan</creatorcontrib><creatorcontrib>Mercuri, Luana</creatorcontrib><creatorcontrib>Di Silvestre, Sara</creatorcontrib><creatorcontrib>Lauro, Renato</creatorcontrib><creatorcontrib>Malatino, Lorenzo</creatorcontrib><creatorcontrib>Consoli, Agostino</creatorcontrib><creatorcontrib>Pellegrini, Fabio</creatorcontrib><creatorcontrib>Pandolfi, Assunta</creatorcontrib><creatorcontrib>Frittitta, Lucia</creatorcontrib><creatorcontrib>Zoccali, Carmine</creatorcontrib><creatorcontrib>Federici, Massimo</creatorcontrib><creatorcontrib>Doria, Alessandro</creatorcontrib><creatorcontrib>Trischitta, Vincenzo</creatorcontrib><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>PubMed Central (Full Participant titles)</collection><jtitle>Atherosclerosis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bacci, Simonetta</au><au>Prudente, Sabrina</au><au>Copetti, Massimiliano</au><au>Spoto, Belinda</au><au>Rizza, Stefano</au><au>Baratta, Roberto</au><au>Di Pietro, Natalia</au><au>Morini, Eleonora</au><au>Di Paola, Rosa</au><au>Testa, Alessandra</au><au>Mallamaci, Francesca</au><au>Tripepi, Giovanni</au><au>Zhang, Yuan-Yuan</au><au>Mercuri, Luana</au><au>Di Silvestre, Sara</au><au>Lauro, Renato</au><au>Malatino, Lorenzo</au><au>Consoli, Agostino</au><au>Pellegrini, Fabio</au><au>Pandolfi, Assunta</au><au>Frittitta, Lucia</au><au>Zoccali, Carmine</au><au>Federici, Massimo</au><au>Doria, Alessandro</au><au>Trischitta, Vincenzo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Joint effect of insulin signaling genes on cardiovascular events and on whole body and endothelial insulin resistance</atitle><jtitle>Atherosclerosis</jtitle><addtitle>Atherosclerosis</addtitle><date>2013-01-01</date><risdate>2013</risdate><volume>226</volume><issue>1</issue><spage>140</spage><epage>145</epage><pages>140-145</pages><issn>0021-9150</issn><eissn>1879-1484</eissn><abstract>Abstract Objective Insulin resistance (IR) and cardiovascular disease (CVD) share a common soil. We investigated the combined role of single nucleotide polymorphisms (SNPs) affecting insulin signaling ( ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on CVD, age at myocardial infarction (MI), in vivo insulin sensitivity and in vitro insulin-stimulated nitric oxide synthase (NOS) activity. Design and setting 1. We first studied, incident cardiovascular events (a composite endpoint comprising myocardial infarction-MI, stroke and cardiovascular death) in 733 patients (2186 person-years, 175 events). 2. In a replication attempt, age at MI was tested in 331 individuals. 3. OGTT-derived insulin sensitivity index (ISI) was assessed in 829 individuals with fasting glucose <126 mg/dl. 4. NOS activity was measured in 40 strains of human vein endothelial cells (HUVECs). Results 1. Risk variants jointly predicted cardiovascular events (HR = 1.181; p = 0.0009) and, when added to clinical risk factors, significantly improved survival C-statistics; they also allowed a significantly correct reclassification (by net reclassification index) in the whole sample (135/733 individuals) and, even more, in obese patients (116/204 individuals). 2. Risk variants were jointly associated with age at MI ( p = 0.006). 3. A significant association was also observed with ISI ( p = 0.02). 4. Finally, risk variants were jointly associated with insulin-stimulated NOS activity in HUVECs ( p = 0.009). Conclusions Insulin signaling genes variants jointly affect cardiovascular disease, very likely by promoting whole body and endothelium-specific insulin resistance. Further studies are needed to address whether their genotyping help identify very high-risk patients who need specific and/or more aggressive preventive strategies.</abstract><cop>Amsterdam</cop><pub>Elsevier Ireland Ltd</pub><pmid>23107043</pmid><doi>10.1016/j.atherosclerosis.2012.10.035</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Atherosclerosis, 2013-01, Vol.226 (1), p.140-145 |
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| subjects | Atherosclerosis (general aspects, experimental research) Biological and medical sciences Blood and lymphatic vessels Cardiology. Vascular system Cardiovascular Cardiovascular Diseases - genetics Cardiovascular system Cells, Cultured Cross-Sectional Studies Endothelial Cells - metabolism Endothelium, Vascular - metabolism Female Genetic susceptibility Humans Insulin - genetics Insulin dependent endothelial function Insulin Resistance - genetics Insulin sensitivity Male Medical sciences Nonsynonymous polymorphism Pharmacology. Drug treatments Prospective Studies Signal Transduction - genetics Vasodilator agents. Cerebral vasodilators |
| title | Joint effect of insulin signaling genes on cardiovascular events and on whole body and endothelial insulin resistance |
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