Polymorphisms of HepG2/Erythrocyte Glucose-Transporter Gene: Linkage Relationships and Implications for Genetic Analysis of NIDDM

To assess the contribution of the HepG2/erythrocyte glucose-transporter (HepG2 GT) gene to the inherited susceptibility to non-insulin-dependent diabetes mellitus (NIDDM), cDNA and genomic probes were used to search for restriction-endonuclease polymorphisms at this locus. Analysis of DNA from 16 unrelated Black American individuals with 19 enzymes and as many as six different probes, defined four polymorphisms over a 45-kilobase region. Nucleotide diversity (π = 0.006) was low relative to that at other loci, with an average of 1 in 1700 base pairs different between two chromosomes at this locus. The observed combined heterozygosity for these four sites was 0.69, which indicates that the markers at this locus could be useful for linkage analysis in families. Linkage-disequilibrium values between the four polymorphisms were evaluated by pairwise analysis and extended haplotypes. Calculating pairwise associations by the disequilibrium statistic Δ or by another measure of disequilibrium, D′ (the maximum likelihood of disequilibrium, which is less dependent on frequency), significant linkage disequilibrium could not be demonstrated. However, the frequencies of the observed extended haplotypes were shown to differ (χ² = 9.1, df = 2, P < 0.025) from predicted frequencies if the sites were in linkage equilibrium in Blacks. The frequencies of these four polymorphisms were determined in Black nondiabetic (n = 44) and NIDDM (n = 63) subjects. Neither the allelic nor genotypic frequencies of the polymorphisms differed between the two groups. Extended haplotypes were evaluated at Bgl II, Taq I, and Pst I restriction-fragment–length polymorphisms (RFLPs) on 176 alleles, and for the combined analysis of all four RFLPs, extended haplotypes could be assigned for 94 alleles. The frequencies of these haplotypes did not differ between nondiabetic NIDDM subjects (P > 0.05). The importance of this analysis is the finding of significant linkage disequilibrium between four polymorphic sites at the HepG2 GT locus and the lack of association with NIDDM in Blacks. Thus, these results suggested that this locus contributes little to the inherited susceptibility to NIDDM in Blacks.