title: Differential promoter activity by nucleotide substitution at a type 2 diabetes genome-wide association study signal upstream of the wolframin gene.
abstract: 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 Wolfram 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.
authors: School of Systems Biomedical Science, Soongsil University, Seoul, Korea.
authors: Jihye
authors: J
authors: Ryu
authors: School of Systems Biomedical Science, Soongsil University, Seoul, Korea.
authors: Chaeyoung
authors: C
authors: Lee
mesh_terms: D000483:Alleles; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D020869:Gene Expression Profiling; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D057809:HEK293 Cells; D006239:Haplotypes; D056945:Hep G2 Cells; D006801:Humans; D015810:Linkage Disequilibrium; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D014157:Transcription Factors; C114987:wolframin protein; D008156:Luciferases
keywords: 2型糖尿病; genome-wide association; linkage disequilibrium; promoter activity; single nucleotide variant; type 2 diabetes; 全基因组关联; 单核苷酸变异; 启动子活性; 连锁不平衡