Association analysis of variation in/near FTO, CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, LOC387761, and CDKN2B with type 2 diabetes and related quantitative traits in Pima Indians.
OBJECTIVE
In recent genome-wide association studies, variants in CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, CDKN2B, LOC387761, and FTO were associated with risk for type 2 diabetes in Caucasians. We investigated the association of these single nucleotide polymorphisms (SNPs) and some additional tag SNPs with type 2 diabetes and related quantitative traits in Pima Indians.


METHODS
Forty-seven SNPs were genotyped in 3,501 Pima Indians informative for type 2 diabetes and BMI, among whom 370 had measures of quantitative traits.


RESULTS
FTO provided the strongest evidence for replication, where SNPs were associated with type 2 diabetes (odds ratio = 1.20 per copy of the risk allele, P = 0.03) and BMI (P = 0.002). None of the other previously reported SNPs were associated with type 2 diabetes; however, associations were found between CDKAL1 and HHEX variants and acute insulin response (AIR), where the Caucasian risk alleles for type 2 diabetes were associated with reduced insulin secretion in normoglycemic Pima Indians. Multiallelic analyses of carrying risk alleles for multiple genes showed correlations between number of risk alleles and type 2 diabetes and impaired insulin secretion in normoglycemic subjects (P = 0.006 and 0.0001 for type 2 diabetes and AIR, respectively), supporting the hypothesis that many of these genes influence diabetes risk by affecting insulin secretion.


CONCLUSIONS
Variation in FTO impacts BMI, but the implicated common variants in the other genes did not confer a significant risk for type 2 diabetes in Pima Indians. However, confidence intervals for their estimated effects were consistent with the small effects reported in Caucasians, and the multiallelic "genetic risk profile" identified in Caucasians is associated with diminished early insulin secretion in Pima Indians.
Rong
Rong
R
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.
Hanson
Robert L
RL
Ortiz
Daniel
D
Wiedrich
Christopher
C
Kobes
Sayuko
S
Knowler
William C
WC
Bogardus
Clifton
C
Baier
Leslie J
LJ
D000293:Adolescent; D000328:Adult; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D027682:Cation Transport Proteins / Q000235:genetics; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D055815:Young Adult; D000075703:Zinc Transporter 8; D012359:tRNA Methyltransferases; D000099065:Exostosin 2
D027682:Cation Transport Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; C078492:HHEX protein, human; D018398:Homeodomain Proteins; C498779:IGF2BP2 protein, human; D011506:Proteins; D016601:RNA-Binding Proteins; C492522:SLC30A8 protein, human; D014157:Transcription Factors; D000075703:Zinc Transporter 8; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; D012359:tRNA Methyltransferases; D017351:N-Acetylglucosaminyltransferases; D000099065:Exostosin 2; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human