Post genome-wide association studies of novel genes associated with type 2 diabetes show gene-gene interaction and high predictive value

Stéphane Cauchi, David Meyre, Emmanuelle Durand, Christine Proença, Michel Marre, Samy Hadjadj, Hélène Choquet, Franck De Graeve, Stefan Gaget, Frederic Allegaert, Jérôme Delplanque, Marshall Alan Permutt, Jon Wasson, Ilana Blech, Guillaume Charpentier, Beverley Balkau, Anne Claire Vergnaud, Sébastien Czernichow, Wolfgang Patsch, Mohamed Chikri & 3 others Benjamin Glaser, Robert Sladek, Philippe Froguel

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

Background: Recently, several Genome Wide Association (GWA) studies in populations of European descent have identified and validated novel single nucleotide polymorphisms (SNPs), highly associated with type 2 diabetes (T2D). Our aims were to validate these markers in other European and non-European populations, then to assess their combined effect in a large French study comparing T2D and normal glucose tolerant (NGT) individuals. Methodology/Principal Findings: In the same French population analyzed in our previous GWA study (3,295 T2D and 3,595 NGT), strong associations with T2D were found for CDKAL1 (ORrs7756992=1.30 [1.19-1.42], P=2.3 × 10-9), CDKN2A/2B (ORrs10811661= 0.74[0.66-0.82], P=3.5 × 10-8) and more modestly for IGFBP2 (ORrs1470579= 1.17[1.07-1.27], P=0.0003) SNPs. These results were replicated in both Israeli Ashkenazi (577 T2D and 552 NGT) and Austrian (504 T2D and 753 NGT) populations (except for CDKAL1) but not in the Moroccan population (521 T2D and 423 NGT). In the overall group of French subjects (4,232 T2D and 4,595 NGT), IGFBP2 and CXCR4 synergistically interacted with (LOC38776, SLC30A8, HHEX) and (NGN3, CDKN2A/2B), respectively, encoding for proteins presumably regulating pancreatic endocrine cell development and function. The T2D risk increased strongly when risk alleles, including the previously discovered T2D associated TCF7L2 rs7903146 SNP, were combined (8.68 fold for the 14% of French individuals carrying 18 to 30 risk alleles with an allelic OR of 1.24). With an area under the ROC curve of 0.86, only 15 novel loci were necessary to discriminate French individuals susceptible to develop T2D. Conclusions/Significance: In addition to TCF7L2, SLC30A8 and HHEX, initially identified by the French GWA scan, CDKAL1, IGFBP2 and CDKN2A/ 2B strongly associated with T2D in French individuals, and mostly in populations of Central European descent but not in Moroccan subjects. Genes expressed in the pancreas interact together and their combined effect dramatically increases the risk for T2D, opening avenues for the development of genetic prediction tests.

Original languageEnglish
Article numbere2031
JournalPLoS One
Volume3
Issue number5
DOIs
Publication statusPublished - 7 May 2008
Externally publishedYes

Fingerprint

gene interaction
Genome-Wide Association Study
Medical problems
noninsulin-dependent diabetes mellitus
Type 2 Diabetes Mellitus
Genes
genes
Glucose
glucose
Polymorphism
single nucleotide polymorphism
Population
Single Nucleotide Polymorphism
Nucleotides
genome-wide association study
Alleles
alleles
Endocrine Cells
pancreas
ROC Curve

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Post genome-wide association studies of novel genes associated with type 2 diabetes show gene-gene interaction and high predictive value. / Cauchi, Stéphane; Meyre, David; Durand, Emmanuelle; Proença, Christine; Marre, Michel; Hadjadj, Samy; Choquet, Hélène; De Graeve, Franck; Gaget, Stefan; Allegaert, Frederic; Delplanque, Jérôme; Permutt, Marshall Alan; Wasson, Jon; Blech, Ilana; Charpentier, Guillaume; Balkau, Beverley; Vergnaud, Anne Claire; Czernichow, Sébastien; Patsch, Wolfgang; Chikri, Mohamed; Glaser, Benjamin; Sladek, Robert; Froguel, Philippe.

In: PLoS One, Vol. 3, No. 5, e2031, 07.05.2008.

Research output: Contribution to journalArticle

Cauchi, S, Meyre, D, Durand, E, Proença, C, Marre, M, Hadjadj, S, Choquet, H, De Graeve, F, Gaget, S, Allegaert, F, Delplanque, J, Permutt, MA, Wasson, J, Blech, I, Charpentier, G, Balkau, B, Vergnaud, AC, Czernichow, S, Patsch, W, Chikri, M, Glaser, B, Sladek, R & Froguel, P 2008, 'Post genome-wide association studies of novel genes associated with type 2 diabetes show gene-gene interaction and high predictive value', PLoS One, vol. 3, no. 5, e2031. https://doi.org/10.1371/journal.pone.0002031
Cauchi, Stéphane ; Meyre, David ; Durand, Emmanuelle ; Proença, Christine ; Marre, Michel ; Hadjadj, Samy ; Choquet, Hélène ; De Graeve, Franck ; Gaget, Stefan ; Allegaert, Frederic ; Delplanque, Jérôme ; Permutt, Marshall Alan ; Wasson, Jon ; Blech, Ilana ; Charpentier, Guillaume ; Balkau, Beverley ; Vergnaud, Anne Claire ; Czernichow, Sébastien ; Patsch, Wolfgang ; Chikri, Mohamed ; Glaser, Benjamin ; Sladek, Robert ; Froguel, Philippe. / Post genome-wide association studies of novel genes associated with type 2 diabetes show gene-gene interaction and high predictive value. In: PLoS One. 2008 ; Vol. 3, No. 5.
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T1 - Post genome-wide association studies of novel genes associated with type 2 diabetes show gene-gene interaction and high predictive value

AU - Cauchi, Stéphane

AU - Meyre, David

AU - Durand, Emmanuelle

AU - Proença, Christine

AU - Marre, Michel

AU - Hadjadj, Samy

AU - Choquet, Hélène

AU - De Graeve, Franck

AU - Gaget, Stefan

AU - Allegaert, Frederic

AU - Delplanque, Jérôme

AU - Permutt, Marshall Alan

AU - Wasson, Jon

AU - Blech, Ilana

AU - Charpentier, Guillaume

AU - Balkau, Beverley

AU - Vergnaud, Anne Claire

AU - Czernichow, Sébastien

AU - Patsch, Wolfgang

AU - Chikri, Mohamed

AU - Glaser, Benjamin

AU - Sladek, Robert

AU - Froguel, Philippe

PY - 2008/5/7

Y1 - 2008/5/7

N2 - Background: Recently, several Genome Wide Association (GWA) studies in populations of European descent have identified and validated novel single nucleotide polymorphisms (SNPs), highly associated with type 2 diabetes (T2D). Our aims were to validate these markers in other European and non-European populations, then to assess their combined effect in a large French study comparing T2D and normal glucose tolerant (NGT) individuals. Methodology/Principal Findings: In the same French population analyzed in our previous GWA study (3,295 T2D and 3,595 NGT), strong associations with T2D were found for CDKAL1 (ORrs7756992=1.30 [1.19-1.42], P=2.3 × 10-9), CDKN2A/2B (ORrs10811661= 0.74[0.66-0.82], P=3.5 × 10-8) and more modestly for IGFBP2 (ORrs1470579= 1.17[1.07-1.27], P=0.0003) SNPs. These results were replicated in both Israeli Ashkenazi (577 T2D and 552 NGT) and Austrian (504 T2D and 753 NGT) populations (except for CDKAL1) but not in the Moroccan population (521 T2D and 423 NGT). In the overall group of French subjects (4,232 T2D and 4,595 NGT), IGFBP2 and CXCR4 synergistically interacted with (LOC38776, SLC30A8, HHEX) and (NGN3, CDKN2A/2B), respectively, encoding for proteins presumably regulating pancreatic endocrine cell development and function. The T2D risk increased strongly when risk alleles, including the previously discovered T2D associated TCF7L2 rs7903146 SNP, were combined (8.68 fold for the 14% of French individuals carrying 18 to 30 risk alleles with an allelic OR of 1.24). With an area under the ROC curve of 0.86, only 15 novel loci were necessary to discriminate French individuals susceptible to develop T2D. Conclusions/Significance: In addition to TCF7L2, SLC30A8 and HHEX, initially identified by the French GWA scan, CDKAL1, IGFBP2 and CDKN2A/ 2B strongly associated with T2D in French individuals, and mostly in populations of Central European descent but not in Moroccan subjects. Genes expressed in the pancreas interact together and their combined effect dramatically increases the risk for T2D, opening avenues for the development of genetic prediction tests.

AB - Background: Recently, several Genome Wide Association (GWA) studies in populations of European descent have identified and validated novel single nucleotide polymorphisms (SNPs), highly associated with type 2 diabetes (T2D). Our aims were to validate these markers in other European and non-European populations, then to assess their combined effect in a large French study comparing T2D and normal glucose tolerant (NGT) individuals. Methodology/Principal Findings: In the same French population analyzed in our previous GWA study (3,295 T2D and 3,595 NGT), strong associations with T2D were found for CDKAL1 (ORrs7756992=1.30 [1.19-1.42], P=2.3 × 10-9), CDKN2A/2B (ORrs10811661= 0.74[0.66-0.82], P=3.5 × 10-8) and more modestly for IGFBP2 (ORrs1470579= 1.17[1.07-1.27], P=0.0003) SNPs. These results were replicated in both Israeli Ashkenazi (577 T2D and 552 NGT) and Austrian (504 T2D and 753 NGT) populations (except for CDKAL1) but not in the Moroccan population (521 T2D and 423 NGT). In the overall group of French subjects (4,232 T2D and 4,595 NGT), IGFBP2 and CXCR4 synergistically interacted with (LOC38776, SLC30A8, HHEX) and (NGN3, CDKN2A/2B), respectively, encoding for proteins presumably regulating pancreatic endocrine cell development and function. The T2D risk increased strongly when risk alleles, including the previously discovered T2D associated TCF7L2 rs7903146 SNP, were combined (8.68 fold for the 14% of French individuals carrying 18 to 30 risk alleles with an allelic OR of 1.24). With an area under the ROC curve of 0.86, only 15 novel loci were necessary to discriminate French individuals susceptible to develop T2D. Conclusions/Significance: In addition to TCF7L2, SLC30A8 and HHEX, initially identified by the French GWA scan, CDKAL1, IGFBP2 and CDKN2A/ 2B strongly associated with T2D in French individuals, and mostly in populations of Central European descent but not in Moroccan subjects. Genes expressed in the pancreas interact together and their combined effect dramatically increases the risk for T2D, opening avenues for the development of genetic prediction tests.

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