title: Insulin Promoter Factor 1 variation is associated with type 2 diabetes in African Americans.
abstract: BACKGROUND
  Defective insulin secretion is a key defect in the pathogenesis of type 2 diabetes (T2DM). The beta-cell specific transcription factor, insulin promoter factor 1 gene (IPF1), is essential to pancreatic development and the maintenance of beta-cell mass. We hypothesized that regulatory or coding variants in IPF1 contribute to defective insulin secretion and thus T2DM.
  
  
  METHODS
  We screened 71 Caucasian and 69 African American individuals for genetic variants in the promoter region, three highly conserved upstream regulatory sequences (PH1, PH2 and PH3), the human beta-cell specific enhancer, and the two exons with adjacent introns. We tested for an association of each variant with T2DM Caucasians (192 cases and 192 controls) and African Americans (341 cases and 186 controls).
  
  
  RESULTS
  We identified 8 variants in the two populations, including a 3 bp insertion in exon 2 (InsCCG243) in African Americans that resulted in an in-frame proline insertion in the transactivation domain. No variant was associated with T2DM in Caucasians, but polymorphisms at -3766 in the human beta-cell enhancer, at -2877 bp in the PH1 domain, and at -108 bp in the promoter region were associated with T2DM in African American subjects (p < 0.01), both individually and as haplotypes (p = 0.01 correcting by permutation test). No SNP altered a binding site for the expected beta-cell transcription factors. The rare alleles of InsCCG243 in exon 2 showed a trend to over-representation among African American diabetic subjects (p < 0.1), but this trend was not significant on permutation test.
  
  
  CONCLUSIONS
  The common alleles of regulatory variants in the 5' enhancer and promoter regions of the IPF1 gene increase susceptibility to type 2 diabetes among African American individuals, likely as a result of gene-gene or gene-environment interactions. In contrast, IPF1 is not a cause of type 2 diabetes in Caucasians. A previously described InsCCG243 variant may contribute to diabetes susceptibility in African American individuals, but is of low penetrance.
authors.affiliation: Endocrinology Section, Medical Service, Central Arkansas Veterans Healthcare System, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. karimmohammada@uams.edu
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Karim
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Wang
authors.forename: Terri C
authors.initials: TC
authors.lastname: Hale
authors.forename: Steven C
authors.initials: SC
authors.lastname: Elbein
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D015534:Trans-Activators / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein