Extension of type 2 diabetes genome-wide association scan results in the diabetes prevention program.
OBJECTIVE
Genome-wide association scans (GWASs) have identified novel diabetes-associated genes. We evaluated how these variants impact diabetes incidence, quantitative glycemic traits, and response to preventive interventions in 3,548 subjects at high risk of type 2 diabetes enrolled in the Diabetes Prevention Program (DPP), which examined the effects of lifestyle intervention, metformin, and troglitazone versus placebo.


METHODS
We genotyped selected single nucleotide polymorphisms (SNPs) in or near diabetes-associated loci, including EXT2, CDKAL1, CDKN2A/B, IGF2BP2, HHEX, LOC387761, and SLC30A8 in DPP participants and performed Cox regression analyses using genotype, intervention, and their interactions as predictors of diabetes incidence. We evaluated their effect on insulin resistance and secretion at 1 year.


RESULTS
None of the selected SNPs were associated with increased diabetes incidence in this population. After adjustments for ethnicity, baseline insulin secretion was lower in subjects with the risk genotype at HHEX rs1111875 (P = 0.01); there were no significant differences in baseline insulin sensitivity. Both at baseline and at 1 year, subjects with the risk genotype at LOC387761 had paradoxically increased insulin secretion; adjustment for self-reported ethnicity abolished these differences. In ethnicity-adjusted analyses, we noted a nominal differential improvement in beta-cell function for carriers of the protective genotype at CDKN2A/B after 1 year of troglitazone treatment (P = 0.01) and possibly lifestyle modification (P = 0.05).


CONCLUSIONS
We were unable to replicate the GWAS findings regarding diabetes risk in the DPP. We did observe genotype associations with differences in baseline insulin secretion at the HHEX locus and a possible pharmacogenetic interaction at CDKNA2/B.
Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Allan F
AF
Moore
Kathleen A
KA
Jablonski
Jarred B
JB
McAteer
Richa
R
Saxena
Toni I
TI
Pollin
Paul W
PW
Franks
Robert L
RL
Hanson
Alan R
AR
Shuldiner
William C
WC
Knowler
David
D
Altshuler
Jose C
JC
Florez
D001741:Black or African American / Q000235:genetics / Q000706:statistics & numerical data; D027682:Cation Transport Proteins / Q000235:genetics; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology* / Q000235:genetics* / Q000517:prevention & control; D005787:Gene Frequency; D023281:Genomics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D015994:Incidence; D008019:Life Style; D008875:Middle Aged; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D016601:RNA-Binding Proteins / Q000235:genetics; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data; D000075703:Zinc Transporter 8; D012359:tRNA Methyltransferases; D000099065:Exostosin 2
C493966:CDKN2B protein, human; D027682:Cation Transport Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; C078492:HHEX protein, human; D018398:Homeodomain Proteins; C498779:IGF2BP2 protein, human; D016601:RNA-Binding Proteins; C492522:SLC30A8 protein, human; D014157:Transcription Factors; D000075703:Zinc Transporter 8; D012359:tRNA Methyltransferases; D017351:N-Acetylglucosaminyltransferases; D000099065:Exostosin 2; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human