TY - JOUR
T1 - Type 2 diabetes-related genetic risk scores associated with variations in fasting plasma glucose and development of impaired glucose homeostasis in the prospective DESIR study
AU - Vaxillaire, Martine
AU - Yengo, Loïc
AU - Lobbens, Stéphane
AU - Rocheleau, Ghislain
AU - Eury, Elodie
AU - Lantieri, Olivier
AU - Marre, Michel
AU - Balkau, Beverley
AU - Bonnefond, Amélie
AU - Froguel, Philippe
N1 - Funding Information:
The DESIR study was supported by Inserm contracts with CNAMTS, Lilly, Novartis Pharma and Sanofi-aventis, and by Inserm (Réseaux en Santé Publique, Interactions entre les déterminants de la santé, Cohortes Santé TGIR 2008), the Association Diabète Risque Vasculaire, the Fédération Française de Cardiologie, La Fondation de France, ALFEDIAM, ONIVINS, Société Francophone du Diabète, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Merck Santé, Novo Nordisk, Pierre Fabre, Roche and Topcon.
Funding Information:
Funding This study was supported by the Contrat de Projets Etat— Région Nord-Pas-DeCalais (CPER Axe Cardio-Diabète to PF), the Délégation Régionale à la Recherche et à la Technologie de la Région Nord-Pas-De-Calais, the European Union (Fonds Européen de Développement Régional to PF) and the Centre National de la Recherche Scientifique.
PY - 2014/8
Y1 - 2014/8
N2 - Aims/hypothesis: Genome-wide association studies have firmly established 65 independent European-derived loci associated with type 2 diabetes and 36 loci contributing to variations in fasting plasma glucose (FPG). Using individual data from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study, we evaluated the contribution of three genetic risk scores (GRS) to variations in metabolic traits, and to the incidence and prevalence of impaired fasting glycaemia (IFG) and type 2 diabetes. Methods: Three GRS (GRS-1, 65 type 2 diabetes-associated single nucleotide polymorphisms [SNPs]; GRS-2, GRS-1 combined with 24 FPG-raising SNPs; and GRS-3, FPG-raising SNPs alone) were analysed in 4,075 DESIR study participants. GRS-mediated effects on longitudinal variations in quantitative traits were assessed in 3,927 nondiabetic individuals using multivariate linear mixed models, and on the incidence and prevalence of hyperglycaemia at 9 years using Cox and logistic regression models. The contribution of each GRS to risk prediction was evaluated using the C-statistic and net reclassification improvement (NRI) analysis. Results: The two most inclusive GRS were significantly associated with increased FPG (β=0.0011 mmol/l per year per risk allele, p GRS-1 =8.2×10-5 and p GRS-2 =6.0×10-6), increased incidence of IFG and type 2 diabetes (per allele: HR GRS-1 1.03, p=4.3×10 -9 and HR GRS-2 1.04, p=1.0×10-16), and the 9 year prevalence (OR GRS-1 1.13 [95% CI 1.10, 1.17], p=1.9×10-14 for type 2 diabetes only; OR GRS-2 1.07 [95% CI 1.05, 1.08], p=7.8×10-25, for IFG and type 2 diabetes). No significant interaction was found between GRS-1 or GRS-2 and potential confounding factors. Each GRS yielded a modest, but significant, improvement in overall reclassification rates (NRI GRS-1 17.3%, p=6.6×10 -7; NRI GRS-2 17.6%, p=4.2×10-7; NRI GRS-3 13.1%, p=1.7×10-4). Conclusions/ interpretation: Polygenic scores based on combined genetic information from type 2 diabetes risk and FPG variation contribute to discriminating middle-aged individuals at risk of developing type 2 diabetes in a general population.
AB - Aims/hypothesis: Genome-wide association studies have firmly established 65 independent European-derived loci associated with type 2 diabetes and 36 loci contributing to variations in fasting plasma glucose (FPG). Using individual data from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study, we evaluated the contribution of three genetic risk scores (GRS) to variations in metabolic traits, and to the incidence and prevalence of impaired fasting glycaemia (IFG) and type 2 diabetes. Methods: Three GRS (GRS-1, 65 type 2 diabetes-associated single nucleotide polymorphisms [SNPs]; GRS-2, GRS-1 combined with 24 FPG-raising SNPs; and GRS-3, FPG-raising SNPs alone) were analysed in 4,075 DESIR study participants. GRS-mediated effects on longitudinal variations in quantitative traits were assessed in 3,927 nondiabetic individuals using multivariate linear mixed models, and on the incidence and prevalence of hyperglycaemia at 9 years using Cox and logistic regression models. The contribution of each GRS to risk prediction was evaluated using the C-statistic and net reclassification improvement (NRI) analysis. Results: The two most inclusive GRS were significantly associated with increased FPG (β=0.0011 mmol/l per year per risk allele, p GRS-1 =8.2×10-5 and p GRS-2 =6.0×10-6), increased incidence of IFG and type 2 diabetes (per allele: HR GRS-1 1.03, p=4.3×10 -9 and HR GRS-2 1.04, p=1.0×10-16), and the 9 year prevalence (OR GRS-1 1.13 [95% CI 1.10, 1.17], p=1.9×10-14 for type 2 diabetes only; OR GRS-2 1.07 [95% CI 1.05, 1.08], p=7.8×10-25, for IFG and type 2 diabetes). No significant interaction was found between GRS-1 or GRS-2 and potential confounding factors. Each GRS yielded a modest, but significant, improvement in overall reclassification rates (NRI GRS-1 17.3%, p=6.6×10 -7; NRI GRS-2 17.6%, p=4.2×10-7; NRI GRS-3 13.1%, p=1.7×10-4). Conclusions/ interpretation: Polygenic scores based on combined genetic information from type 2 diabetes risk and FPG variation contribute to discriminating middle-aged individuals at risk of developing type 2 diabetes in a general population.
KW - DESIR
KW - Genotype risk score
KW - Hyperglycaemia
KW - Impaired fasting glucose
KW - Incidence analysis
KW - Metabochip
KW - Quantitative metabolic trait
KW - Type 2 diabetes
UR - https://www.scopus.com/pages/publications/84904746615
U2 - 10.1007/s00125-014-3277-x
DO - 10.1007/s00125-014-3277-x
M3 - Article
C2 - 24893864
AN - SCOPUS:84904746615
SN - 0012-186X
VL - 57
SP - 1601
EP - 1610
JO - Diabetologia
JF - Diabetologia
IS - 8
ER -