title: Quantitative trait analysis of type 2 diabetes susceptibility loci identified from whole genome association studies in the Insulin Resistance Atherosclerosis Family Study.
abstract: OBJECTIVE
  Evaluate type 2 diabetes susceptibility variants identified from genome-wide association studies in Hispanic Americans and African Americans from the Insulin Resistance Atherosclerosis Family Study (IRAS-FS) for association with quantitative measures of glucose homeostasis and determine their biological role in vivo.
  
  
  METHODS
  Seventeen type 2 diabetes-associated single nucleotide polymorphisms (SNPs) were genotyped in 1,268 Hispanic- and 581 African-American participants from the IRAS-FS. SNPs were tested for association with quantitative measures of glucose homeostasis, including insulin sensitivity index (S(I)), acute insulin response (AIR), and disposition index.
  
  
  RESULTS
  Previously identified risk variants in cyclin-dependent kinase 5 regulatory subunit associated protein 1-like 1 (CDKAL1) were associated with reduced AIR (P < 0.0046) in Hispanic Americans. Additionally in Hispanic Americans, the variant in a hypothetical gene (chromosome 11; LOC387761) was significantly associated with AIR (P = 0.0046) with the risk allele showing protective effects, i.e., increased AIR. In both Hispanic- and African-American populations, risk variants at the solute carrier family 30, member 8 (SLC30A8) locus were nominally associated with decreased disposition index (P < 0.078). Risk variants in the insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) locus were associated with a decreased disposition index (P = 0.011) exclusively in Hispanic Americans.
  
  
  CONCLUSIONS
  These data indicate a distinct, limited number of diabetes-related genes, more specifically the SNPs in the genes identified in European-derived populations, with modest evidence for association with glucose homeostasis traits in Hispanic Americans and African Americans. We observe evidence that diabetes risk for CDKAL1, SLC30A8, IGF2BP2, and LOC387761 is specifically mediated through defects in insulin secretion. The mechanisms of other predisposing genes remain to be elucidated.
authors.affiliation: Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.forename: Mark O
authors.initials: MO
authors.lastname: Goodarzi
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: Julie
authors.initials: J
authors.lastname: Ziegler
authors.forename: Jill M
authors.initials: JM
authors.lastname: Norris
authors.forename: Steven M
authors.initials: SM
authors.lastname: Haffner
authors.forename: Michael
authors.initials: M
authors.lastname: Bryer-Ash
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bergman
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Wagenknecht
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
mesh_terms: D000328:Adult; D050197:Atherosclerosis / Q000235:genetics*; D044383:Black People / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D003120:Colorado; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D015141:Los Angeles; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D008962:Models, Theoretical; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D001741:Black or African American
chemical_list: D001786:Blood Glucose