The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations
The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations Evidence From an Updated Meta-Analysis in 42,042 Subjects Jarred B. McAteer 1 2 , Sabrina Prudente 3 4 , Simonetta Bacci 5 , Helen N. Lyon 2 6 7 , Joel N. Hirschhorn 2 6 7 , Vincenzo Trischitta 3 4 5 8 , Jose C....
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| creator | McAteer, Jarred B. Prudente, Sabrina Bacci, Simonetta Lyon, Helen N. Hirschhorn, Joel N. Trischitta, Vincenzo Florez, Jose C. |
| description | The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations
Evidence From an Updated Meta-Analysis in 42,042 Subjects
Jarred B. McAteer 1 2 ,
Sabrina Prudente 3 4 ,
Simonetta Bacci 5 ,
Helen N. Lyon 2 6 7 ,
Joel N. Hirschhorn 2 6 7 ,
Vincenzo Trischitta 3 4 5 8 ,
Jose C. Florez 1 2 9 and
for the ENPP1 Consortium *
1 Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
2 Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
3 Research Unit of Diabetes and Endocrine Diseases, CSS Scientific Institute, San Giovanni Rotondo, Italy
4 CSS-Mendel Institute, Rome, Italy
5 Unit of Endocrinology, CSS Scientific Institute, San Giovanni Rotondo, Italy
6 Divisions of Genetics and Endocrinology, Children's Hospital Boston, Boston, Massachusetts
7 Department of Genetics, Harvard Medical School, Boston, Massachusetts
8 Department of Clinical Sciences, Sapienza University of Rome, Rome, Italy
9 Department of Medicine, Harvard Medical School, Boston, Massachusetts
Address correspondence and reprint requests to Jose C. Florez, Simches Research Building, CPZN 5.250, Diabetes Unit/Center
for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114. E-mail: jcflorez{at}partners.org
Abstract
OBJECTIVE— Functional studies suggest that the nonsynonymous K121Q polymorphism in the ectoenzyme nucleotide pyrophosphate phosphodiesterase
1 (ENPP1) may confer susceptibility to insulin resistance; genetic evidence on its effect on type 2 diabetes, however, has
been conflicting. We therefore conducted a new meta-analysis that includes novel unpublished data from the ENPP1 Consortium
and recent negative findings from large association studies to address the contribution of K121Q to type 2 diabetes.
RESEARCH DESIGN AND METHODS— After a systematic review of the literature, we evaluated the effect of ENPP1 K121Q on diabetes risk under three genetic models using a random-effects approach. Our primary analysis consisted of 30 studies
comprising 15,801 case and 26,241 control subjects. Due to considerable heterogeneity and large differences in allele frequencies
across populations, we limited our meta-analysis to those of self-reported European descent and, when available, included
BMI as a covariate.
RESULTS— We found a modest increase in risk of type 2 diabetes for QQ homozygotes in white populations (combined odds ratio [OR] 1.38
[95% CI 1.10–1.74 |
| doi_str_mv | 10.2337/db07-1336 |
| format | Article |
| fullrecord | <record><control><sourceid>highwire_cross</sourceid><recordid>TN_cdi_highwire_diabetes_diabetes_57_4_1125</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>diabetes_57_4_1125</sourcerecordid><originalsourceid>FETCH-LOGICAL-c1105-b3127993c677fe688ae8cf6d0f67b0d794f965e432e47ac10f8e101b874719233</originalsourceid><addsrcrecordid>eNpFkEFLw0AQhRdRbK0e_Ad7FYnO7CY72WPRqsWiFSr1tmySjVlpm5BNkf57U1qQObw5vPfgfYxdI9wJKem-yIAilFKdsCFqqSMp6OuUDQFQREiaBuwihB8AUP2dswGmQAgiGbLlonJ88jafI39FgR98Xq9267ptKh_WfBr4OIQ697ZzBV_6ruKLXeO44I_eZq5zgfsNn2zbunF202eb7cp2vt6ES3ZW2lVwV0cdsc-nyeLhJZq9P08fxrMoR4QkyiQK0lrmiqh0Kk2tS_NSFVAqyqAgHZdaJS6WwsVkc4QydQiYpRQT6n78iN0cevO2DqF1pWlav7btziCYPRyzh2P2cHrv7cFb-e_q17fOFMcV_09CJjaIIpF_G6xh_w</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations</title><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><creator>McAteer, Jarred B. ; Prudente, Sabrina ; Bacci, Simonetta ; Lyon, Helen N. ; Hirschhorn, Joel N. ; Trischitta, Vincenzo ; Florez, Jose C.</creator><creatorcontrib>McAteer, Jarred B. ; Prudente, Sabrina ; Bacci, Simonetta ; Lyon, Helen N. ; Hirschhorn, Joel N. ; Trischitta, Vincenzo ; Florez, Jose C. ; for the ENPP1 Consortium</creatorcontrib><description>The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations
Evidence From an Updated Meta-Analysis in 42,042 Subjects
Jarred B. McAteer 1 2 ,
Sabrina Prudente 3 4 ,
Simonetta Bacci 5 ,
Helen N. Lyon 2 6 7 ,
Joel N. Hirschhorn 2 6 7 ,
Vincenzo Trischitta 3 4 5 8 ,
Jose C. Florez 1 2 9 and
for the ENPP1 Consortium *
1 Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
2 Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
3 Research Unit of Diabetes and Endocrine Diseases, CSS Scientific Institute, San Giovanni Rotondo, Italy
4 CSS-Mendel Institute, Rome, Italy
5 Unit of Endocrinology, CSS Scientific Institute, San Giovanni Rotondo, Italy
6 Divisions of Genetics and Endocrinology, Children's Hospital Boston, Boston, Massachusetts
7 Department of Genetics, Harvard Medical School, Boston, Massachusetts
8 Department of Clinical Sciences, Sapienza University of Rome, Rome, Italy
9 Department of Medicine, Harvard Medical School, Boston, Massachusetts
Address correspondence and reprint requests to Jose C. Florez, Simches Research Building, CPZN 5.250, Diabetes Unit/Center
for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114. E-mail: jcflorez{at}partners.org
Abstract
OBJECTIVE— Functional studies suggest that the nonsynonymous K121Q polymorphism in the ectoenzyme nucleotide pyrophosphate phosphodiesterase
1 (ENPP1) may confer susceptibility to insulin resistance; genetic evidence on its effect on type 2 diabetes, however, has
been conflicting. We therefore conducted a new meta-analysis that includes novel unpublished data from the ENPP1 Consortium
and recent negative findings from large association studies to address the contribution of K121Q to type 2 diabetes.
RESEARCH DESIGN AND METHODS— After a systematic review of the literature, we evaluated the effect of ENPP1 K121Q on diabetes risk under three genetic models using a random-effects approach. Our primary analysis consisted of 30 studies
comprising 15,801 case and 26,241 control subjects. Due to considerable heterogeneity and large differences in allele frequencies
across populations, we limited our meta-analysis to those of self-reported European descent and, when available, included
BMI as a covariate.
RESULTS— We found a modest increase in risk of type 2 diabetes for QQ homozygotes in white populations (combined odds ratio [OR] 1.38
[95% CI 1.10–1.74], P = 0.005). There was no evidence of publication bias, but we noted significant residual heterogeneity among studies ( P = 0.02). On meta-regression, 16% of the effect was accounted for by the mean BMI of control subjects. This association was
stronger in studies in which control subjects were leaner but disappeared after adjustment for mean control BMI (combined
OR 0.93 [95% CI 0.75–1.15], P = 0.50).
CONCLUSIONS— The ENPP1 Q121 variant increases risk of type 2 diabetes under a recessive model of inheritance in whites, an effect that appears to
be modulated by BMI.
ENPP1, ectoenzyme nucleotide pyrophosphate phosphodiesterase 1
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 10 December 2007. DOI: 10.2337/db07-1336.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1336 .
*
* A complete list of the investigators of the ENPP1 Consortium can be found in the appendix .
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 November 30, 2007.
Received September 19, 2007.
DIABETES</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db07-1336</identifier><identifier>PMID: 18071025</identifier><language>eng</language><publisher>American Diabetes Association</publisher><ispartof>Diabetes (New York, N.Y.), 2008-04, Vol.57 (4), p.1125-1130</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1105-b3127993c677fe688ae8cf6d0f67b0d794f965e432e47ac10f8e101b874719233</citedby><cites>FETCH-LOGICAL-c1105-b3127993c677fe688ae8cf6d0f67b0d794f965e432e47ac10f8e101b874719233</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>McAteer, Jarred B.</creatorcontrib><creatorcontrib>Prudente, Sabrina</creatorcontrib><creatorcontrib>Bacci, Simonetta</creatorcontrib><creatorcontrib>Lyon, Helen N.</creatorcontrib><creatorcontrib>Hirschhorn, Joel N.</creatorcontrib><creatorcontrib>Trischitta, Vincenzo</creatorcontrib><creatorcontrib>Florez, Jose C.</creatorcontrib><creatorcontrib>for the ENPP1 Consortium</creatorcontrib><title>The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations</title><title>Diabetes (New York, N.Y.)</title><description>The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations
Evidence From an Updated Meta-Analysis in 42,042 Subjects
Jarred B. McAteer 1 2 ,
Sabrina Prudente 3 4 ,
Simonetta Bacci 5 ,
Helen N. Lyon 2 6 7 ,
Joel N. Hirschhorn 2 6 7 ,
Vincenzo Trischitta 3 4 5 8 ,
Jose C. Florez 1 2 9 and
for the ENPP1 Consortium *
1 Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
2 Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
3 Research Unit of Diabetes and Endocrine Diseases, CSS Scientific Institute, San Giovanni Rotondo, Italy
4 CSS-Mendel Institute, Rome, Italy
5 Unit of Endocrinology, CSS Scientific Institute, San Giovanni Rotondo, Italy
6 Divisions of Genetics and Endocrinology, Children's Hospital Boston, Boston, Massachusetts
7 Department of Genetics, Harvard Medical School, Boston, Massachusetts
8 Department of Clinical Sciences, Sapienza University of Rome, Rome, Italy
9 Department of Medicine, Harvard Medical School, Boston, Massachusetts
Address correspondence and reprint requests to Jose C. Florez, Simches Research Building, CPZN 5.250, Diabetes Unit/Center
for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114. E-mail: jcflorez{at}partners.org
Abstract
OBJECTIVE— Functional studies suggest that the nonsynonymous K121Q polymorphism in the ectoenzyme nucleotide pyrophosphate phosphodiesterase
1 (ENPP1) may confer susceptibility to insulin resistance; genetic evidence on its effect on type 2 diabetes, however, has
been conflicting. We therefore conducted a new meta-analysis that includes novel unpublished data from the ENPP1 Consortium
and recent negative findings from large association studies to address the contribution of K121Q to type 2 diabetes.
RESEARCH DESIGN AND METHODS— After a systematic review of the literature, we evaluated the effect of ENPP1 K121Q on diabetes risk under three genetic models using a random-effects approach. Our primary analysis consisted of 30 studies
comprising 15,801 case and 26,241 control subjects. Due to considerable heterogeneity and large differences in allele frequencies
across populations, we limited our meta-analysis to those of self-reported European descent and, when available, included
BMI as a covariate.
RESULTS— We found a modest increase in risk of type 2 diabetes for QQ homozygotes in white populations (combined odds ratio [OR] 1.38
[95% CI 1.10–1.74], P = 0.005). There was no evidence of publication bias, but we noted significant residual heterogeneity among studies ( P = 0.02). On meta-regression, 16% of the effect was accounted for by the mean BMI of control subjects. This association was
stronger in studies in which control subjects were leaner but disappeared after adjustment for mean control BMI (combined
OR 0.93 [95% CI 0.75–1.15], P = 0.50).
CONCLUSIONS— The ENPP1 Q121 variant increases risk of type 2 diabetes under a recessive model of inheritance in whites, an effect that appears to
be modulated by BMI.
ENPP1, ectoenzyme nucleotide pyrophosphate phosphodiesterase 1
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 10 December 2007. DOI: 10.2337/db07-1336.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1336 .
*
* A complete list of the investigators of the ENPP1 Consortium can be found in the appendix .
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 November 30, 2007.
Received September 19, 2007.
DIABETES</description><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><recordid>eNpFkEFLw0AQhRdRbK0e_Ad7FYnO7CY72WPRqsWiFSr1tmySjVlpm5BNkf57U1qQObw5vPfgfYxdI9wJKem-yIAilFKdsCFqqSMp6OuUDQFQREiaBuwihB8AUP2dswGmQAgiGbLlonJ88jafI39FgR98Xq9267ptKh_WfBr4OIQ697ZzBV_6ruKLXeO44I_eZq5zgfsNn2zbunF202eb7cp2vt6ES3ZW2lVwV0cdsc-nyeLhJZq9P08fxrMoR4QkyiQK0lrmiqh0Kk2tS_NSFVAqyqAgHZdaJS6WwsVkc4QydQiYpRQT6n78iN0cevO2DqF1pWlav7btziCYPRyzh2P2cHrv7cFb-e_q17fOFMcV_09CJjaIIpF_G6xh_w</recordid><startdate>20080401</startdate><enddate>20080401</enddate><creator>McAteer, Jarred B.</creator><creator>Prudente, Sabrina</creator><creator>Bacci, Simonetta</creator><creator>Lyon, Helen N.</creator><creator>Hirschhorn, Joel N.</creator><creator>Trischitta, Vincenzo</creator><creator>Florez, Jose C.</creator><general>American Diabetes Association</general><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20080401</creationdate><title>The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations</title><author>McAteer, Jarred B. ; Prudente, Sabrina ; Bacci, Simonetta ; Lyon, Helen N. ; Hirschhorn, Joel N. ; Trischitta, Vincenzo ; Florez, Jose C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1105-b3127993c677fe688ae8cf6d0f67b0d794f965e432e47ac10f8e101b874719233</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>McAteer, Jarred B.</creatorcontrib><creatorcontrib>Prudente, Sabrina</creatorcontrib><creatorcontrib>Bacci, Simonetta</creatorcontrib><creatorcontrib>Lyon, Helen N.</creatorcontrib><creatorcontrib>Hirschhorn, Joel N.</creatorcontrib><creatorcontrib>Trischitta, Vincenzo</creatorcontrib><creatorcontrib>Florez, Jose C.</creatorcontrib><creatorcontrib>for the ENPP1 Consortium</creatorcontrib><collection>CrossRef</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>McAteer, Jarred B.</au><au>Prudente, Sabrina</au><au>Bacci, Simonetta</au><au>Lyon, Helen N.</au><au>Hirschhorn, Joel N.</au><au>Trischitta, Vincenzo</au><au>Florez, Jose C.</au><aucorp>for the ENPP1 Consortium</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><date>2008-04-01</date><risdate>2008</risdate><volume>57</volume><issue>4</issue><spage>1125</spage><epage>1130</epage><pages>1125-1130</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><abstract>The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations
Evidence From an Updated Meta-Analysis in 42,042 Subjects
Jarred B. McAteer 1 2 ,
Sabrina Prudente 3 4 ,
Simonetta Bacci 5 ,
Helen N. Lyon 2 6 7 ,
Joel N. Hirschhorn 2 6 7 ,
Vincenzo Trischitta 3 4 5 8 ,
Jose C. Florez 1 2 9 and
for the ENPP1 Consortium *
1 Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
2 Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
3 Research Unit of Diabetes and Endocrine Diseases, CSS Scientific Institute, San Giovanni Rotondo, Italy
4 CSS-Mendel Institute, Rome, Italy
5 Unit of Endocrinology, CSS Scientific Institute, San Giovanni Rotondo, Italy
6 Divisions of Genetics and Endocrinology, Children's Hospital Boston, Boston, Massachusetts
7 Department of Genetics, Harvard Medical School, Boston, Massachusetts
8 Department of Clinical Sciences, Sapienza University of Rome, Rome, Italy
9 Department of Medicine, Harvard Medical School, Boston, Massachusetts
Address correspondence and reprint requests to Jose C. Florez, Simches Research Building, CPZN 5.250, Diabetes Unit/Center
for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114. E-mail: jcflorez{at}partners.org
Abstract
OBJECTIVE— Functional studies suggest that the nonsynonymous K121Q polymorphism in the ectoenzyme nucleotide pyrophosphate phosphodiesterase
1 (ENPP1) may confer susceptibility to insulin resistance; genetic evidence on its effect on type 2 diabetes, however, has
been conflicting. We therefore conducted a new meta-analysis that includes novel unpublished data from the ENPP1 Consortium
and recent negative findings from large association studies to address the contribution of K121Q to type 2 diabetes.
RESEARCH DESIGN AND METHODS— After a systematic review of the literature, we evaluated the effect of ENPP1 K121Q on diabetes risk under three genetic models using a random-effects approach. Our primary analysis consisted of 30 studies
comprising 15,801 case and 26,241 control subjects. Due to considerable heterogeneity and large differences in allele frequencies
across populations, we limited our meta-analysis to those of self-reported European descent and, when available, included
BMI as a covariate.
RESULTS— We found a modest increase in risk of type 2 diabetes for QQ homozygotes in white populations (combined odds ratio [OR] 1.38
[95% CI 1.10–1.74], P = 0.005). There was no evidence of publication bias, but we noted significant residual heterogeneity among studies ( P = 0.02). On meta-regression, 16% of the effect was accounted for by the mean BMI of control subjects. This association was
stronger in studies in which control subjects were leaner but disappeared after adjustment for mean control BMI (combined
OR 0.93 [95% CI 0.75–1.15], P = 0.50).
CONCLUSIONS— The ENPP1 Q121 variant increases risk of type 2 diabetes under a recessive model of inheritance in whites, an effect that appears to
be modulated by BMI.
ENPP1, ectoenzyme nucleotide pyrophosphate phosphodiesterase 1
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 10 December 2007. DOI: 10.2337/db07-1336.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1336 .
*
* A complete list of the investigators of the ENPP1 Consortium can be found in the appendix .
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 November 30, 2007.
Received September 19, 2007.
DIABETES</abstract><pub>American Diabetes Association</pub><pmid>18071025</pmid><doi>10.2337/db07-1336</doi><tpages>6</tpages></addata></record> |
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| title | The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations |
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