title: Lack of association of the HMGA1 IVS5-13insC variant with type 2 diabetes in an ethnically diverse hypertensive case control cohort.
abstract: BACKGROUND
  Recently, the high-mobility group A1 gene (HMGA1) variant IVS5-13insC has been associated with type 2 diabetes, but reported associations are inconsistent and data are lacking in Hispanic and African American populations. We sought to investigate the HMGA1-diabetes association and to characterize IVS5-13insC allele frequencies and linkage disequilibrium (LD) in 3,070 Caucasian, Hispanic, and African American patients from the INternational VErapamil SR-Trandolapril STudy (INVEST).
  
  
  METHODS
  INVEST was a randomized, multicenter trial comparing two antihypertensive treatment strategies in an ethnically diverse cohort of hypertensive, coronary artery disease patients. Controls, who were diabetes-free throughout the study, and type 2 diabetes cases, either prevalent or incident, were genotyped for IVS5-13insC using Taqman®, confirmed with Pyrosequencing and Sanger sequencing. For LD analysis, genotyping for eight additional HMGA1 single nucleotide polymorphisms (SNPs) was performed using the Illumina® HumanCVD BeadChip. We used logistic regression to test association of the HMGA1 IVS5-13insC and diabetes, adjusted for age, gender, body mass index, and percentage European, African, and Native American ancestry.
  
  
  RESULTS
  We observed IVS5-13insC minor allele frequencies consistent with previous literature in Caucasians and African Americans (0.03 in cases and 0.04 in controls for both race/ethnic groups), and higher frequencies in Hispanics (0.07 in cases and 0.07 in controls). The IVS5-13insC was not associated with type 2 diabetes overall (odds ratio 0.98 [0.76-1.26], p=0.88) or in any race/ethnic group. Pairwise LD (r2) of IVS5-13insC and rs9394200, a SNP previously used as a tag SNP for IVS5-13insC, was low (r2=0.47 in Caucasians, r2=0.25 in Hispanics, and r2=0.06 in African Americans). Furthermore, in silico analysis suggested a lack of functional consequences for the IVS5-13insC variant.
  
  
  CONCLUSIONS
  Our results suggest that IVS5-13insC is not a functional variant and not associated with type 2 diabetes in an ethnically diverse, hypertensive, coronary artery disease population. Larger, more adequately powered studies need to be performed to confirm our findings.
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University, Nashiville, TN 37232-0575, USA.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Karnes
authors.forename: Taimour Y
authors.initials: TY
authors.lastname: Langaee
authors.forename: Caitrin W
authors.initials: CW
authors.lastname: McDonough
authors.forename: Shin-Wen
authors.initials: SW
authors.lastname: Chang
authors.forename: Miguel
authors.initials: M
authors.lastname: Ramos
authors.forename: James R
authors.initials: JR
authors.lastname: Catlin
authors.forename: Octavio E
authors.initials: OE
authors.lastname: Casanova
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Pepine
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Cooper-Dehoff
mesh_terms: D000368:Aged; D044383:Black People; D016022:Case-Control Studies; D015331:Cohort Studies; D018864:Cultural Diversity; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000208:ethnology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D025741:HMGA1a Protein / Q000235:genetics*; D006630:Hispanic or Latino; D006801:Humans; D006973:Hypertension / Q000150:complications* / Q000208:ethnology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044465:White People; D001741:Black or African American
chemical_list: D025741:HMGA1a Protein