Open AccessDifferential promoter activity by nucleotide substitution at a type 2 diabetes genome‐wide association study signal upstream of the wolframin gene
Author(s) -
Ryu Jihye,
Lee Chaeyoung
Publication year - 2016
Publication title -
journal of diabetes
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.949
H-Index - 43
eISSN - 1753-0407
pISSN - 1753-0393
DOI - 10.1111/1753-0407.12289
Subject(s) - single nucleotide polymorphism , genome wide association study , genetics , haplotype , linkage disequilibrium , genetic association , biology , allele , promoter , gene , genotype , gene expression
Background Functional knowledge of most genetic variants identified from genome‐wide association studies ( GWAS ) for type 2 diabetes ( T2D ) is limited. A recent T2D GWAS revealed an association signal (rs4689388) upstream of the gene encoding W olfram syndrome 1 ( WFS1 ) whose intrinsic nucleotide variants had been previously associated with T2D in several candidate gene analyses. The aim of the present study was to identify functional variants of the GWAS signal. Methods Promoter activity of luciferase reporter constructs was compared with haplotypes including variants composing a linkage disequilibrium block in the vicinity of rs4689388 in HEK293 and HepG2 cells. Results Promoter activity was highest with the most frequent haplotype ( H1 ; ATCGT ) and lowest with second most frequent haplotype ( H2 ; GATCG ), whose nucleotide alleles were all complementary to those of H1 . Further analysis with artificial haplotypes revealed differential transcriptional activity by nucleotide substitution of rs4320200 , rs13107806 , or rs13127445 ( P < 0.05). This concurred with changes in predicted transcription factor binding site by their allele substitutions. Conclusions The previously reported GWAS signal for T2D may be identified by the differential promoter activity of rs4320200 , rs13107806 , and rs13127445 in the promoter of WFS1 by nucleotide substitution.