Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study
Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study Allison B. Lehtinen 1 2 , Christopher Newton-Cheh 3 4 , Julie T. Ziegler 5 , Carl D. Langefeld 5 , Barry I. Freedman 6 , Kurt R. Daniel 6 , David M. Herrington 6 and Donald W. Bowden 1 2 6 1 De...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2008-04, Vol.57 (4), p.1108-1114 |
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| creator | LEHTINEN, Allison B NEWTON-CHEH, Christopher ZIEGLER, Julie T LANGEFELD, Carl D FREEDMAN, Barry I DANIEL, Kurt R HERRINGTON, David M BOWDEN, Donald W |
| description | Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study
Allison B. Lehtinen 1 2 ,
Christopher Newton-Cheh 3 4 ,
Julie T. Ziegler 5 ,
Carl D. Langefeld 5 ,
Barry I. Freedman 6 ,
Kurt R. Daniel 6 ,
David M. Herrington 6 and
Donald W. Bowden 1 2 6
1 Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina
2 Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
3 Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts
4 Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
5 Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
6 Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
Address correspondence and reprint requests to Donald W. Bowden, PhD, Department of Biochemistry, Wake Forest University School
of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail: dbowden{at}wfubmc.edu
Abstract
OBJECTIVES— Prolongation of the electrocardiographic QT interval is a risk factor for sudden cardiac death (SCD). Diabetic individuals
are at increased risk for prolonged QT interval and SCD. We sought to replicate the finding that genetic variants in the nitric
oxide synthase 1 adaptor protein ( NOS1AP ) gene are associated with QT interval duration in a type 2 diabetes–enriched sample of European ancestry.
RESEARCH DESIGN AND METHODS— Two single nucleotide polymorphisms (SNPs) in NOS1AP were genotyped in 624 European Americans and 127 African Americans from 400 pedigrees enriched for type 2 diabetes. An additive
genetic model was tested for each SNP in ancestry-specific analyses in the total sample and the diabetic subset (European
Americans, n = 514; African Americans, n = 115), excluding from the analyses individuals taking QT-altering medications.
RESULTS— In European Americans, rs10494366 minor homozygotes had a 9.3-ms-longer QT interval compared with major homozygotes ( P = 5.7 × 10 −5 ); rs10918594 minor homozygotes had a 12.5-ms-longer QT interval compared with major homozygotes ( P = 1.5 × 10 −6 ). Restricting analyses to the diabetic European Americans strengthened the effect despite the reduction in sample size (11.3-ms
difference, P = 5.1 × 10 −5 ; 13.9-ms difference, P = 1.6 × 10 −6 , respectively). No association between the N |
| doi_str_mv | 10.2337/db07-1365 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_gale_incontextgauss_8GL_A177721300</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A177721300</galeid><sourcerecordid>A177721300</sourcerecordid><originalsourceid>FETCH-LOGICAL-c643t-f5cb160b8b09cefc36c237a260c8177cc82c41ea7565d5888d39c70d94ac45fe3</originalsourceid><addsrcrecordid>eNp9kl1v0zAUhiMEYmNwwR9AFggkhDL8kcTODVLV0W5SRUEbH3eW4zipq8QetjPYv8dRo42iCvnC1vFzXp_j8ybJcwRPMSH0fV1BmiJS5A-SY1SSMiWY_niYHEOIcIpoSY-SJ95vIYRFXI-TI8QwySFhx8l25r2VWgRtDbAN-LS-RLPPYKmMClqCb8JpYYIH33XYgC9X4MIE5W5EB84Gt0vSBixErzutPFg424OwUeBMi0qFGDlXwgVwGYb69mnyqBGdV8-m_ST5uvh4NT9PV-vlxXy2SmWRkZA2uaxQAStWwVKqRpJCYkIFLqBkiFIpGZYZUoLmRV7njLGalJLCusyEzPJGkZPkw073eqh6VUtlghMdv3a6F-6WW6H5_o3RG97aG16WRYnKIgq8mQSc_TkoH3ivvVRdJ4yyg-cUZjmCkEbw5T_g1g7OxOY4RkXGGC5hhF7toFZ0imvT2PioHBX5LPZDMSJwpNIDVBvHECu0RjU6hvf40wN8XLXqtTyY8HYvITJB_Q6tGLznbLn6XzETK23XqVbxOK35-qC2dNZ7p5q7z0aQjw7lo0P56NDIvvh7OvfkZMkIvJ4A4aXoGieM1P6OwxBjhtD4-e923Ea3m1_aKV5Pprs_5JRnHCHIyB_hk_hk</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>216488290</pqid></control><display><type>article</type><title>Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><creator>LEHTINEN, Allison B ; NEWTON-CHEH, Christopher ; ZIEGLER, Julie T ; LANGEFELD, Carl D ; FREEDMAN, Barry I ; DANIEL, Kurt R ; HERRINGTON, David M ; BOWDEN, Donald W</creator><creatorcontrib>LEHTINEN, Allison B ; NEWTON-CHEH, Christopher ; ZIEGLER, Julie T ; LANGEFELD, Carl D ; FREEDMAN, Barry I ; DANIEL, Kurt R ; HERRINGTON, David M ; BOWDEN, Donald W</creatorcontrib><description>Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study
Allison B. Lehtinen 1 2 ,
Christopher Newton-Cheh 3 4 ,
Julie T. Ziegler 5 ,
Carl D. Langefeld 5 ,
Barry I. Freedman 6 ,
Kurt R. Daniel 6 ,
David M. Herrington 6 and
Donald W. Bowden 1 2 6
1 Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina
2 Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
3 Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts
4 Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
5 Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
6 Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
Address correspondence and reprint requests to Donald W. Bowden, PhD, Department of Biochemistry, Wake Forest University School
of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail: dbowden{at}wfubmc.edu
Abstract
OBJECTIVES— Prolongation of the electrocardiographic QT interval is a risk factor for sudden cardiac death (SCD). Diabetic individuals
are at increased risk for prolonged QT interval and SCD. We sought to replicate the finding that genetic variants in the nitric
oxide synthase 1 adaptor protein ( NOS1AP ) gene are associated with QT interval duration in a type 2 diabetes–enriched sample of European ancestry.
RESEARCH DESIGN AND METHODS— Two single nucleotide polymorphisms (SNPs) in NOS1AP were genotyped in 624 European Americans and 127 African Americans from 400 pedigrees enriched for type 2 diabetes. An additive
genetic model was tested for each SNP in ancestry-specific analyses in the total sample and the diabetic subset (European
Americans, n = 514; African Americans, n = 115), excluding from the analyses individuals taking QT-altering medications.
RESULTS— In European Americans, rs10494366 minor homozygotes had a 9.3-ms-longer QT interval compared with major homozygotes ( P = 5.7 × 10 −5 ); rs10918594 minor homozygotes had a 12.5-ms-longer QT interval compared with major homozygotes ( P = 1.5 × 10 −6 ). Restricting analyses to the diabetic European Americans strengthened the effect despite the reduction in sample size (11.3-ms
difference, P = 5.1 × 10 −5 ; 13.9-ms difference, P = 1.6 × 10 −6 , respectively). No association between the NOS1AP SNPs and QT interval duration was observed in the limited number of African Americans.
CONCLUSIONS— Two NOS1AP SNPs are strongly associated with QT interval duration in a predominately diabetic European-American sample. Stronger effects
of NOS1AP variants in diabetic individuals suggest that this patient subset may be particularly susceptible to genetic variants that
influence myocardial depolarization and repolarization as manifest in the QT interval.
ECG, electrocardiogram
NOS1AP, nitric oxide synthase 1 adaptor protein
QTc, corrected QT interval
SCD, sudden cardiac death
SNP, single nucleotide polymorphism
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 30 January 2008. DOI: 10.2337/db07-1365.
A.B.L. and C.N.-C. contributed equally to this work.
Additional information can be found in an online appendix at http://dx.doi.org/10.2337/db07-1365 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted January 10, 2008.
Received September 25, 2007.
DIABETES</description><identifier>ISSN: 0012-1797</identifier><identifier>ISSN: 1939-327X</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db07-1365</identifier><identifier>PMID: 18235038</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>Alexandria, VA: American Diabetes Association</publisher><subject>Adaptor Proteins, Signal Transducing - genetics ; African Americans ; Aged ; Biological and medical sciences ; Black or African American ; Black People - genetics ; Body Mass Index ; Cardiac arrest ; Complications and side effects ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Type 2 - enzymology ; Diabetes Mellitus, Type 2 - genetics ; Diabetes. Impaired glucose tolerance ; Diabetic Angiopathies - enzymology ; Diabetic Angiopathies - genetics ; DNA - blood ; DNA - genetics ; DNA - isolation & purification ; Electrocardiography ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Female ; Genetic aspects ; Genetic Variation ; Genotype ; Health aspects ; Heart attacks ; Heart rate ; Hormone replacement therapy ; Humans ; Long QT Syndrome - genetics ; Long QT Syndrome - physiopathology ; Male ; Medical sciences ; Middle Aged ; Myocardial Infarction - enzymology ; Myocardial Infarction - genetics ; Nitric oxide ; Polymorphism, Single Nucleotide ; Proteins ; Reference Values ; Research design ; Risk factors ; Sudden cardiac death ; White People - genetics</subject><ispartof>Diabetes (New York, N.Y.), 2008-04, Vol.57 (4), p.1108-1114</ispartof><rights>2008 INIST-CNRS</rights><rights>COPYRIGHT 2008 American Diabetes Association</rights><rights>Copyright American Diabetes Association Apr 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c643t-f5cb160b8b09cefc36c237a260c8177cc82c41ea7565d5888d39c70d94ac45fe3</citedby><cites>FETCH-LOGICAL-c643t-f5cb160b8b09cefc36c237a260c8177cc82c41ea7565d5888d39c70d94ac45fe3</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/PMC9969196/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9969196/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20228117$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18235038$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>LEHTINEN, Allison B</creatorcontrib><creatorcontrib>NEWTON-CHEH, Christopher</creatorcontrib><creatorcontrib>ZIEGLER, Julie T</creatorcontrib><creatorcontrib>LANGEFELD, Carl D</creatorcontrib><creatorcontrib>FREEDMAN, Barry I</creatorcontrib><creatorcontrib>DANIEL, Kurt R</creatorcontrib><creatorcontrib>HERRINGTON, David M</creatorcontrib><creatorcontrib>BOWDEN, Donald W</creatorcontrib><title>Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study
Allison B. Lehtinen 1 2 ,
Christopher Newton-Cheh 3 4 ,
Julie T. Ziegler 5 ,
Carl D. Langefeld 5 ,
Barry I. Freedman 6 ,
Kurt R. Daniel 6 ,
David M. Herrington 6 and
Donald W. Bowden 1 2 6
1 Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina
2 Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
3 Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts
4 Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
5 Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
6 Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
Address correspondence and reprint requests to Donald W. Bowden, PhD, Department of Biochemistry, Wake Forest University School
of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail: dbowden{at}wfubmc.edu
Abstract
OBJECTIVES— Prolongation of the electrocardiographic QT interval is a risk factor for sudden cardiac death (SCD). Diabetic individuals
are at increased risk for prolonged QT interval and SCD. We sought to replicate the finding that genetic variants in the nitric
oxide synthase 1 adaptor protein ( NOS1AP ) gene are associated with QT interval duration in a type 2 diabetes–enriched sample of European ancestry.
RESEARCH DESIGN AND METHODS— Two single nucleotide polymorphisms (SNPs) in NOS1AP were genotyped in 624 European Americans and 127 African Americans from 400 pedigrees enriched for type 2 diabetes. An additive
genetic model was tested for each SNP in ancestry-specific analyses in the total sample and the diabetic subset (European
Americans, n = 514; African Americans, n = 115), excluding from the analyses individuals taking QT-altering medications.
RESULTS— In European Americans, rs10494366 minor homozygotes had a 9.3-ms-longer QT interval compared with major homozygotes ( P = 5.7 × 10 −5 ); rs10918594 minor homozygotes had a 12.5-ms-longer QT interval compared with major homozygotes ( P = 1.5 × 10 −6 ). Restricting analyses to the diabetic European Americans strengthened the effect despite the reduction in sample size (11.3-ms
difference, P = 5.1 × 10 −5 ; 13.9-ms difference, P = 1.6 × 10 −6 , respectively). No association between the NOS1AP SNPs and QT interval duration was observed in the limited number of African Americans.
CONCLUSIONS— Two NOS1AP SNPs are strongly associated with QT interval duration in a predominately diabetic European-American sample. Stronger effects
of NOS1AP variants in diabetic individuals suggest that this patient subset may be particularly susceptible to genetic variants that
influence myocardial depolarization and repolarization as manifest in the QT interval.
ECG, electrocardiogram
NOS1AP, nitric oxide synthase 1 adaptor protein
QTc, corrected QT interval
SCD, sudden cardiac death
SNP, single nucleotide polymorphism
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 30 January 2008. DOI: 10.2337/db07-1365.
A.B.L. and C.N.-C. contributed equally to this work.
Additional information can be found in an online appendix at http://dx.doi.org/10.2337/db07-1365 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted January 10, 2008.
Received September 25, 2007.
DIABETES</description><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>African Americans</subject><subject>Aged</subject><subject>Biological and medical sciences</subject><subject>Black or African American</subject><subject>Black People - genetics</subject><subject>Body Mass Index</subject><subject>Cardiac arrest</subject><subject>Complications and side effects</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Type 2 - enzymology</subject><subject>Diabetes Mellitus, Type 2 - genetics</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Diabetic Angiopathies - enzymology</subject><subject>Diabetic Angiopathies - genetics</subject><subject>DNA - blood</subject><subject>DNA - genetics</subject><subject>DNA - isolation & purification</subject><subject>Electrocardiography</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Female</subject><subject>Genetic aspects</subject><subject>Genetic Variation</subject><subject>Genotype</subject><subject>Health aspects</subject><subject>Heart attacks</subject><subject>Heart rate</subject><subject>Hormone replacement therapy</subject><subject>Humans</subject><subject>Long QT Syndrome - genetics</subject><subject>Long QT Syndrome - physiopathology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Myocardial Infarction - enzymology</subject><subject>Myocardial Infarction - genetics</subject><subject>Nitric oxide</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Proteins</subject><subject>Reference Values</subject><subject>Research design</subject><subject>Risk factors</subject><subject>Sudden cardiac death</subject><subject>White People - genetics</subject><issn>0012-1797</issn><issn>1939-327X</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kl1v0zAUhiMEYmNwwR9AFggkhDL8kcTODVLV0W5SRUEbH3eW4zipq8QetjPYv8dRo42iCvnC1vFzXp_j8ybJcwRPMSH0fV1BmiJS5A-SY1SSMiWY_niYHEOIcIpoSY-SJ95vIYRFXI-TI8QwySFhx8l25r2VWgRtDbAN-LS-RLPPYKmMClqCb8JpYYIH33XYgC9X4MIE5W5EB84Gt0vSBixErzutPFg424OwUeBMi0qFGDlXwgVwGYb69mnyqBGdV8-m_ST5uvh4NT9PV-vlxXy2SmWRkZA2uaxQAStWwVKqRpJCYkIFLqBkiFIpGZYZUoLmRV7njLGalJLCusyEzPJGkZPkw073eqh6VUtlghMdv3a6F-6WW6H5_o3RG97aG16WRYnKIgq8mQSc_TkoH3ivvVRdJ4yyg-cUZjmCkEbw5T_g1g7OxOY4RkXGGC5hhF7toFZ0imvT2PioHBX5LPZDMSJwpNIDVBvHECu0RjU6hvf40wN8XLXqtTyY8HYvITJB_Q6tGLznbLn6XzETK23XqVbxOK35-qC2dNZ7p5q7z0aQjw7lo0P56NDIvvh7OvfkZMkIvJ4A4aXoGieM1P6OwxBjhtD4-e923Ea3m1_aKV5Pprs_5JRnHCHIyB_hk_hk</recordid><startdate>20080401</startdate><enddate>20080401</enddate><creator>LEHTINEN, Allison B</creator><creator>NEWTON-CHEH, Christopher</creator><creator>ZIEGLER, Julie T</creator><creator>LANGEFELD, Carl D</creator><creator>FREEDMAN, Barry I</creator><creator>DANIEL, Kurt R</creator><creator>HERRINGTON, David M</creator><creator>BOWDEN, Donald W</creator><general>American Diabetes Association</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>8GL</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7P</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>S0X</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20080401</creationdate><title>Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study</title><author>LEHTINEN, Allison B ; NEWTON-CHEH, Christopher ; ZIEGLER, Julie T ; LANGEFELD, Carl D ; FREEDMAN, Barry I ; DANIEL, Kurt R ; HERRINGTON, David M ; BOWDEN, Donald W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c643t-f5cb160b8b09cefc36c237a260c8177cc82c41ea7565d5888d39c70d94ac45fe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>African Americans</topic><topic>Aged</topic><topic>Biological and medical sciences</topic><topic>Black or African American</topic><topic>Black People - genetics</topic><topic>Body Mass Index</topic><topic>Cardiac arrest</topic><topic>Complications and side effects</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Type 2 - enzymology</topic><topic>Diabetes Mellitus, Type 2 - genetics</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Diabetic Angiopathies - enzymology</topic><topic>Diabetic Angiopathies - genetics</topic><topic>DNA - blood</topic><topic>DNA - genetics</topic><topic>DNA - isolation & purification</topic><topic>Electrocardiography</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>Female</topic><topic>Genetic aspects</topic><topic>Genetic Variation</topic><topic>Genotype</topic><topic>Health aspects</topic><topic>Heart attacks</topic><topic>Heart rate</topic><topic>Hormone replacement therapy</topic><topic>Humans</topic><topic>Long QT Syndrome - genetics</topic><topic>Long QT Syndrome - physiopathology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Myocardial Infarction - enzymology</topic><topic>Myocardial Infarction - genetics</topic><topic>Nitric oxide</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Proteins</topic><topic>Reference Values</topic><topic>Research design</topic><topic>Risk factors</topic><topic>Sudden cardiac death</topic><topic>White People - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>LEHTINEN, Allison B</creatorcontrib><creatorcontrib>NEWTON-CHEH, Christopher</creatorcontrib><creatorcontrib>ZIEGLER, Julie T</creatorcontrib><creatorcontrib>LANGEFELD, Carl D</creatorcontrib><creatorcontrib>FREEDMAN, Barry I</creatorcontrib><creatorcontrib>DANIEL, Kurt R</creatorcontrib><creatorcontrib>HERRINGTON, David M</creatorcontrib><creatorcontrib>BOWDEN, Donald W</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>Gale In Context: High School</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech 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>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>LEHTINEN, Allison B</au><au>NEWTON-CHEH, Christopher</au><au>ZIEGLER, Julie T</au><au>LANGEFELD, Carl D</au><au>FREEDMAN, Barry I</au><au>DANIEL, Kurt R</au><au>HERRINGTON, David M</au><au>BOWDEN, Donald W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2008-04-01</date><risdate>2008</risdate><volume>57</volume><issue>4</issue><spage>1108</spage><epage>1114</epage><pages>1108-1114</pages><issn>0012-1797</issn><issn>1939-327X</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study
Allison B. Lehtinen 1 2 ,
Christopher Newton-Cheh 3 4 ,
Julie T. Ziegler 5 ,
Carl D. Langefeld 5 ,
Barry I. Freedman 6 ,
Kurt R. Daniel 6 ,
David M. Herrington 6 and
Donald W. Bowden 1 2 6
1 Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina
2 Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
3 Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts
4 Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
5 Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
6 Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
Address correspondence and reprint requests to Donald W. Bowden, PhD, Department of Biochemistry, Wake Forest University School
of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail: dbowden{at}wfubmc.edu
Abstract
OBJECTIVES— Prolongation of the electrocardiographic QT interval is a risk factor for sudden cardiac death (SCD). Diabetic individuals
are at increased risk for prolonged QT interval and SCD. We sought to replicate the finding that genetic variants in the nitric
oxide synthase 1 adaptor protein ( NOS1AP ) gene are associated with QT interval duration in a type 2 diabetes–enriched sample of European ancestry.
RESEARCH DESIGN AND METHODS— Two single nucleotide polymorphisms (SNPs) in NOS1AP were genotyped in 624 European Americans and 127 African Americans from 400 pedigrees enriched for type 2 diabetes. An additive
genetic model was tested for each SNP in ancestry-specific analyses in the total sample and the diabetic subset (European
Americans, n = 514; African Americans, n = 115), excluding from the analyses individuals taking QT-altering medications.
RESULTS— In European Americans, rs10494366 minor homozygotes had a 9.3-ms-longer QT interval compared with major homozygotes ( P = 5.7 × 10 −5 ); rs10918594 minor homozygotes had a 12.5-ms-longer QT interval compared with major homozygotes ( P = 1.5 × 10 −6 ). Restricting analyses to the diabetic European Americans strengthened the effect despite the reduction in sample size (11.3-ms
difference, P = 5.1 × 10 −5 ; 13.9-ms difference, P = 1.6 × 10 −6 , respectively). No association between the NOS1AP SNPs and QT interval duration was observed in the limited number of African Americans.
CONCLUSIONS— Two NOS1AP SNPs are strongly associated with QT interval duration in a predominately diabetic European-American sample. Stronger effects
of NOS1AP variants in diabetic individuals suggest that this patient subset may be particularly susceptible to genetic variants that
influence myocardial depolarization and repolarization as manifest in the QT interval.
ECG, electrocardiogram
NOS1AP, nitric oxide synthase 1 adaptor protein
QTc, corrected QT interval
SCD, sudden cardiac death
SNP, single nucleotide polymorphism
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 30 January 2008. DOI: 10.2337/db07-1365.
A.B.L. and C.N.-C. contributed equally to this work.
Additional information can be found in an online appendix at http://dx.doi.org/10.2337/db07-1365 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted January 10, 2008.
Received September 25, 2007.
DIABETES</abstract><cop>Alexandria, VA</cop><pub>American Diabetes Association</pub><pmid>18235038</pmid><doi>10.2337/db07-1365</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0012-1797 |
| ispartof | Diabetes (New York, N.Y.), 2008-04, Vol.57 (4), p.1108-1114 |
| issn | 0012-1797 1939-327X 1939-327X |
| language | eng |
| recordid | cdi_gale_incontextgauss_8GL_A177721300 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Adaptor Proteins, Signal Transducing - genetics African Americans Aged Biological and medical sciences Black or African American Black People - genetics Body Mass Index Cardiac arrest Complications and side effects Diabetes Diabetes mellitus Diabetes Mellitus, Type 2 - enzymology Diabetes Mellitus, Type 2 - genetics Diabetes. Impaired glucose tolerance Diabetic Angiopathies - enzymology Diabetic Angiopathies - genetics DNA - blood DNA - genetics DNA - isolation & purification Electrocardiography Endocrine pancreas. Apud cells (diseases) Endocrinopathies Etiopathogenesis. Screening. Investigations. Target tissue resistance Female Genetic aspects Genetic Variation Genotype Health aspects Heart attacks Heart rate Hormone replacement therapy Humans Long QT Syndrome - genetics Long QT Syndrome - physiopathology Male Medical sciences Middle Aged Myocardial Infarction - enzymology Myocardial Infarction - genetics Nitric oxide Polymorphism, Single Nucleotide Proteins Reference Values Research design Risk factors Sudden cardiac death White People - genetics |
| title | Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study |
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