Aim: Type 2 diabetes (T2D) is a complex polygenic disorder. Genetic predisposition may vary in different ethnic groups. A potential candidate gene for T2D is Neurogenin 3 (Ngn3, NEUROG3), which lies on chromosome 10 in a region with several potential linkage signals to T2D in various population studies. The goal of this study was to establish whether NEUROG3 gene variants are contributing to T2D in an Italian T2D cohort.
Methods: We genotyped AFMa210xh1 macrosatellite marker in 202 Italian T2D families/sib-pairs. We performed two-point linkage analysis in the late- and early-onset dataset. For the case control study, we selected families with a positive logarithm of odds (LOD) score. Then, we screened NEUROG3 in the selected 61 single unrelated T2D patients and 101 Italian controls and performed association studies.
Results: Several variants were identified: a new 152ntC/G, and 44-45delCA, Gly167Arg, Ser 199Phe single nucleotide polymorphisms (SNPs) and 2 new 5'UTR variations (-nt498G/T and nt367C/T) and a new Gly167fsinsCAE Arg167X234 mutation. The variants 44-45delCA/ Ser199Phe and Gly167Arg/Ser199Phe show significant linkage disequilibrium. The haplotype CCCAGT/A/C shows association to T2D in our cohort, while the allele 167Arg, the haplotypes CCCAGT/A and A/C and the diplotype LL/GA/TC show a trend towards association to disease. The 5'UTR and frameshift variants are absent in the controls. Nonparametric linkage analysis within NEUROG3 variants in 9 early-onset T2D families shows a nonparametric LOD score=2.49 (P=0.006).
Conclusions: The biological impact of NEUROG3 might be due to the presence of either CCCAGT at 44-45nt, 167Arg, 199Ser or by a haplotype combination of these 3 or 2 of them.