title: Variants of the PPARG, IGF2BP2, CDKAL1, HHEX, and TCF7L2 genes confer risk of type 2 diabetes independently of BMI in the German KORA studies.
abstract: Genome-wide association (GWA) studies identified novel gene variants that are associated with type 2 diabetes. However, results were not always consistent across different populations. Thus, the aims of this study were (i) to replicate findings from previous GWA studies in mainly Northern European populations using data from the German KORA 500 K diabetes project and (ii) to assess the impact of BMI on associations between single nucleotide polymorphisms (SNPs) and type 2 diabetes. The KORA 500 K diabetes project includes 433 cases with validated type 2 diabetes and 1 438 nondiabetic controls from two population-based KORA surveys. Genotyping was performed using the Affymetrix GeneChip Human Mapping 500 K Array Set. We investigated associations between SNPs and type 2 diabetes in 10 genes that have been reported to increase the risk of type 2 diabetes or were in complete or near-complete linkage disequilibrium with these variants. SNPs in the CDKAL1 gene showed the strongest association with type 2 diabetes [range of age and sex-adjusted odds ratios (OR): 1.30-1.39, p-values 0.0008-0.0004]. In addition, we found evidence for association of SNPs in the genes PPARG, IGF2BP2, HHEX, TCF7L2, and FTO with type 2 diabetes in the same directions as previously described (p<0.05), but not for WFS1, CDKN2A/B, KCNJ11, or EXT2. Adjustment for BMI slightly strengthened the link between CDKAL1 and type 2 diabetes, but had almost no impact on the other associations. We conclude that gene variants of CDKAL1, PPARG, IGF2BP2, HHEX, TCF7L2, and FTO predispose to type 2 diabetes in the German KORA 500 K study population. These associations appear to be independent of BMI.
authors.affiliation: Institute for Clinical Diabetes Research, German Diabetes Centre, Leibniz Centre at Heinrich Heine University Düsseldorf, Düsseldorf, Germany. christian.herder@ddz.uni-duesseldorf.de
authors.forename: C
authors.initials: C
authors.lastname: Herder
authors.forename: W
authors.initials: W
authors.lastname: Rathmann
authors.forename: K
authors.initials: K
authors.lastname: Strassburger
authors.forename: H
authors.initials: H
authors.lastname: Finner
authors.forename: H
authors.initials: H
authors.lastname: Grallert
authors.forename: C
authors.initials: C
authors.lastname: Huth
authors.forename: C
authors.initials: C
authors.lastname: Meisinger
authors.forename: C
authors.initials: C
authors.lastname: Gieger
authors.forename: S
authors.initials: S
authors.lastname: Martin
authors.forename: G
authors.initials: G
authors.lastname: Giani
authors.forename: W A
authors.initials: WA
authors.lastname: Scherbaum
authors.forename: H-E
authors.initials: HE
authors.lastname: Wichmann
authors.forename: T
authors.initials: T
authors.lastname: Illig
mesh_terms: D000328:Adult; D000368:Aged; D015992:Body Mass Index; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005858:Germany; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics*; D051820:TCF Transcription Factors / Q000235:genetics; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics; D044465:White People / Q000235:genetics*; D012359:tRNA Methyltransferases; D000099065:Exostosin 2; D000099161:Kcnj11 Channel
chemical_list: D051360:Cyclin-Dependent Kinase 5; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D017351:N-Acetylglucosaminyltransferases; D047495:PPAR gamma; D024661:Potassium Channels, Inwardly Rectifying; D016601:RNA-Binding Proteins; D051820:TCF Transcription Factors; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D012359:tRNA Methyltransferases; D000099065:Exostosin 2; D000099161:Kcnj11 Channel; C493966:CDKN2B protein, human; C078492:HHEX protein, human; C498779:IGF2BP2 protein, human; C544894:TCF7L2 protein, human; C114987:wolframin protein; C525110:CDKAL1 protein, human