Exp Clin Endocrinol Diabetes 2005; 113 - 101
DOI: 10.1055/s-2005-862960

Association of two genetic markers within the protein kinase C beta gene with type 2 diabetes mellitus

MA Osterhoff 1, M Herrmann 1, M Lazdins 2, S Kaiser 1, R Assert 2, MO Weickert 1, J Spranger 1, M Möhlig 1, AFH Pfeiffer 1
  • 1German Institute of Human Nutrition, Potsdam-Rehbruecke, Charité – Campus Benjamin Franklin, Berlin
  • 2University Hospital, Bergmannsheil, Bochum

Background and Aims: Type 2 Diabetes Mellitus is a multifactorial disease with a strong genetic background. The protein kinase Cb (PKCb) was proposed to be in part responsible for cellular insulin resistance and diabetic complications. In the PKCb gene (PRKCB1) we investigated a highly polymorphic (AC)n tandem repeat we found between exons 18 and 19 as well as five single nucleotide polymorphisms (SNP) regarding their influence on the risk for T2DM.

Material and Methods: We investigated 430 Caucasian control patients and 402 Caucasian T2DM patients in a case-control association study. The length of the (AC)n tandem repeat was sequenced. The genotype of the SNPs was determined by the single nucleotide primer extension method or by TaqMan technology.

Results: The case-control association study revealed highly significant differences in the distribution of the (AC)n allele frequencies between controls and T2DM patients. The appearance of allele *9 representing 23 AC repeats is significantly increased among T2DM patients (24% vs. 18%, Pc8=0.029). From 2 promoter and 3 exon SNPs one T/C-SNP in exon 11 not only was associated with the appearance of allele *9 (Pc8=0.0012) but also with T2DM increasing the risk 1.7 fold (CI(95%)=1.2–2.5, P=0.0025). The heterozygous genotype seems to be strongly protective. Between carriers and non-carriers of allele *9 there is no significant difference in susceptibility for T2DM when the genotype of exon 11 is TC heterozygous. In carriers of allele *9 together with the TT-genotype in exon 11 the relative risk for T2DM is increased 1.7 fold (CI(95%)=1.2–2.5, P=0.0025). The occurrence of the CC-genotype alone in non-carriers of allele *9 increases the risk for T2DM 1.7 fold (CI(95%)=1.1–2.6, P=0.0268) compared to the TT-genotype. A combination of allele *9 and the CC-genotype seems to increase the relative risk even more.

Conclusions: We postulate a novel T2DM susceptibility locus involving an (AC)n microsatellite-marker in combination with a single nucleotide polymorphism in exon 11 of the PRKCB1 gene locus acting synergistically.