Extension of Type 2 Diabetes Genome-Wide Association Scan Results in the Diabetes Prevention Program
Extension of Type 2 Diabetes Genome-Wide Association Scan Results in the Diabetes Prevention Program Allan F. Moore 1 2 3 4 † , Kathleen A. Jablonski 5 , Jarred B. McAteer 1 4 , Richa Saxena 1 4 , Toni I. Pollin 6 , Paul W. Franks 7 , Robert L. Hanson 8 , Alan R. Shuldiner 6 , William C. Knowler 8 ,...
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| creator | MOORE, Allan F JABLONSKI, Kathleen A FLOREZ, Jose C MCATEER, Jarred B SAXENA, Richa POLLIN, Toni I FRANKS, Paul W HANSON, Robert L SHULDINER, Alan R KNOWLER, William C ALTSHULER, David |
| description | Extension of Type 2 Diabetes Genome-Wide Association Scan Results in the Diabetes Prevention Program
Allan F. Moore 1 2 3 4 † ,
Kathleen A. Jablonski 5 ,
Jarred B. McAteer 1 4 ,
Richa Saxena 1 4 ,
Toni I. Pollin 6 ,
Paul W. Franks 7 ,
Robert L. Hanson 8 ,
Alan R. Shuldiner 6 ,
William C. Knowler 8 ,
David Altshuler 1 2 3 4 9 ,
Jose C. Florez 1 2 3 4 and
for the Diabetes Prevention Program Research Group
1 Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
2 Diabetes Center, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
3 Department of Medicine, Harvard Medical School, Boston, Massachusetts
4 Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge,
Massachusetts
5 The Biostatistics Center, George Washington University, Rockville, Maryland
6 Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore,
Maryland
7 Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Division of Medicine,
Umeå University Hospital, Umeå, Sweden
8 Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix,
Arizona
9 Department of Genetics, Harvard Medical School, Boston, Massachusetts
Corresponding author: Jose C. Florez, dppmail{at}biostat.bsc.gwu.edu
Abstract
OBJECTIVE— Genome-wide association scans (GWASs) have identified novel diabetes-associated genes. We evaluated how these variants impact
diabetes incidence, quantitative glycemic traits, and response to preventive interventions in 3,548 subjects at high risk
of type 2 diabetes enrolled in the Diabetes Prevention Program (DPP), which examined the effects of lifestyle intervention,
metformin, and troglitazone versus placebo.
RESEARCH DESIGN AND METHODS— We genotyped selected single nucleotide polymorphisms (SNPs) in or near diabetes-associated loci, including EXT2 , CDKAL1 , CDKN2A/B , IGF2BP2 , HHEX , LOC387761, and SLC30A8 in DPP participants and performed Cox regression analyses using genotype, intervention, and their interactions as predictors
of diabetes incidence. We evaluated their effect on insulin resistance and secretion at 1 year.
RESULTS— None of the selected SNPs were associated with increased diabetes incidence in this population. After adjustments for ethnicity,
baselin |
| doi_str_mv | 10.2337/db08-0284 |
| format | Article |
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Allan F. Moore 1 2 3 4 † ,
Kathleen A. Jablonski 5 ,
Jarred B. McAteer 1 4 ,
Richa Saxena 1 4 ,
Toni I. Pollin 6 ,
Paul W. Franks 7 ,
Robert L. Hanson 8 ,
Alan R. Shuldiner 6 ,
William C. Knowler 8 ,
David Altshuler 1 2 3 4 9 ,
Jose C. Florez 1 2 3 4 and
for the Diabetes Prevention Program Research Group
1 Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
2 Diabetes Center, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
3 Department of Medicine, Harvard Medical School, Boston, Massachusetts
4 Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge,
Massachusetts
5 The Biostatistics Center, George Washington University, Rockville, Maryland
6 Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore,
Maryland
7 Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Division of Medicine,
Umeå University Hospital, Umeå, Sweden
8 Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix,
Arizona
9 Department of Genetics, Harvard Medical School, Boston, Massachusetts
Corresponding author: Jose C. Florez, dppmail{at}biostat.bsc.gwu.edu
Abstract
OBJECTIVE— Genome-wide association scans (GWASs) have identified novel diabetes-associated genes. We evaluated how these variants impact
diabetes incidence, quantitative glycemic traits, and response to preventive interventions in 3,548 subjects at high risk
of type 2 diabetes enrolled in the Diabetes Prevention Program (DPP), which examined the effects of lifestyle intervention,
metformin, and troglitazone versus placebo.
RESEARCH DESIGN AND METHODS— We genotyped selected single nucleotide polymorphisms (SNPs) in or near diabetes-associated loci, including EXT2 , CDKAL1 , CDKN2A/B , IGF2BP2 , HHEX , LOC387761, and SLC30A8 in DPP participants and performed Cox regression analyses using genotype, intervention, and their interactions as predictors
of diabetes incidence. We evaluated their effect on insulin resistance and secretion at 1 year.
RESULTS— None of the selected SNPs were associated with increased diabetes incidence in this population. After adjustments for ethnicity,
baseline insulin secretion was lower in subjects with the risk genotype at HHEX rs1111875 ( P = 0.01); there were no significant differences in baseline insulin sensitivity. Both at baseline and at 1 year, subjects
with the risk genotype at LOC387761 had paradoxically increased insulin secretion; adjustment for self-reported ethnicity
abolished these differences. In ethnicity-adjusted analyses, we noted a nominal differential improvement in β-cell function
for carriers of the protective genotype at CDKN2A/B after 1 year of troglitazone treatment ( P = 0.01) and possibly lifestyle modification ( P = 0.05).
CONCLUSIONS— We were unable to replicate the GWAS findings regarding diabetes risk in the DPP. We did observe genotype associations with
differences in baseline insulin secretion at the HHEX locus and a possible pharmacogenetic interaction at CDKNA2/B .
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 10 June 2008.
Clinical trial reg. no. NCT00004992, clinicaltrials.gov.
A complete list of Diabetes Prevention Program Research Group investigators is provided in the online appendix available at
http://dx.doi.org/10.2337/db08-0284 .
†
† Dr. Allan F. Moore passed away on 24 July 2008. This article, to which he contributed his privileged intellect and unwavering
enthusiasm, is dedicated to his memory. His colleagues and peers will miss him.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
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 June 1, 2008.
Received February 28, 2008.
DIABETES</description><identifier>ISSN: 0012-1797</identifier><identifier>ISSN: 1939-327X</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db08-0284</identifier><identifier>PMID: 18544707</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>Alexandria, VA: American Diabetes Association</publisher><subject>African Americans - genetics ; African Americans - statistics & numerical data ; beta-cell function ; Biological and medical sciences ; Cation Transport Proteins - genetics ; CDKAL1 ; Cellular signal transduction ; Cyclin-Dependent Kinase 5 - genetics ; Cyclin-Dependent Kinase Inhibitor p15 - genetics ; Cyclin-Dependent Kinase Inhibitor p16 - genetics ; Diabetes ; Diabetes Mellitus, Type 2 - ethnology ; Diabetes Mellitus, Type 2 - genetics ; Diabetes Mellitus, Type 2 - prevention & control ; Diabetes. Impaired glucose tolerance ; Disease prevention ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Ethnicity ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; European Continental Ancestry Group - genetics ; European Continental Ancestry Group - statistics & numerical data ; Gene Frequency ; Genes ; Genetics ; Genomes ; Genomics ; Genotype & phenotype ; Glucose ; glucose tolerance ; Health aspects ; Hispanic Americans ; Homeodomain Proteins - genetics ; Humans ; Incidence ; Insulin resistance ; Life Style ; Lifestyles ; loci ; Medical sciences ; Middle Aged ; N-Acetylglucosaminyltransferases - genetics ; Physiological aspects ; Polymorphism, Single Nucleotide ; polymorphisms ; Prevention ; Prevention programs ; Quantitative Trait Loci ; Research design ; Risk Factors ; RNA-Binding Proteins - genetics ; secretion ; susceptibility ; Transcription Factors - genetics ; tRNA Methyltransferases ; Type 2 diabetes ; variants ; Wellness programs ; Zinc Transporter 8</subject><ispartof>Diabetes (New York, N.Y.), 2008-09, Vol.57 (9), p.2503-2510</ispartof><rights>2008 INIST-CNRS</rights><rights>COPYRIGHT 2008 American Diabetes Association</rights><rights>Copyright American Diabetes Association Sep 2008</rights><rights>Copyright © 2008, American Diabetes Association</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c782t-d8d8a3b258efcc850fdc1e58e9ce27a7400c4f17f150bcd253421bf4b3486c713</citedby><cites>FETCH-LOGICAL-c782t-d8d8a3b258efcc850fdc1e58e9ce27a7400c4f17f150bcd253421bf4b3486c713</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/PMC2518503/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518503/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,887,27931,27932,53798,53800</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20623323$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18544707$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-19086$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>MOORE, Allan F</creatorcontrib><creatorcontrib>JABLONSKI, Kathleen A</creatorcontrib><creatorcontrib>FLOREZ, Jose C</creatorcontrib><creatorcontrib>MCATEER, Jarred B</creatorcontrib><creatorcontrib>SAXENA, Richa</creatorcontrib><creatorcontrib>POLLIN, Toni I</creatorcontrib><creatorcontrib>FRANKS, Paul W</creatorcontrib><creatorcontrib>HANSON, Robert L</creatorcontrib><creatorcontrib>SHULDINER, Alan R</creatorcontrib><creatorcontrib>KNOWLER, William C</creatorcontrib><creatorcontrib>ALTSHULER, David</creatorcontrib><creatorcontrib>Diabetes Prevention Program Research Group</creatorcontrib><creatorcontrib>for the Diabetes Prevention Program Research Group</creatorcontrib><title>Extension of Type 2 Diabetes Genome-Wide Association Scan Results in the Diabetes Prevention Program</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Extension of Type 2 Diabetes Genome-Wide Association Scan Results in the Diabetes Prevention Program
Allan F. Moore 1 2 3 4 † ,
Kathleen A. Jablonski 5 ,
Jarred B. McAteer 1 4 ,
Richa Saxena 1 4 ,
Toni I. Pollin 6 ,
Paul W. Franks 7 ,
Robert L. Hanson 8 ,
Alan R. Shuldiner 6 ,
William C. Knowler 8 ,
David Altshuler 1 2 3 4 9 ,
Jose C. Florez 1 2 3 4 and
for the Diabetes Prevention Program Research Group
1 Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
2 Diabetes Center, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
3 Department of Medicine, Harvard Medical School, Boston, Massachusetts
4 Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge,
Massachusetts
5 The Biostatistics Center, George Washington University, Rockville, Maryland
6 Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore,
Maryland
7 Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Division of Medicine,
Umeå University Hospital, Umeå, Sweden
8 Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix,
Arizona
9 Department of Genetics, Harvard Medical School, Boston, Massachusetts
Corresponding author: Jose C. Florez, dppmail{at}biostat.bsc.gwu.edu
Abstract
OBJECTIVE— Genome-wide association scans (GWASs) have identified novel diabetes-associated genes. We evaluated how these variants impact
diabetes incidence, quantitative glycemic traits, and response to preventive interventions in 3,548 subjects at high risk
of type 2 diabetes enrolled in the Diabetes Prevention Program (DPP), which examined the effects of lifestyle intervention,
metformin, and troglitazone versus placebo.
RESEARCH DESIGN AND METHODS— We genotyped selected single nucleotide polymorphisms (SNPs) in or near diabetes-associated loci, including EXT2 , CDKAL1 , CDKN2A/B , IGF2BP2 , HHEX , LOC387761, and SLC30A8 in DPP participants and performed Cox regression analyses using genotype, intervention, and their interactions as predictors
of diabetes incidence. We evaluated their effect on insulin resistance and secretion at 1 year.
RESULTS— None of the selected SNPs were associated with increased diabetes incidence in this population. After adjustments for ethnicity,
baseline insulin secretion was lower in subjects with the risk genotype at HHEX rs1111875 ( P = 0.01); there were no significant differences in baseline insulin sensitivity. Both at baseline and at 1 year, subjects
with the risk genotype at LOC387761 had paradoxically increased insulin secretion; adjustment for self-reported ethnicity
abolished these differences. In ethnicity-adjusted analyses, we noted a nominal differential improvement in β-cell function
for carriers of the protective genotype at CDKN2A/B after 1 year of troglitazone treatment ( P = 0.01) and possibly lifestyle modification ( P = 0.05).
CONCLUSIONS— We were unable to replicate the GWAS findings regarding diabetes risk in the DPP. We did observe genotype associations with
differences in baseline insulin secretion at the HHEX locus and a possible pharmacogenetic interaction at CDKNA2/B .
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 10 June 2008.
Clinical trial reg. no. NCT00004992, clinicaltrials.gov.
A complete list of Diabetes Prevention Program Research Group investigators is provided in the online appendix available at
http://dx.doi.org/10.2337/db08-0284 .
†
† Dr. Allan F. Moore passed away on 24 July 2008. This article, to which he contributed his privileged intellect and unwavering
enthusiasm, is dedicated to his memory. His colleagues and peers will miss him.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
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 June 1, 2008.
Received February 28, 2008.
DIABETES</description><subject>African Americans - genetics</subject><subject>African Americans - statistics & numerical data</subject><subject>beta-cell function</subject><subject>Biological and medical sciences</subject><subject>Cation Transport Proteins - genetics</subject><subject>CDKAL1</subject><subject>Cellular signal transduction</subject><subject>Cyclin-Dependent Kinase 5 - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p15 - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p16 - genetics</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Type 2 - ethnology</subject><subject>Diabetes Mellitus, Type 2 - genetics</subject><subject>Diabetes Mellitus, Type 2 - prevention & control</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Disease prevention</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Ethnicity</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>European Continental Ancestry Group - genetics</subject><subject>European Continental Ancestry Group - statistics & numerical data</subject><subject>Gene Frequency</subject><subject>Genes</subject><subject>Genetics</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Genotype & phenotype</subject><subject>Glucose</subject><subject>glucose tolerance</subject><subject>Health aspects</subject><subject>Hispanic Americans</subject><subject>Homeodomain Proteins - genetics</subject><subject>Humans</subject><subject>Incidence</subject><subject>Insulin resistance</subject><subject>Life Style</subject><subject>Lifestyles</subject><subject>loci</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>N-Acetylglucosaminyltransferases - genetics</subject><subject>Physiological aspects</subject><subject>Polymorphism, Single Nucleotide</subject><subject>polymorphisms</subject><subject>Prevention</subject><subject>Prevention programs</subject><subject>Quantitative Trait Loci</subject><subject>Research design</subject><subject>Risk Factors</subject><subject>RNA-Binding Proteins - genetics</subject><subject>secretion</subject><subject>susceptibility</subject><subject>Transcription Factors - genetics</subject><subject>tRNA Methyltransferases</subject><subject>Type 2 diabetes</subject><subject>variants</subject><subject>Wellness programs</subject><subject>Zinc Transporter 8</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>eNqNkltv0zAYhiMEYmVwwR9AEdJACDJsJ46dG6SqGwWp0iYYhzvLcb6knhK72MkO_x5nrVaKKoR84dPzvfoObxQ9x-iYpCl7X5WIJ4jw7EE0wUVaJClhPx9GE4QwSTAr2EH0xPtLhFAe1uPoAHOaZQyxSVSd3vRgvLYmtnV8cbuCmMQnWpbQg4_nYGwHyQ9dQTz13iot-xH9qqSJv4Af2t7H2sT9ErZB5w6uwNxx5842TnZPo0e1bD082-yH0bePpxezT8nibP55Nl0kinHSJxWvuExLQjnUSnGK6kphCLdCAWGSZQiprMasxhSVqiI0zQgu66xMM54rhtPD6N1a11_DaijFyulOulthpRYn-vtUWNeIoRsELhDPA_5hjQe2g0qFpJ1sd6J2f4xeisZeCUJDA1EaBF5vBJz9NYDvRae9graVBuzgBctoEWbA6X-SiI6ar_5J5kXGaJhpAF_-BV7awZnQX0FwnnHKyaiWrKFGtiC0qW0oRDVgINRjDdQ6PE9DhjhnPB_zPN7Dh1VBp9XegDc7AYHp4aZv5OC94PPFLpvsY5VtW2hABCvMzvZqK2e9d1DfjwYjMRpfjMYXo_ED--LPWW7JjdMDcLQBpFeyrZ00Svt7jqA8KN517O2aW-pmea0diGpj7O2BMlEEEwQH_AakNxc5</recordid><startdate>20080901</startdate><enddate>20080901</enddate><creator>MOORE, Allan F</creator><creator>JABLONSKI, Kathleen A</creator><creator>FLOREZ, Jose C</creator><creator>MCATEER, Jarred B</creator><creator>SAXENA, Richa</creator><creator>POLLIN, Toni I</creator><creator>FRANKS, Paul W</creator><creator>HANSON, Robert L</creator><creator>SHULDINER, Alan R</creator><creator>KNOWLER, William C</creator><creator>ALTSHULER, David</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>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D93</scope></search><sort><creationdate>20080901</creationdate><title>Extension of Type 2 Diabetes Genome-Wide Association Scan Results in the Diabetes Prevention Program</title><author>MOORE, Allan F ; JABLONSKI, Kathleen A ; FLOREZ, Jose C ; MCATEER, Jarred B ; SAXENA, Richa ; POLLIN, Toni I ; FRANKS, Paul W ; HANSON, Robert L ; SHULDINER, Alan R ; KNOWLER, William C ; ALTSHULER, David</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c782t-d8d8a3b258efcc850fdc1e58e9ce27a7400c4f17f150bcd253421bf4b3486c713</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>African Americans - genetics</topic><topic>African Americans - statistics & numerical data</topic><topic>beta-cell function</topic><topic>Biological and medical sciences</topic><topic>Cation Transport Proteins - genetics</topic><topic>CDKAL1</topic><topic>Cellular signal transduction</topic><topic>Cyclin-Dependent Kinase 5 - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p15 - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p16 - genetics</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Type 2 - ethnology</topic><topic>Diabetes Mellitus, Type 2 - genetics</topic><topic>Diabetes Mellitus, Type 2 - prevention & control</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Disease prevention</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Ethnicity</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>European Continental Ancestry Group - genetics</topic><topic>European Continental Ancestry Group - statistics & numerical data</topic><topic>Gene Frequency</topic><topic>Genes</topic><topic>Genetics</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Genotype & phenotype</topic><topic>Glucose</topic><topic>glucose tolerance</topic><topic>Health aspects</topic><topic>Hispanic Americans</topic><topic>Homeodomain Proteins - genetics</topic><topic>Humans</topic><topic>Incidence</topic><topic>Insulin resistance</topic><topic>Life Style</topic><topic>Lifestyles</topic><topic>loci</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>N-Acetylglucosaminyltransferases - genetics</topic><topic>Physiological aspects</topic><topic>Polymorphism, Single Nucleotide</topic><topic>polymorphisms</topic><topic>Prevention</topic><topic>Prevention programs</topic><topic>Quantitative Trait Loci</topic><topic>Research design</topic><topic>Risk Factors</topic><topic>RNA-Binding Proteins - genetics</topic><topic>secretion</topic><topic>susceptibility</topic><topic>Transcription Factors - genetics</topic><topic>tRNA Methyltransferases</topic><topic>Type 2 diabetes</topic><topic>variants</topic><topic>Wellness programs</topic><topic>Zinc Transporter 8</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MOORE, Allan F</creatorcontrib><creatorcontrib>JABLONSKI, Kathleen A</creatorcontrib><creatorcontrib>FLOREZ, Jose C</creatorcontrib><creatorcontrib>MCATEER, Jarred B</creatorcontrib><creatorcontrib>SAXENA, Richa</creatorcontrib><creatorcontrib>POLLIN, Toni I</creatorcontrib><creatorcontrib>FRANKS, Paul W</creatorcontrib><creatorcontrib>HANSON, Robert L</creatorcontrib><creatorcontrib>SHULDINER, Alan R</creatorcontrib><creatorcontrib>KNOWLER, William C</creatorcontrib><creatorcontrib>ALTSHULER, David</creatorcontrib><creatorcontrib>Diabetes Prevention Program Research Group</creatorcontrib><creatorcontrib>for the Diabetes Prevention Program Research Group</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>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Umeå universitet</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MOORE, Allan F</au><au>JABLONSKI, Kathleen A</au><au>FLOREZ, Jose C</au><au>MCATEER, Jarred B</au><au>SAXENA, Richa</au><au>POLLIN, Toni I</au><au>FRANKS, Paul W</au><au>HANSON, Robert L</au><au>SHULDINER, Alan R</au><au>KNOWLER, William C</au><au>ALTSHULER, David</au><aucorp>Diabetes Prevention Program Research Group</aucorp><aucorp>for the Diabetes Prevention Program Research Group</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Extension of Type 2 Diabetes Genome-Wide Association Scan Results in the Diabetes Prevention Program</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2008-09-01</date><risdate>2008</risdate><volume>57</volume><issue>9</issue><spage>2503</spage><epage>2510</epage><pages>2503-2510</pages><issn>0012-1797</issn><issn>1939-327X</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Extension of Type 2 Diabetes Genome-Wide Association Scan Results in the Diabetes Prevention Program
Allan F. Moore 1 2 3 4 † ,
Kathleen A. Jablonski 5 ,
Jarred B. McAteer 1 4 ,
Richa Saxena 1 4 ,
Toni I. Pollin 6 ,
Paul W. Franks 7 ,
Robert L. Hanson 8 ,
Alan R. Shuldiner 6 ,
William C. Knowler 8 ,
David Altshuler 1 2 3 4 9 ,
Jose C. Florez 1 2 3 4 and
for the Diabetes Prevention Program Research Group
1 Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
2 Diabetes Center, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
3 Department of Medicine, Harvard Medical School, Boston, Massachusetts
4 Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge,
Massachusetts
5 The Biostatistics Center, George Washington University, Rockville, Maryland
6 Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore,
Maryland
7 Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Division of Medicine,
Umeå University Hospital, Umeå, Sweden
8 Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix,
Arizona
9 Department of Genetics, Harvard Medical School, Boston, Massachusetts
Corresponding author: Jose C. Florez, dppmail{at}biostat.bsc.gwu.edu
Abstract
OBJECTIVE— Genome-wide association scans (GWASs) have identified novel diabetes-associated genes. We evaluated how these variants impact
diabetes incidence, quantitative glycemic traits, and response to preventive interventions in 3,548 subjects at high risk
of type 2 diabetes enrolled in the Diabetes Prevention Program (DPP), which examined the effects of lifestyle intervention,
metformin, and troglitazone versus placebo.
RESEARCH DESIGN AND METHODS— We genotyped selected single nucleotide polymorphisms (SNPs) in or near diabetes-associated loci, including EXT2 , CDKAL1 , CDKN2A/B , IGF2BP2 , HHEX , LOC387761, and SLC30A8 in DPP participants and performed Cox regression analyses using genotype, intervention, and their interactions as predictors
of diabetes incidence. We evaluated their effect on insulin resistance and secretion at 1 year.
RESULTS— None of the selected SNPs were associated with increased diabetes incidence in this population. After adjustments for ethnicity,
baseline insulin secretion was lower in subjects with the risk genotype at HHEX rs1111875 ( P = 0.01); there were no significant differences in baseline insulin sensitivity. Both at baseline and at 1 year, subjects
with the risk genotype at LOC387761 had paradoxically increased insulin secretion; adjustment for self-reported ethnicity
abolished these differences. In ethnicity-adjusted analyses, we noted a nominal differential improvement in β-cell function
for carriers of the protective genotype at CDKN2A/B after 1 year of troglitazone treatment ( P = 0.01) and possibly lifestyle modification ( P = 0.05).
CONCLUSIONS— We were unable to replicate the GWAS findings regarding diabetes risk in the DPP. We did observe genotype associations with
differences in baseline insulin secretion at the HHEX locus and a possible pharmacogenetic interaction at CDKNA2/B .
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 10 June 2008.
Clinical trial reg. no. NCT00004992, clinicaltrials.gov.
A complete list of Diabetes Prevention Program Research Group investigators is provided in the online appendix available at
http://dx.doi.org/10.2337/db08-0284 .
†
† Dr. Allan F. Moore passed away on 24 July 2008. This article, to which he contributed his privileged intellect and unwavering
enthusiasm, is dedicated to his memory. His colleagues and peers will miss him.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
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 June 1, 2008.
Received February 28, 2008.
DIABETES</abstract><cop>Alexandria, VA</cop><pub>American Diabetes Association</pub><pmid>18544707</pmid><doi>10.2337/db08-0284</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0012-1797 |
| ispartof | Diabetes (New York, N.Y.), 2008-09, Vol.57 (9), p.2503-2510 |
| issn | 0012-1797 1939-327X 1939-327X |
| language | eng |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | African Americans - genetics African Americans - statistics & numerical data beta-cell function Biological and medical sciences Cation Transport Proteins - genetics CDKAL1 Cellular signal transduction Cyclin-Dependent Kinase 5 - genetics Cyclin-Dependent Kinase Inhibitor p15 - genetics Cyclin-Dependent Kinase Inhibitor p16 - genetics Diabetes Diabetes Mellitus, Type 2 - ethnology Diabetes Mellitus, Type 2 - genetics Diabetes Mellitus, Type 2 - prevention & control Diabetes. Impaired glucose tolerance Disease prevention Endocrine pancreas. Apud cells (diseases) Endocrinopathies Ethnicity Etiopathogenesis. Screening. Investigations. Target tissue resistance European Continental Ancestry Group - genetics European Continental Ancestry Group - statistics & numerical data Gene Frequency Genes Genetics Genomes Genomics Genotype & phenotype Glucose glucose tolerance Health aspects Hispanic Americans Homeodomain Proteins - genetics Humans Incidence Insulin resistance Life Style Lifestyles loci Medical sciences Middle Aged N-Acetylglucosaminyltransferases - genetics Physiological aspects Polymorphism, Single Nucleotide polymorphisms Prevention Prevention programs Quantitative Trait Loci Research design Risk Factors RNA-Binding Proteins - genetics secretion susceptibility Transcription Factors - genetics tRNA Methyltransferases Type 2 diabetes variants Wellness programs Zinc Transporter 8 |
| title | Extension of Type 2 Diabetes Genome-Wide Association Scan Results in the Diabetes Prevention Program |
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