Association Of (s)ANK1 Gene With Type 2 Diabetes Risk

Type 2 diabetes(T2D)is one of the most importantpublic health problems worldwide,results from complex interaction between a number of genetic and environmental factors.Genetic studies have identified the(small)ankyrin-1[(s)ANK1]locus as a strong susceptibility locus forT2D.But these studies showed inconsistent results regarding the relationship between SNPs in(s)ANK1 and T2D,underlying mechanisms of susceptibility were unclear yet.And,the relationship of these variants with T2D was unrevealed in a Chinese population.The purpose of this study was to evaluate the association between(s)ANK1 gene and T2D in Han Chinese population,and to explore the mechanism of the association.Part ?:Associaton between(s)ANK1 gene and T2DEight tag or reported SNPs were genotyped in one cohort(Cohort A:441 T2D versus 441 controls),and 3 SNPswith P-value of<0.01 were evaluated in another cohort(Cohort A:773 T2D versus 773 controls).Then,rs508419,first reported here,rs515071 and rs516946 in(s)ANK1 were identified associated with T2D in the Chinese population(P<0.001).The mapping and cluster of these SNPs were analyzed,and we found that the 3 SNPs were all located in sANK1 and tightly linked and rs508419 was located in the promoter region of sANK1.All of these founding suggested that the association between(s)ANK1 and T2D mainly relied on the small ankyrin1(sANK1),nor the regular transcript,which provided direction for the next mechanism exploration.Part ?:Exploration of the mechanisms by which the(s)ANK1 gene increase the risk of developing Type 2Based on the results found in Part ?,the underlying mechanism of how(s)ANKl gene increase T2D risk would be explored in such facts as follow:whether rs508419 affect the transcription and translation of sANK1;whether and how the protein level of sANKl associated with T2D.Methods used in this part were dual luciferase assay system,qPCR and western blot.Here,we found that the promoter activity of the rs508419-C allele increased 100-200%in C2C12 and Hela cell lines(P<0.001),and subjects carrying rs508419-CC genotype showed higher mRNA and protein express of sANKl in skeletal musclethan rs508419-CT/TT.Additionally,db/db mice with diabetes showed decreased expression of sANKl in skeletal muscle.To sum up,sANK1 increased T2D risk in Chinese population.The rs508419-C allele up regulated the transcription and translation of sANK1.But the mRNA and protein level of sANK1 in the muscle of obesity/diabetic db/db mice were decreased.More study is need to illuminate the role of sANKl in developing T2D.