Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of Type II diabetes mellitus in Caucasians

K+ inwardly rectifier channel (KIR) is one of the two sub-units of the panc reatic islet ATP-sensitive potassium channel complex (I-KATP), which has a key role in glucose-stimulated insulin secretion and thus is a potential ca ndidate for a genetic defect in Type II (non-insulin-dependent) diabetes me llitus. We did a molecular screening of the KIR6.2 gene by single strand co nformational polymorphism (SSCP) and direct sequencing in 72 French Caucasi an Type II diabetic families. We identified three nucleotide substitutions resulting in three amino acid changes (E23K, L270V and I337V), that have al so been identified in other Caucasian Type II diabetic subjects. These vari ants were genotyped in French cohorts of 191 unrelated Type II diabetic pro bands and 119 normoglycaemic control subjects and association studies were done. The genotype frequencies of the L270V and I337V variants were not ver y different between Type II diabetic subjects and control groups. In contra st, analysis of the E23K variant showed that the KK homozygocity was more f requent in Type II diabetic than in control subjects (27 vs 14%, p = 0.015) Analyses in a recessive model (KK vs EK/EE) tended to show a stronger asso ciation of the K allele with diabetes (p = 0.0097, corrected p-value for mu ltiple testing < 0.02). The data for the E23K variant obtained here and tho se obtained from three other Caucasian groups studied so far were combined and investigated by meta-analysis. Overall, the E23K variant was found to b e significantly associated with Type II diabetes (0.001 less than or equal to p less than or equal to 0.0016, corrected p-values for multiple testing p less than or equal to 0.01). This study shows that KIR6.2 polymorphisms a re frequently associated with Type II diabetes in French Caucasians. Furthe r more, a meta-analysis combining different Caucasian groups suggests an si gnificant role of KIR6.2 in the polygenic context of Type II diabetes.