Strong association of common variants in the CDKN2A/CDKN2B region with type 2 diabetes in French Europids

• Published in: Diabetologia Vol. 51; no. 5; pp. 821 - 826
• Main Authors: Duesing, K, Fatemifar, G, Charpentier, G, Marre, M, Tichet, J, Hercberg, S, Balkau, B, Froguel, P, Gibson, F
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.05.2008; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: 5' Untranslated Regions - genetics; Association; Biological and medical sciences; CDKN2A/CDKN2B; Common variant; Cyclin-Dependent Kinase Inhibitor p15 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-dependent kinases; Diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; European Continental Ancestry Group - genetics; Exons - genetics; France; Genealogy; Genetic Predisposition to Disease; Genetic Variation; Genomes; Genotype & phenotype; Human Physiology; Humans; Internal Medicine; Introns - genetics; Kinases; Linkage Disequilibrium; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; noninsulin-dependent diabetes mellitus; Polymorphism; Polymorphism, Single Nucleotide; Replication; Short Communication; single nucleotide polymorphism; SNP; tag SNP; France; Paris France; CDKN2A/CDKN2B; Type 2 diabetes; Common variant; Association; SNP; Replication; Single nucleotide polymorphism; tag SNP; Endocrinopathy; Metabolic diseases; Variant; French; Polymorphism
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-008-0973-4

Aims/hypothesis Genome-wide association studies (GWASs) recently identified common variants in the CDKN2A/CDKN2B region on chromosome 9p as being strongly associated with type 2 diabetes. Since these association signals were not picked up by the French-Canadian GWAS, we sought to replicate these findings in the French Europid population and to further characterise the susceptibility variants at this novel locus. Methods We genotyped 20 single nucleotide polymorphisms (SNPs) spanning the CDKN2A/CDKN2B locus in our type 2 diabetes case-control cohort. The association between CDKN2A/CDKN2B SNPs and quantitative metabolic traits was also examined in the normoglycaemic participants comprising the control cohort. Results We report replication of the strong association of rs10811661 with type 2 diabetes found in the GWASs ( [graphic removed] ; OR 1.43 [95% CI 1.24-1.64]). The other CDKN2A/CDKN2B susceptibility variant, rs564398, did not attain statistical significance (p = 0.053; OR 1.11 [95% CI 1.00-1.24]) in the present study. We also obtained several additional nominal association signals (p < 0.05) at the CDKN2A/CDKN2B locus; however, only the rs3218018 result (p = 0.002) survived Bonferroni correction for multiple testing (adjusted p = 0.04). Conclusions/interpretation Our comprehensive association study of common variation spanning the CDKN2A/CDKN2B locus confirms the strong association between the distal susceptibility variant rs10811661 and type 2 diabetes in the French population. Further genetic and functional studies are required to identify the aetiological variants at this locus and determine the cellular and physiological mechanisms by which they act to modulate type 2 diabetes susceptibility.