Identification of a New Signal for Type 2 Diabetes in the Previously Established GLIS3 Gene

OBJECTIVES: The Kruppel-like zinc finger protein Gli-similar (GLIS) 3 plays a crucial role in pancreatic β-cell development, and loss-of function mutations in this gene cause neonatal diabetes. Common variation in GLIS3 is also associated with both type 1 and type 2 diabetes in GWAS of other populations. GLI3 was analyzed as a candidate gene for T2D in Pima Indians. RESEARCH DESIGN AND METHODS: 280 tag SNPs across ~576 kb GLIS3 region (r2≥0.85, minor allele frequency ≥0.05; Chr9:3774128-4350035, ~50kb flanking each side of the gene) were genotyped in the Affymetrix Axiom Custom Chips as part of ongoing genome-wide association studies in a population-based sample of 3494 full-heritage Pima Indians. Data were analyzed for associations with T2D at early-onset (onset age<25 years) in a case/control sample (n=606) and at all ages (n=3494), and with acute insulin response assessed by an intravenous glucose bolus in full-heritage Pima Indians with normal glucose tolerance (n=298). RESULTS: An intronic SNP rs7850128, with a risk allele frequency (RAF) of 0.53, was associated with early-onset T2D [OR=1.45 (???-???) per risk allele, p=9.7 x 10-4] and T2D onset at any age [OR=1.22 (1.08-1.37) per risk allele, p=8.7 x 10-4]. Another intronic SNP rs7035478 (RAF=0.58) was also associated with early-onset T2D [OR=1.38 (???-???) per risk allele, p=0.004] and T2D onset at any age [OR=1.19 (1.06-1.34) per risk allele, p=0.004]. These two tags are in high LD (D’=0.99, r2=0.83), and conditional analyses demonstrated that both SNPs contributed to the same signal. However, the T2D risk allele at rs7850128 or 7035478 was not associated with acute insulin response (p=0.47, 0.53 respectively). SNP rs7041847, an established T2D variant in East Asians, was not associated with T2D in Pima Indians [RAF=0.65, OR=1.07 (0.95-1.22), p=0.27], suggesting that the SNP identified in Pima Indians represents a new signal in GLIS3 (D’=0.53, r2=0.22 between the Pima SNP and established SNP). CONCLUSION: An independent variant in GLIS3 affects risk for T2D in Pima Indian adults and children.