Lack of replication of common EXT2 gene variants with susceptibility to type 2 diabetes in Lebanese Arabs

Objective: Recent genome-wide association studies and replication analyses have reported the association of variants of the exostosin-2 (EXT2) gene and risk of type 2 diabetes mellitus (T2DM) in some populations, but not in others. This study investigated the associations of EXT2 variants rs1113132, rs3740878 and rs11037909 with T2DM in a Lebanese Arab population.

Methods: This case-control study involved 995 T2DM patients and 1076 control subjects. Genotyping was done by the allelic exclusion method.

Results: While minor allele frequencies (MAFs) of rs11037909 (P=0.028) and rs3740878 (P=0.048), but not rs1113132 (P=0.841), were higher in patients, this was lost after correcting for multiple testing. Apart from EXT2 rs1113132, which was marginally associated with T2DM in the additive model (P=0.054), but not after adjustment for covariates, none of the tested EXT2 SNPs were associated with T2DM in any of the genetic models tested. However, variable associations of EXT2 variants with T2DM were noted according to BMI status. While the three tested EXT2 variants were not associated with T2DM in obese subjects, rs1113132 and rs11037909, but not rs3740878, were associated with T2DM in non-obese subjects. Meta-analysis revealed a significant association of rs11037909 and a marginal association of rs3740878 with T2DM in the fixed model. Using a common (GTA) haplotype as reference, three-locus (rs1113132/rs11037909/rs3740878) haplotype analysis demonstrated no association between any of the EXT2 haplotypes with T2DM, not even before correcting for multiple testing.

Conclusion: This study demonstrated no association of rs1113132, rs3740878 and rs11037909 EXT2 variants with T2DM.