Association analysis of 29,956 individuals confirms that a low-frequency variant at CCND2 halves the risk of type 2 diabetes by enhancing insulin secretion.

2.50
Hdl Handle:
http://hdl.handle.net/11287/618117
Title:
Association analysis of 29,956 individuals confirms that a low-frequency variant at CCND2 halves the risk of type 2 diabetes by enhancing insulin secretion.
Authors:
Yaghootkar, Hanieh; Stancáková, A.; Freathy, Rachel M.; Vangipurapu, J.; Weedon, M. N.; Xie, W.; Wood, A. R.; Ferrannini, E.; Mari, A.; Ring, S. M.; Lawlor, D. A.; Davey Smith, G.; Jørgensen, T.; Hansen, T.; Pedersen, O.; Steinthorsdottir, V.; Guðbjartsson, D. F.; Thorleifsson, G.; Thorsteinsdottir, U.; Stefansson, K.; Hattersley, Andrew T.; Walker, M.; Morris, A. D.; McCarthy, M. I.; Palmer, C. N. A.; Laakso, M.; Frayling, Timothy M.
Abstract:
A recent study identified a low-frequency variant at CCND2 associated with lower risk of type 2 diabetes, enhanced insulin response to a glucose challenge, higher height, and, paradoxically, higher BMI. We aimed to replicate the strength and effect size of these associations in independent samples and to assess the underlying mechanism. We genotyped the variant in 29,956 individuals and tested its association with type 2 diabetes and related traits. The low-frequency allele was associated with a lower risk of type 2 diabetes (OR 0.53; P = 2 × 10(-13); 6,647 case vs. 12,645 control subjects), higher disposition index (β = 0.07 log10; P = 2 × 10(-11); n = 13,028), and higher Matsuda index of insulin sensitivity (β = 0.02 log10; P = 5 × 10(-3); n = 13,118) but not fasting proinsulin (β = 0.01 log10; P = 0.5; n = 6,985). The low frequency allele was associated with higher adult height (β = 1.38 cm; P = 6 × 10(-9); n = 13,927), but the association of the variant with BMI (β = 0.36 kg/m(2); P = 0.02; n = 24,807), estimated in four population-based samples, was less than in the original publication where the effect estimate was biased by analyzing case subjects with type 2 diabetes and control subjects without diabetes separately. Our study establishes that a low-frequency allele in CCND2 halves the risk of type 2 diabetes primarily through enhanced insulin secretion.
Citation:
Association analysis of 29,956 individuals confirms that a low-frequency variant at CCND2 halves the risk of type 2 diabetes by enhancing insulin secretion. 2015, 64 (6):2279-85 Diabetes
Publisher:
American Diabetes Association
Journal:
Diabetes
Issue Date:
Jun-2015
URI:
http://hdl.handle.net/11287/618117
DOI:
10.2337/db14-1456
PubMed ID:
25605810
Additional Links:
http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=25605810
Note:
This article is freely available, click on the 'Additional Link' above to access the full-text.
Type:
Journal Article; Research Support, Non-U.S. Gov't
Language:
en
ISSN:
1939-327X
Appears in Collections:
2015 RD&E publications; Diabetes/Endocrine Services; Honorary contracts publications

Full metadata record

DC FieldValue Language
dc.contributor.authorYaghootkar, Haniehen
dc.contributor.authorStancáková, A.en
dc.contributor.authorFreathy, Rachel M.en
dc.contributor.authorVangipurapu, J.en
dc.contributor.authorWeedon, M. N.en
dc.contributor.authorXie, W.en
dc.contributor.authorWood, A. R.en
dc.contributor.authorFerrannini, E.en
dc.contributor.authorMari, A.en
dc.contributor.authorRing, S. M.en
dc.contributor.authorLawlor, D. A.en
dc.contributor.authorDavey Smith, G.en
dc.contributor.authorJørgensen, T.en
dc.contributor.authorHansen, T.en
dc.contributor.authorPedersen, O.en
dc.contributor.authorSteinthorsdottir, V.en
dc.contributor.authorGuðbjartsson, D. F.en
dc.contributor.authorThorleifsson, G.en
dc.contributor.authorThorsteinsdottir, U.en
dc.contributor.authorStefansson, K.en
dc.contributor.authorHattersley, Andrew T.en
dc.contributor.authorWalker, M.en
dc.contributor.authorMorris, A. D.en
dc.contributor.authorMcCarthy, M. I.en
dc.contributor.authorPalmer, C. N. A.en
dc.contributor.authorLaakso, M.en
dc.contributor.authorFrayling, Timothy M.en
dc.date.accessioned2016-08-09T12:22:04Z-
dc.date.available2016-08-09T12:22:04Z-
dc.date.issued2015-06-
dc.identifier.citationAssociation analysis of 29,956 individuals confirms that a low-frequency variant at CCND2 halves the risk of type 2 diabetes by enhancing insulin secretion. 2015, 64 (6):2279-85 Diabetesen
dc.identifier.issn1939-327X-
dc.identifier.pmid25605810-
dc.identifier.doi10.2337/db14-1456-
dc.identifier.urihttp://hdl.handle.net/11287/618117-
dc.description.abstractA recent study identified a low-frequency variant at CCND2 associated with lower risk of type 2 diabetes, enhanced insulin response to a glucose challenge, higher height, and, paradoxically, higher BMI. We aimed to replicate the strength and effect size of these associations in independent samples and to assess the underlying mechanism. We genotyped the variant in 29,956 individuals and tested its association with type 2 diabetes and related traits. The low-frequency allele was associated with a lower risk of type 2 diabetes (OR 0.53; P = 2 × 10(-13); 6,647 case vs. 12,645 control subjects), higher disposition index (β = 0.07 log10; P = 2 × 10(-11); n = 13,028), and higher Matsuda index of insulin sensitivity (β = 0.02 log10; P = 5 × 10(-3); n = 13,118) but not fasting proinsulin (β = 0.01 log10; P = 0.5; n = 6,985). The low frequency allele was associated with higher adult height (β = 1.38 cm; P = 6 × 10(-9); n = 13,927), but the association of the variant with BMI (β = 0.36 kg/m(2); P = 0.02; n = 24,807), estimated in four population-based samples, was less than in the original publication where the effect estimate was biased by analyzing case subjects with type 2 diabetes and control subjects without diabetes separately. Our study establishes that a low-frequency allele in CCND2 halves the risk of type 2 diabetes primarily through enhanced insulin secretion.en
dc.language.isoenen
dc.publisherAmerican Diabetes Associationen
dc.relation.urlhttp://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=25605810en
dc.rightsArchived with thanks to Diabetesen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.subjectWessex Classification Subject Headings::Endocrinology::Diabetesen
dc.titleAssociation analysis of 29,956 individuals confirms that a low-frequency variant at CCND2 halves the risk of type 2 diabetes by enhancing insulin secretion.en
dc.typeJournal Articleen
dc.typeResearch Support, Non-U.S. Gov'ten
dc.identifier.journalDiabetesen
dc.description.noteThis article is freely available, click on the 'Additional Link' above to access the full-text.en
dc.type.versionPublisheden

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