Association of genetic variations in TCF7L2, SLC30A8, HHEX, LOC387761, and EXT2 with Type 2 diabetes mellitus in Tunisia

In recent genome-wide association studies, genetic variants in TCF7L2, SLC30A8, HHEX, LOC387761, and EXT2 were associated with risk for type 2 diabetes mellitus (T2DM). We aimed at investigating the association of these single-nucleotide polymorphisms (SNPs) with T2DM and defining their corresponding allelic and genotypic combinations in the Tunisian population. We also tried to determine the effect of R325W of SLC30A8 on the modeled structural properties of the protein. Five SNPs were genotyped in 331 T2DM Tunisian patients and 403 healthy subjects by polymerase chain reaction-restriction fragment length polymorphism. A model of residues 318-366 of the SLC30A8 protein was built by homology modeling. LOC387761 provided the strongest evidence for replication, where rs7480010 presented a risk of 2.41 with T2DM, followed by rs1111875 in HHEX (odds ratio=1.95) and rs13266634 in SLC30A8 (odds ratio=1.59). None of the two other SNPs previously reported was associated. The highest risk of T2DM was 3.1, obtained by the genotype combination of the three associated SNPs. Modeling of the cytoplasmic part of the SLC30A8 protein showed that the R325W change might affect the electrostatic potential of the SLC30A8 protein. We concluded that the SLC30A8, HHEX, and LOC387761 are more likely to represent the genuine signals of T2DM in the Tunisian population.