The association of ENPP1 K121Q with diabetes incidence is abolished by lifestyle modification in the diabetes prevention program.
BACKGROUND
Insulin resistance is an important feature of type 2 diabetes. Ectoenzyme nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin signaling, and a recent meta-analysis reported a nominal association between the Q allele in the K121Q (rs1044498) single nucleotide polymorphism in its gene ENPP1 and type 2 diabetes. OBJECTIVE AND INTERVENTION: We examined the impact of this polymorphism on diabetes incidence as well as insulin secretion and sensitivity at baseline and after treatment with a lifestyle intervention or metformin vs. placebo in the Diabetes Prevention Program (DPP). DESIGN, SETTING, PARTICIPANTS, AND OUTCOME: We genotyped ENPP1 K121Q in 3548 DPP participants and performed Cox regression analyses using genotype, intervention, and interactions as predictors of diabetes incidence.


RESULTS
Fasting glucose and glycated hemoglobin were higher in QQ homozygotes at baseline (P < 0.001 for both). There was a significant interaction between genotype at rs1044498 and intervention under the dominant model (P = 0.03). In analyses stratified by treatment arm, a positive association with diabetes incidence was found in Q allele carriers compared to KK homozygotes [hazard ratio (HR), 1.38; 95% confidence interval (CI), 1.08-1.76; P = 0.009] in the placebo arm (n = 996). Lifestyle modification eliminated this increased risk. These findings persisted after adjustment for body mass index and race/ethnicity. Association of ENPP1 K121Q genotype with diabetes incidence under the additive and recessive genetic models showed consistent trends [HR, 1.10 (95% CI, 0.99-1.23), P = 0.08; and HR, 1.16 (95% CI, 0.92-1.45), P = 0.20, respectively] but did not reach statistical significance.


CONCLUSIONS
ENPP1 K121Q is associated with increased diabetes incidence; the DPP lifestyle intervention eliminates this increased risk.
Moore
Allan F
AF
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114-2622, USA.
Jablonski
Kathleen A
KA
Mason
Clinton C
CC
McAteer
Jarred B
JB
Arakaki
Richard F
RF
Goldstein
Barry J
BJ
Kahn
Steven E
SE
Kitabchi
Abbas E
AE
Hanson
Robert L
RL
Knowler
William C
WC
Florez
Jose C
JC
D002839:Chromans / Q000008:administration & dosage; D003131:Combined Modality Therapy; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics / Q000517:prevention & control*; D005081:Exercise Therapy; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000517:prevention & control*; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D015994:Incidence; D008239:Lysine / Q000235:genetics; D008297:Male; D008687:Metformin / Q000008:administration & dosage; D008875:Middle Aged; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000235:genetics*; D040242:Risk Reduction Behavior; D045162:Thiazolidinediones / Q000008:administration & dosage; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D018698:Glutamic Acid; D008687:Metformin; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases; D000077288:Troglitazone; D008239:Lysine