Common variants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the diabetes prevention program.
OBJECTIVE
Genome-wide association studies have begun to elucidate the genetic architecture of type 2 diabetes. We examined whether single nucleotide polymorphisms (SNPs) identified through targeted complementary approaches affect diabetes incidence in the at-risk population of the Diabetes Prevention Program (DPP) and whether they influence a response to preventive interventions.


METHODS
We selected SNPs identified by prior genome-wide association studies for type 2 diabetes and related traits, or capturing common variation in 40 candidate genes previously associated with type 2 diabetes, implicated in monogenic diabetes, encoding type 2 diabetes drug targets or drug-metabolizing/transporting enzymes, or involved in relevant physiological processes. We analyzed 1,590 SNPs for association with incident diabetes and their interaction with response to metformin or lifestyle interventions in 2,994 DPP participants. We controlled for multiple hypothesis testing by assessing false discovery rates.


RESULTS
We replicated the association of variants in the metformin transporter gene SLC47A1 with metformin response and detected nominal interactions in the AMP kinase (AMPK) gene STK11, the AMPK subunit genes PRKAA1 and PRKAA2, and a missense SNP in SLC22A1, which encodes another metformin transporter. The most significant association with diabetes incidence occurred in the AMPK subunit gene PRKAG2 (hazard ratio 1.24, 95% CI 1.09-1.40, P = 7 × 10(-4)). Overall, there were nominal associations with diabetes incidence at 85 SNPs and nominal interactions with the metformin and lifestyle interventions at 91 and 69 mostly nonoverlapping SNPs, respectively. The lowest P values were consistent with experiment-wide 33% false discovery rates.


CONCLUSIONS
We have identified potential genetic determinants of metformin response. These results merit confirmation in independent samples.
Jablonski
Kathleen A
KA
The Biostatistics Center, George Washington University, Rockville, Maryland, USA. dppmail@biostat.bsc.gwu.edu
McAteer
Jarred B
JB
de Bakker
Paul I W
PI
Franks
Paul W
PW
Pollin
Toni I
TI
Hanson
Robert L
RL
Saxena
Richa
R
Fowler
Sarah
S
Shuldiner
Alan R
AR
Knowler
William C
WC
Altshuler
David
D
Florez
Jose C
JC
D000328:Adult; D015992:Body Mass Index; D003920:Diabetes Mellitus / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005006:Ethnicity; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006420:Hemeproteins / Q000235:genetics; D006801:Humans; D015994:Incidence; D008019:Life Style; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D044469:Racial Groups
D006420:Hemeproteins; D027701:Organic Cation Transport Proteins; D008687:Metformin