title: Type 2 diabetes (T2D) associated polymorphisms regulate expression of adjacent transcripts in transformed lymphocytes, adipose, and muscle from Caucasian and African-American subjects.
abstract: BACKGROUND
  Genome-wide association scans (GWAS) have identified novel single nucleotide polymorphisms (SNPs) that increase T2D susceptibility and indicated the role of nearby genes in T2D pathogenesis.
  
  
  OBJECTIVE
  We hypothesized that T2D-associated SNPs act as cis-regulators of nearby genes in human tissues and that expression of these transcripts may correlate with metabolic traits, including insulin sensitivity (S(I)).
  
  
  METHODS
  Association of SNPs with the expression of their nearest transcripts was tested in adipose and muscle from 168 healthy individuals who spanned a broad range of S(I) and body mass index (BMI) and in transformed lymphocytes (TLs). We tested correlations between the expression of these transcripts in adipose and muscle with metabolic traits. Utilizing allelic expression imbalance (AEI) analysis we examined the presence of other cis-regulators for those transcripts in TLs.
  
  
  RESULTS
  SNP rs9472138 was significantly (P = 0.037) associated with the expression of VEGFA in TLs while rs6698181 was detected as a cis-regulator for the PKN2 in muscle (P = 0.00027) and adipose (P = 0.018). Significant association was also observed for rs17036101 (P = 0.001) with expression of SYN2 in adipose of Caucasians. Among 19 GWAS-implicated transcripts, expression of VEGFA in adipose was correlated with BMI (r = -0.305) and S(I) (r = 0.230). Although only a minority of the T2D-associated SNPs were validated as cis-eQTLs for nearby transcripts, AEI analysis indicated presence of other cis-regulatory polymorphisms in 54% of these transcripts.
  
  
  CONCLUSIONS
  Our study suggests that a small subset of GWAS-identified SNPs may increase T2D susceptibility by modulating expression of nearby transcripts in adipose or muscle.
authors.affiliation: Section on Endocrinology and Metabolism, Department of Internal Medicine, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.
authors.forename: Neeraj K
authors.initials: NK
authors.lastname: Sharma
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Langberg
authors.forename: Ashis K
authors.initials: AK
authors.lastname: Mondal
authors.forename: Steven C
authors.initials: SC
authors.lastname: Elbein
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Das
mesh_terms: D000328:Adult; D022981:Allelic Imbalance; D044383:Black People; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D005947:Glucose; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci; D050151:Subcutaneous Fat / Q000378:metabolism*; D044465:White People; D055815:Young Adult; D001741:Black or African American
chemical_list: D007328:Insulin; D005947:Glucose