POSITIVE ASSOCIATION IN THE ABSENCE OF LINKAGE SUGGESTS A MINOR ROLE FOR THE GLUCOKINASE GENE IN THE PATHOGENESIS OF TYPE-2 (NON-INSULIN-DEPENDENT) DIABETES-MELLITUS AMONGST SOUTH INDIANS

Mutations of the glucokinase gene have been implicated in the developm ent of glucose intolerance in pedigrees with maturity-onset diabetes o f the young. However, the contribution of the glucokinase gene to the aetiology of common Type 2 (non-insulin-dependent) diabetes mellitus i s uncertain. We have studied the role of the glucokinase gene in the p athogenesis of Type 2 diabetes in South Indians, using both population -association and linkage methodology. A pair of CA-repeat sequences (G CK(3') and GCK(5')) straddling the glucokinase gene were employed as m arkers, each subject being typed using the polymerase chain reaction a nd polyacrylamide gel electrophoresis. Comparisons of allele frequenci es at these markers were made between 168 Type 2 diabetic subjects and 70 racially-matched control subjects. No differences in allele freque ncies were apparent at the GCK(5') marker; however, there were signifi cant differences in allele frequencies at the GCK(3') marker between t he Type 2 diabetic subjects and control subjects (chi2 = 11.6, df = 3, p = 0.009) with an increase of the z allele (78.0 % vs 66.4 %) and a decrease of the z + 2 allele (I 3.7 % vs 25.0 %) amongst the diabetic subjects. Linkage between glucose intolerance and the glucokinase gene was studied in 53 nuclear pedigrees under a variety of genetic models . Linkage was excluded (lod score < -2) at a recombination fraction of zero under five of the ten models used and highly unlikely (-2 < lod score < -1) under the others. The combination of positive association and negative linkage suggests that glucokinase acts as a minor gene in fluencing the development of Type 2 diabetes within this population.