A NOVEL (TA)(N) POLYMORPHISM IN THE HEXOKINASE-II GENE - APPLICATION TO NONINSULIN-DEPENDENT DIABETES-MELLITUS IN THE PIMA-INDIANS

Hexokinase II, one member of a family of structurally similar enzymes that catalyze the phosphorylation of glucose in the 6-position, has be en suggested to play a role in the pathophysiology of noninsulin-depen dent diabetes mellitus (NIDDM). The gene for hexokinase II, HK2, has b een previously mapped to human chromosome 2p13 by fluorescence in situ hybridization, and two-point linkage analysis has placed it near the locus for transforming growth factor alpha, TGFA. We now report the ch aracterization of a (TA)(n) polymorphism in intron 12 of HK2. Using mu ltipoint analysis of CEPH family genotypes, we have determined the mos t likely locus order to be S286-HK2]-[D2S145-D2S291]-[D2S45-D2S101-TGF A]-tel. As HKII is a candidate gene that could contribute to the manif estation of insulin resistance and NIDDM, we genotyped 1152 Pima India ns, a Native American tribe that has the highest reported prevalence o f NIDDM in the world. Although we did not detect any linkage or associ ation of HK2 with insulin resistance or NIDDM in the Pima Indians, the polymorphism and detailed mapping of HK2 described in this report sho uld prove useful in the assessment of the role of this gene in the pre disposition to NIDDM in other populations.