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

Vaxillaire, Martine, Yengo, Loic, Lobbens, Stephane, Rocheleau, Ghislain, Eury, Elodie, Lantieri, Olivier, Marre, Michel, Balkau, Beverley, Bonnefond, Amelie and Froguel, Philippe (2014) 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. Diabetologia, 57 8: 1601-1610. doi:10.1007/s00125-014-3277-x


Author Vaxillaire, Martine
Yengo, Loic
Lobbens, Stephane
Rocheleau, Ghislain
Eury, Elodie
Lantieri, Olivier
Marre, Michel
Balkau, Beverley
Bonnefond, Amelie
Froguel, Philippe
Title 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
Journal name Diabetologia   Check publisher's open access policy
ISSN 1432-0428
0012-186X
Publication date 2014-08-01
Year available 2014
Sub-type Article (original research)
DOI 10.1007/s00125-014-3277-x
Open Access Status Not yet assessed
Volume 57
Issue 8
Start page 1601
End page 1610
Total pages 10
Place of publication Heidelberg, Germany
Publisher Springer
Language eng
Formatted abstract
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, pGRS-1 =8.2×10-5 and pGRS-2 =6.0×10-6), increased incidence of IFG and type 2 diabetes (per allele: HRGRS-1 1.03, p=4.3×10 -9 and HRGRS-2 1.04, p=1.0×10-16), and the 9 year prevalence (ORGRS-1 1.13 [95% CI 1.10, 1.17], p=1.9×10-14 for type 2 diabetes only; ORGRS-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 (NRIGRS-1 17.3%, p=6.6×10-7; NRIGRS-2 17.6%, p=4.2×10-7; NRIGRS-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.
Keyword DESIR
Genotype risk score
Hyperglycaemia
Impaired fasting glucose
Incidence analysis
Metabochip
Quantitative metabolic trait
Type 2 diabetes
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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