Common Variants in Maturity-Onset Diabetes of the Young Genes and Future Risk of Type 2 Diabetes
Common Variants in Maturity-Onset Diabetes of the Young Genes and Future Risk of Type 2 Diabetes Johan Holmkvist 1 , Peter Almgren 1 , Valeriya Lyssenko 1 , Cecilia M. Lindgren 2 3 , Karl-Fredrik Eriksson 1 , Bo Isomaa 4 5 , Tiinamaija Tuomi 5 6 , Peter Nilsson 7 and Leif Groop 1 5 1 Department of C...
Gespeichert in:
| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2008-06, Vol.57 (6), p.1738-1744 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1744 |
|---|---|
| container_issue | 6 |
| container_start_page | 1738 |
| container_title | Diabetes (New York, N.Y.) |
| container_volume | 57 |
| creator | HOLMKVIST, Johan ALMGREN, Peter LYSSENKO, Valeriya LINDGREN, Cecilia M ERIKSSON, Karl-Fredrik ISOMAA, Bo TUOMI, Tiinamaija NILSSON, Peter GROOP, Leif |
| description | Common Variants in Maturity-Onset Diabetes of the Young Genes and Future Risk of Type 2 Diabetes
Johan Holmkvist 1 ,
Peter Almgren 1 ,
Valeriya Lyssenko 1 ,
Cecilia M. Lindgren 2 3 ,
Karl-Fredrik Eriksson 1 ,
Bo Isomaa 4 5 ,
Tiinamaija Tuomi 5 6 ,
Peter Nilsson 7 and
Leif Groop 1 5
1 Department of Clinical Sciences—Diabetes and Endocrinology, CRC, Malmö University Hospital MAS, Lund University, Malmö, Sweden
2 Wellcome Trust Centre for Human Genetics and Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University,
Oxford, U.K
3 Clinical Research Centre, Karolinska Institute, Stockholm, Sweden
4 Malmska Municipal Health Care Center and Hospital, Jakobstad, Finland
5 Folkhalsan Research Centre, Helsinki, Finland
6 Department of Medicine, Helsinki University Central Hospital, and Research Program of Molecular Medicine, University of Helsinki,
Helsinki, Finland
7 Department of Medicine, Malmö University Hospital MAS, Lund University, Malmö, Sweden
Corresponding author: Johan Holmkvist, Department of Clinical Sciences—Diabetes and Endocrinology, CRC Malmö University Hospital
MAS, Lund University, S-205 02 Malmö, Sweden. E-mail: johan.holmkvist{at}med.lu.se
Abstract
OBJECTIVE— Mutations in the hepatocyte nuclear factor ( HNF ) -1 α, HNF-4 α, glucokinase ( GCK ), and HNF-1 β genes cause maturity-onset diabetes of the young (MODY), but it is not known whether common variants in these genes predict
future type 2 diabetes.
RESEARCH DESIGN AND METHODS— We tested 14 previously associated polymorphisms in HNF-1 α, HNF-4 α, GCK , and HNF-1 β for association with type 2 diabetes–related traits and future risk of type 2 diabetes in 2,293 individuals from the Botnia
study (Finland) and in 15,538 individuals from the Malmö Preventive Project (Sweden) with a total follow-up >360,000 years.
RESULTS— The polymorphism rs1169288 in HNF-1 α strongly predicted future type 2 diabetes (hazard ratio [HR] 1.2, P = 0.0002). Also, SNPs rs4810424 and rs3212198 in HNF-4 α nominally predicted future type 2 diabetes (HR 1.3 [95% CI 1.0–1.6], P = 0.03; and 1.1 [1.0–1.2], P = 0.04). The rs2144908 polymorphism in HNF-4 α was associated with elevated rate of hepatic glucose production during a hyperinsulinemic-euglycemic clamp ( P = 0.03) but not with deterioration of insulin secretion over time. The SNP rs1799884 in the GCK promoter was associated with elevated fasting plasma glucose (fPG) concentrations that remained unchanged during the follow-up
period ( P = 0.4; SE 0.004 [− |
| doi_str_mv | 10.2337/db06-1464 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmed_primary_18332101</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A279723301</galeid><sourcerecordid>A279723301</sourcerecordid><originalsourceid>FETCH-LOGICAL-c726t-53f8047d489a18091867d9ad15220b9979c1b2bdecc74c833c8a28f7953764083</originalsourceid><addsrcrecordid>eNqF0l2L1DAUBuAiijuuXvgHpAgKIl3z0TbJ5TK6ozAyIKvoVUzT007WNhmblnX-vWeYYZaVAQmhJTw5Lee8SfKckgvGuXhXV6TMaF7mD5IZVVxlnInvD5MZIZRlVChxljyJ8YYQUuJ6nJxRyTmjhM6Sn_PQ98Gn38zgjB9j6nz62YzT4MZttvIRxvS9MxWMENPQpOMa0h9h8m26AI9Hxtfp1YQc0i8u_tqR6-0GUna89TR51JguwrPD8zz5evXhev4xW64Wn-aXy8wKVo5ZwRtJclHnUhkqiaKyFLUyNS0YI5VSQllasaoGa0Vu8fetNEw2QhVclDmR_DxZ7uvGW9hMld4MrjfDVgfjdDdtcFe4dQRdKQmWCtBGNULnQlItTUE0q5itgRWNITmWe70vtxnC7wniqHsXLXSd8RCmqAURsiiE-i9kOARCFUP48h94E6bBY080o2UuRZ7vULZHrelAO9-EcTC2xV4PpgseGofHlwxHioMnFP3FCY-rht7Zkxfe3LuAZoQ_Y2umGLVcLO_b7JS1oeugBY3jm69O1rZDiHGA5jgEit3FoOpdUPUuqGhfHLoxVT3Ud_KQTASvDsBEa7pmMN66eHSMcMyE2rm3e7d27frWDaDrQ_LuXgqh8bOCS_4XzAT4qg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>216487442</pqid></control><display><type>article</type><title>Common Variants in Maturity-Onset Diabetes of the Young Genes and Future Risk of Type 2 Diabetes</title><source>MEDLINE</source><source>PubMed Central</source><source>SWEPUB Freely available online</source><source>EZB Electronic Journals Library</source><creator>HOLMKVIST, Johan ; ALMGREN, Peter ; LYSSENKO, Valeriya ; LINDGREN, Cecilia M ; ERIKSSON, Karl-Fredrik ; ISOMAA, Bo ; TUOMI, Tiinamaija ; NILSSON, Peter ; GROOP, Leif</creator><creatorcontrib>HOLMKVIST, Johan ; ALMGREN, Peter ; LYSSENKO, Valeriya ; LINDGREN, Cecilia M ; ERIKSSON, Karl-Fredrik ; ISOMAA, Bo ; TUOMI, Tiinamaija ; NILSSON, Peter ; GROOP, Leif</creatorcontrib><description>Common Variants in Maturity-Onset Diabetes of the Young Genes and Future Risk of Type 2 Diabetes
Johan Holmkvist 1 ,
Peter Almgren 1 ,
Valeriya Lyssenko 1 ,
Cecilia M. Lindgren 2 3 ,
Karl-Fredrik Eriksson 1 ,
Bo Isomaa 4 5 ,
Tiinamaija Tuomi 5 6 ,
Peter Nilsson 7 and
Leif Groop 1 5
1 Department of Clinical Sciences—Diabetes and Endocrinology, CRC, Malmö University Hospital MAS, Lund University, Malmö, Sweden
2 Wellcome Trust Centre for Human Genetics and Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University,
Oxford, U.K
3 Clinical Research Centre, Karolinska Institute, Stockholm, Sweden
4 Malmska Municipal Health Care Center and Hospital, Jakobstad, Finland
5 Folkhalsan Research Centre, Helsinki, Finland
6 Department of Medicine, Helsinki University Central Hospital, and Research Program of Molecular Medicine, University of Helsinki,
Helsinki, Finland
7 Department of Medicine, Malmö University Hospital MAS, Lund University, Malmö, Sweden
Corresponding author: Johan Holmkvist, Department of Clinical Sciences—Diabetes and Endocrinology, CRC Malmö University Hospital
MAS, Lund University, S-205 02 Malmö, Sweden. E-mail: johan.holmkvist{at}med.lu.se
Abstract
OBJECTIVE— Mutations in the hepatocyte nuclear factor ( HNF ) -1 α, HNF-4 α, glucokinase ( GCK ), and HNF-1 β genes cause maturity-onset diabetes of the young (MODY), but it is not known whether common variants in these genes predict
future type 2 diabetes.
RESEARCH DESIGN AND METHODS— We tested 14 previously associated polymorphisms in HNF-1 α, HNF-4 α, GCK , and HNF-1 β for association with type 2 diabetes–related traits and future risk of type 2 diabetes in 2,293 individuals from the Botnia
study (Finland) and in 15,538 individuals from the Malmö Preventive Project (Sweden) with a total follow-up >360,000 years.
RESULTS— The polymorphism rs1169288 in HNF-1 α strongly predicted future type 2 diabetes (hazard ratio [HR] 1.2, P = 0.0002). Also, SNPs rs4810424 and rs3212198 in HNF-4 α nominally predicted future type 2 diabetes (HR 1.3 [95% CI 1.0–1.6], P = 0.03; and 1.1 [1.0–1.2], P = 0.04). The rs2144908 polymorphism in HNF-4 α was associated with elevated rate of hepatic glucose production during a hyperinsulinemic-euglycemic clamp ( P = 0.03) but not with deterioration of insulin secretion over time. The SNP rs1799884 in the GCK promoter was associated with elevated fasting plasma glucose (fPG) concentrations that remained unchanged during the follow-up
period ( P = 0.4; SE 0.004 [−0.003–0.007]) but did not predict future type 2 diabetes (HR 0.9 [0.8–1.0], P = 0.1). Polymorphisms in HNF-1 β (transcription factor 2 [ TCF2 ]) did not significantly influence insulin or glucose values nor did they predict future type 2 diabetes.
CONCLUSIONS— In conclusion, genetic variation in both HNF-1 α and HNF-4 α predict future type 2 diabetes, whereas variation in the GCK promoter results in a sustained but subtle elevation of fPG that is not sufficient to increase risk for future type 2 diabetes.
EGP, endogenous glucose production
FFM, fat-free mass
fPG, fasting plasma glucose
G6Pase, glucose-6-phosphatase
GCK, glucokinase
GEE, general estimation equation
HNF, hepatocyte nuclear factor
HOMA, homeostasis model assessment
IFG, impaired fasting glucose
IGT, impaired glucose tolerance
MPP, Malmö Preventive Project
MODY, maturity-onset diabetes of the young
OGTT, oral glucose tolerance test
PCK-1, phosphoenolpyruvate carboxykinase 1
PGC-1α, peroxisome proliferator–activated receptor-γ coactivator-1α
PPAR, peroxisome proliferator–activated receptor
TCF, transcription factor
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 10 March 2008. DOI: 10.2337/db06-1464.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1464 .
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 February 27, 2008.
Received October 18, 2006.
DIABETES</description><identifier>ISSN: 0012-1797</identifier><identifier>ISSN: 1939-327X</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db06-1464</identifier><identifier>PMID: 18332101</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>Alexandria, VA: American Diabetes Association</publisher><subject>Adult ; Age Factors ; Biological and medical sciences ; Blood Glucose - analysis ; Chromosomes ; Clinical Medicine ; Diabetes ; Diabetes Mellitus, Type 2 - epidemiology ; Diabetes Mellitus, Type 2 - genetics ; Diabetes. Impaired glucose tolerance ; Endocrine pancreas. Apud cells (diseases) ; Endocrinology and Diabetes ; Endocrinopathies ; Endokrinologi och diabetes ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Fasting ; Female ; Genes ; Genetic aspects ; Genetic susceptibility ; Genetic Variation ; Glucokinase - genetics ; Glucose ; Hepatocyte Nuclear Factor 1-beta - genetics ; Hepatocyte Nuclear Factor 4 - genetics ; Humans ; Insulin ; Insulin - blood ; Klinisk medicin ; Liver ; Male ; Medical and Health Sciences ; Medical sciences ; Medicin och hälsovetenskap ; Middle Aged ; Mutation ; Phosphatase ; Physiological aspects ; Polymorphism ; Polymorphism, Genetic ; Research design ; Risk Factors ; Transcription factors ; Type 2 diabetes ; White people</subject><ispartof>Diabetes (New York, N.Y.), 2008-06, Vol.57 (6), p.1738-1744</ispartof><rights>2008 INIST-CNRS</rights><rights>COPYRIGHT 2008 American Diabetes Association</rights><rights>COPYRIGHT 2008 American Diabetes Association</rights><rights>Copyright American Diabetes Association Jun 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c726t-53f8047d489a18091867d9ad15220b9979c1b2bdecc74c833c8a28f7953764083</citedby><cites>FETCH-LOGICAL-c726t-53f8047d489a18091867d9ad15220b9979c1b2bdecc74c833c8a28f7953764083</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,550,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20397991$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18332101$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://lup.lub.lu.se/record/1201421$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>HOLMKVIST, Johan</creatorcontrib><creatorcontrib>ALMGREN, Peter</creatorcontrib><creatorcontrib>LYSSENKO, Valeriya</creatorcontrib><creatorcontrib>LINDGREN, Cecilia M</creatorcontrib><creatorcontrib>ERIKSSON, Karl-Fredrik</creatorcontrib><creatorcontrib>ISOMAA, Bo</creatorcontrib><creatorcontrib>TUOMI, Tiinamaija</creatorcontrib><creatorcontrib>NILSSON, Peter</creatorcontrib><creatorcontrib>GROOP, Leif</creatorcontrib><title>Common Variants in Maturity-Onset Diabetes of the Young Genes and Future Risk of Type 2 Diabetes</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Common Variants in Maturity-Onset Diabetes of the Young Genes and Future Risk of Type 2 Diabetes
Johan Holmkvist 1 ,
Peter Almgren 1 ,
Valeriya Lyssenko 1 ,
Cecilia M. Lindgren 2 3 ,
Karl-Fredrik Eriksson 1 ,
Bo Isomaa 4 5 ,
Tiinamaija Tuomi 5 6 ,
Peter Nilsson 7 and
Leif Groop 1 5
1 Department of Clinical Sciences—Diabetes and Endocrinology, CRC, Malmö University Hospital MAS, Lund University, Malmö, Sweden
2 Wellcome Trust Centre for Human Genetics and Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University,
Oxford, U.K
3 Clinical Research Centre, Karolinska Institute, Stockholm, Sweden
4 Malmska Municipal Health Care Center and Hospital, Jakobstad, Finland
5 Folkhalsan Research Centre, Helsinki, Finland
6 Department of Medicine, Helsinki University Central Hospital, and Research Program of Molecular Medicine, University of Helsinki,
Helsinki, Finland
7 Department of Medicine, Malmö University Hospital MAS, Lund University, Malmö, Sweden
Corresponding author: Johan Holmkvist, Department of Clinical Sciences—Diabetes and Endocrinology, CRC Malmö University Hospital
MAS, Lund University, S-205 02 Malmö, Sweden. E-mail: johan.holmkvist{at}med.lu.se
Abstract
OBJECTIVE— Mutations in the hepatocyte nuclear factor ( HNF ) -1 α, HNF-4 α, glucokinase ( GCK ), and HNF-1 β genes cause maturity-onset diabetes of the young (MODY), but it is not known whether common variants in these genes predict
future type 2 diabetes.
RESEARCH DESIGN AND METHODS— We tested 14 previously associated polymorphisms in HNF-1 α, HNF-4 α, GCK , and HNF-1 β for association with type 2 diabetes–related traits and future risk of type 2 diabetes in 2,293 individuals from the Botnia
study (Finland) and in 15,538 individuals from the Malmö Preventive Project (Sweden) with a total follow-up >360,000 years.
RESULTS— The polymorphism rs1169288 in HNF-1 α strongly predicted future type 2 diabetes (hazard ratio [HR] 1.2, P = 0.0002). Also, SNPs rs4810424 and rs3212198 in HNF-4 α nominally predicted future type 2 diabetes (HR 1.3 [95% CI 1.0–1.6], P = 0.03; and 1.1 [1.0–1.2], P = 0.04). The rs2144908 polymorphism in HNF-4 α was associated with elevated rate of hepatic glucose production during a hyperinsulinemic-euglycemic clamp ( P = 0.03) but not with deterioration of insulin secretion over time. The SNP rs1799884 in the GCK promoter was associated with elevated fasting plasma glucose (fPG) concentrations that remained unchanged during the follow-up
period ( P = 0.4; SE 0.004 [−0.003–0.007]) but did not predict future type 2 diabetes (HR 0.9 [0.8–1.0], P = 0.1). Polymorphisms in HNF-1 β (transcription factor 2 [ TCF2 ]) did not significantly influence insulin or glucose values nor did they predict future type 2 diabetes.
CONCLUSIONS— In conclusion, genetic variation in both HNF-1 α and HNF-4 α predict future type 2 diabetes, whereas variation in the GCK promoter results in a sustained but subtle elevation of fPG that is not sufficient to increase risk for future type 2 diabetes.
EGP, endogenous glucose production
FFM, fat-free mass
fPG, fasting plasma glucose
G6Pase, glucose-6-phosphatase
GCK, glucokinase
GEE, general estimation equation
HNF, hepatocyte nuclear factor
HOMA, homeostasis model assessment
IFG, impaired fasting glucose
IGT, impaired glucose tolerance
MPP, Malmö Preventive Project
MODY, maturity-onset diabetes of the young
OGTT, oral glucose tolerance test
PCK-1, phosphoenolpyruvate carboxykinase 1
PGC-1α, peroxisome proliferator–activated receptor-γ coactivator-1α
PPAR, peroxisome proliferator–activated receptor
TCF, transcription factor
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 10 March 2008. DOI: 10.2337/db06-1464.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1464 .
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 February 27, 2008.
Received October 18, 2006.
DIABETES</description><subject>Adult</subject><subject>Age Factors</subject><subject>Biological and medical sciences</subject><subject>Blood Glucose - analysis</subject><subject>Chromosomes</subject><subject>Clinical Medicine</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Type 2 - epidemiology</subject><subject>Diabetes Mellitus, Type 2 - genetics</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinology and Diabetes</subject><subject>Endocrinopathies</subject><subject>Endokrinologi och diabetes</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Fasting</subject><subject>Female</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic susceptibility</subject><subject>Genetic Variation</subject><subject>Glucokinase - genetics</subject><subject>Glucose</subject><subject>Hepatocyte Nuclear Factor 1-beta - genetics</subject><subject>Hepatocyte Nuclear Factor 4 - genetics</subject><subject>Humans</subject><subject>Insulin</subject><subject>Insulin - blood</subject><subject>Klinisk medicin</subject><subject>Liver</subject><subject>Male</subject><subject>Medical and Health Sciences</subject><subject>Medical sciences</subject><subject>Medicin och hälsovetenskap</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Phosphatase</subject><subject>Physiological aspects</subject><subject>Polymorphism</subject><subject>Polymorphism, Genetic</subject><subject>Research design</subject><subject>Risk Factors</subject><subject>Transcription factors</subject><subject>Type 2 diabetes</subject><subject>White people</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>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><sourceid>D8T</sourceid><recordid>eNqF0l2L1DAUBuAiijuuXvgHpAgKIl3z0TbJ5TK6ozAyIKvoVUzT007WNhmblnX-vWeYYZaVAQmhJTw5Lee8SfKckgvGuXhXV6TMaF7mD5IZVVxlnInvD5MZIZRlVChxljyJ8YYQUuJ6nJxRyTmjhM6Sn_PQ98Gn38zgjB9j6nz62YzT4MZttvIRxvS9MxWMENPQpOMa0h9h8m26AI9Hxtfp1YQc0i8u_tqR6-0GUna89TR51JguwrPD8zz5evXhev4xW64Wn-aXy8wKVo5ZwRtJclHnUhkqiaKyFLUyNS0YI5VSQllasaoGa0Vu8fetNEw2QhVclDmR_DxZ7uvGW9hMld4MrjfDVgfjdDdtcFe4dQRdKQmWCtBGNULnQlItTUE0q5itgRWNITmWe70vtxnC7wniqHsXLXSd8RCmqAURsiiE-i9kOARCFUP48h94E6bBY080o2UuRZ7vULZHrelAO9-EcTC2xV4PpgseGofHlwxHioMnFP3FCY-rht7Zkxfe3LuAZoQ_Y2umGLVcLO_b7JS1oeugBY3jm69O1rZDiHGA5jgEit3FoOpdUPUuqGhfHLoxVT3Ud_KQTASvDsBEa7pmMN66eHSMcMyE2rm3e7d27frWDaDrQ_LuXgqh8bOCS_4XzAT4qg</recordid><startdate>20080601</startdate><enddate>20080601</enddate><creator>HOLMKVIST, Johan</creator><creator>ALMGREN, Peter</creator><creator>LYSSENKO, Valeriya</creator><creator>LINDGREN, Cecilia M</creator><creator>ERIKSSON, Karl-Fredrik</creator><creator>ISOMAA, Bo</creator><creator>TUOMI, Tiinamaija</creator><creator>NILSSON, Peter</creator><creator>GROOP, Leif</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>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>ADTPV</scope><scope>AGCHP</scope><scope>AOWAS</scope><scope>D8T</scope><scope>D95</scope><scope>ZZAVC</scope></search><sort><creationdate>20080601</creationdate><title>Common Variants in Maturity-Onset Diabetes of the Young Genes and Future Risk of Type 2 Diabetes</title><author>HOLMKVIST, Johan ; ALMGREN, Peter ; LYSSENKO, Valeriya ; LINDGREN, Cecilia M ; ERIKSSON, Karl-Fredrik ; ISOMAA, Bo ; TUOMI, Tiinamaija ; NILSSON, Peter ; GROOP, Leif</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c726t-53f8047d489a18091867d9ad15220b9979c1b2bdecc74c833c8a28f7953764083</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Adult</topic><topic>Age Factors</topic><topic>Biological and medical sciences</topic><topic>Blood Glucose - analysis</topic><topic>Chromosomes</topic><topic>Clinical Medicine</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Type 2 - epidemiology</topic><topic>Diabetes Mellitus, Type 2 - genetics</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinology and Diabetes</topic><topic>Endocrinopathies</topic><topic>Endokrinologi och diabetes</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>Fasting</topic><topic>Female</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genetic susceptibility</topic><topic>Genetic Variation</topic><topic>Glucokinase - genetics</topic><topic>Glucose</topic><topic>Hepatocyte Nuclear Factor 1-beta - genetics</topic><topic>Hepatocyte Nuclear Factor 4 - genetics</topic><topic>Humans</topic><topic>Insulin</topic><topic>Insulin - blood</topic><topic>Klinisk medicin</topic><topic>Liver</topic><topic>Male</topic><topic>Medical and Health Sciences</topic><topic>Medical sciences</topic><topic>Medicin och hälsovetenskap</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Phosphatase</topic><topic>Physiological aspects</topic><topic>Polymorphism</topic><topic>Polymorphism, Genetic</topic><topic>Research design</topic><topic>Risk Factors</topic><topic>Transcription factors</topic><topic>Type 2 diabetes</topic><topic>White people</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>HOLMKVIST, Johan</creatorcontrib><creatorcontrib>ALMGREN, Peter</creatorcontrib><creatorcontrib>LYSSENKO, Valeriya</creatorcontrib><creatorcontrib>LINDGREN, Cecilia M</creatorcontrib><creatorcontrib>ERIKSSON, Karl-Fredrik</creatorcontrib><creatorcontrib>ISOMAA, Bo</creatorcontrib><creatorcontrib>TUOMI, Tiinamaija</creatorcontrib><creatorcontrib>NILSSON, Peter</creatorcontrib><creatorcontrib>GROOP, Leif</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)</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>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</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</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Biological Sciences</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest 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>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>SwePub</collection><collection>SWEPUB Lunds universitet full text</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SWEPUB Lunds universitet</collection><collection>SwePub Articles full text</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>HOLMKVIST, Johan</au><au>ALMGREN, Peter</au><au>LYSSENKO, Valeriya</au><au>LINDGREN, Cecilia M</au><au>ERIKSSON, Karl-Fredrik</au><au>ISOMAA, Bo</au><au>TUOMI, Tiinamaija</au><au>NILSSON, Peter</au><au>GROOP, Leif</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Common Variants in Maturity-Onset Diabetes of the Young Genes and Future Risk of Type 2 Diabetes</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2008-06-01</date><risdate>2008</risdate><volume>57</volume><issue>6</issue><spage>1738</spage><epage>1744</epage><pages>1738-1744</pages><issn>0012-1797</issn><issn>1939-327X</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Common Variants in Maturity-Onset Diabetes of the Young Genes and Future Risk of Type 2 Diabetes
Johan Holmkvist 1 ,
Peter Almgren 1 ,
Valeriya Lyssenko 1 ,
Cecilia M. Lindgren 2 3 ,
Karl-Fredrik Eriksson 1 ,
Bo Isomaa 4 5 ,
Tiinamaija Tuomi 5 6 ,
Peter Nilsson 7 and
Leif Groop 1 5
1 Department of Clinical Sciences—Diabetes and Endocrinology, CRC, Malmö University Hospital MAS, Lund University, Malmö, Sweden
2 Wellcome Trust Centre for Human Genetics and Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University,
Oxford, U.K
3 Clinical Research Centre, Karolinska Institute, Stockholm, Sweden
4 Malmska Municipal Health Care Center and Hospital, Jakobstad, Finland
5 Folkhalsan Research Centre, Helsinki, Finland
6 Department of Medicine, Helsinki University Central Hospital, and Research Program of Molecular Medicine, University of Helsinki,
Helsinki, Finland
7 Department of Medicine, Malmö University Hospital MAS, Lund University, Malmö, Sweden
Corresponding author: Johan Holmkvist, Department of Clinical Sciences—Diabetes and Endocrinology, CRC Malmö University Hospital
MAS, Lund University, S-205 02 Malmö, Sweden. E-mail: johan.holmkvist{at}med.lu.se
Abstract
OBJECTIVE— Mutations in the hepatocyte nuclear factor ( HNF ) -1 α, HNF-4 α, glucokinase ( GCK ), and HNF-1 β genes cause maturity-onset diabetes of the young (MODY), but it is not known whether common variants in these genes predict
future type 2 diabetes.
RESEARCH DESIGN AND METHODS— We tested 14 previously associated polymorphisms in HNF-1 α, HNF-4 α, GCK , and HNF-1 β for association with type 2 diabetes–related traits and future risk of type 2 diabetes in 2,293 individuals from the Botnia
study (Finland) and in 15,538 individuals from the Malmö Preventive Project (Sweden) with a total follow-up >360,000 years.
RESULTS— The polymorphism rs1169288 in HNF-1 α strongly predicted future type 2 diabetes (hazard ratio [HR] 1.2, P = 0.0002). Also, SNPs rs4810424 and rs3212198 in HNF-4 α nominally predicted future type 2 diabetes (HR 1.3 [95% CI 1.0–1.6], P = 0.03; and 1.1 [1.0–1.2], P = 0.04). The rs2144908 polymorphism in HNF-4 α was associated with elevated rate of hepatic glucose production during a hyperinsulinemic-euglycemic clamp ( P = 0.03) but not with deterioration of insulin secretion over time. The SNP rs1799884 in the GCK promoter was associated with elevated fasting plasma glucose (fPG) concentrations that remained unchanged during the follow-up
period ( P = 0.4; SE 0.004 [−0.003–0.007]) but did not predict future type 2 diabetes (HR 0.9 [0.8–1.0], P = 0.1). Polymorphisms in HNF-1 β (transcription factor 2 [ TCF2 ]) did not significantly influence insulin or glucose values nor did they predict future type 2 diabetes.
CONCLUSIONS— In conclusion, genetic variation in both HNF-1 α and HNF-4 α predict future type 2 diabetes, whereas variation in the GCK promoter results in a sustained but subtle elevation of fPG that is not sufficient to increase risk for future type 2 diabetes.
EGP, endogenous glucose production
FFM, fat-free mass
fPG, fasting plasma glucose
G6Pase, glucose-6-phosphatase
GCK, glucokinase
GEE, general estimation equation
HNF, hepatocyte nuclear factor
HOMA, homeostasis model assessment
IFG, impaired fasting glucose
IGT, impaired glucose tolerance
MPP, Malmö Preventive Project
MODY, maturity-onset diabetes of the young
OGTT, oral glucose tolerance test
PCK-1, phosphoenolpyruvate carboxykinase 1
PGC-1α, peroxisome proliferator–activated receptor-γ coactivator-1α
PPAR, peroxisome proliferator–activated receptor
TCF, transcription factor
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 10 March 2008. DOI: 10.2337/db06-1464.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1464 .
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 February 27, 2008.
Received October 18, 2006.
DIABETES</abstract><cop>Alexandria, VA</cop><pub>American Diabetes Association</pub><pmid>18332101</pmid><doi>10.2337/db06-1464</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0012-1797 |
| ispartof | Diabetes (New York, N.Y.), 2008-06, Vol.57 (6), p.1738-1744 |
| issn | 0012-1797 1939-327X 1939-327X |
| language | eng |
| recordid | cdi_pubmed_primary_18332101 |
| source | MEDLINE; PubMed Central; SWEPUB Freely available online; EZB Electronic Journals Library |
| subjects | Adult Age Factors Biological and medical sciences Blood Glucose - analysis Chromosomes Clinical Medicine Diabetes Diabetes Mellitus, Type 2 - epidemiology Diabetes Mellitus, Type 2 - genetics Diabetes. Impaired glucose tolerance Endocrine pancreas. Apud cells (diseases) Endocrinology and Diabetes Endocrinopathies Endokrinologi och diabetes Etiopathogenesis. Screening. Investigations. Target tissue resistance Fasting Female Genes Genetic aspects Genetic susceptibility Genetic Variation Glucokinase - genetics Glucose Hepatocyte Nuclear Factor 1-beta - genetics Hepatocyte Nuclear Factor 4 - genetics Humans Insulin Insulin - blood Klinisk medicin Liver Male Medical and Health Sciences Medical sciences Medicin och hälsovetenskap Middle Aged Mutation Phosphatase Physiological aspects Polymorphism Polymorphism, Genetic Research design Risk Factors Transcription factors Type 2 diabetes White people |
| title | Common Variants in Maturity-Onset Diabetes of the Young Genes and Future Risk of Type 2 Diabetes |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-04T16%3A05%3A53IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Common%20Variants%20in%20Maturity-Onset%20Diabetes%20of%20the%20Young%20Genes%20and%20Future%20Risk%20of%20Type%202%20Diabetes&rft.jtitle=Diabetes%20(New%20York,%20N.Y.)&rft.au=HOLMKVIST,%20Johan&rft.date=2008-06-01&rft.volume=57&rft.issue=6&rft.spage=1738&rft.epage=1744&rft.pages=1738-1744&rft.issn=0012-1797&rft.eissn=1939-327X&rft.coden=DIAEAZ&rft_id=info:doi/10.2337/db06-1464&rft_dat=%3Cgale_pubme%3EA279723301%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=216487442&rft_id=info:pmid/18332101&rft_galeid=A279723301&rfr_iscdi=true |