Studies of the relationship between the ENPP1 K121Q polymorphism and type 2 diabetes, insulin resistance and obesity in 7,333 Danish white subjects.
OBJECTIVE
Plasma cell membrane glycoprotein 1 (PC-1) inhibits insulin signalling by direct interaction with the insulin receptor alpha subunit. This inhibition is enhanced by the minor Q allele of the K121Q polymorphism (rs1044498) in the gene (ENPP1) encoding PC-1. This polymorphism has been studied in relation to insulin resistance, type 2 diabetes and obesity in several populations with conflicting results. We assessed the impact of the ENPP1 K121Q polymorphism on type 2 diabetes, obesity and quantitative metabolic traits in 7,333 Danes.


METHODS
The K121Q polymorphism was genotyped in the population-based Inter99 study cohort (5,961 subjects) and in a group of 1,386 patients with type 2 diabetes. All subjects were Danish whites.


RESULTS
No significant associations with type 2 diabetes or related quantitative metabolic traits, including measures of insulin resistance, were detected. However, a meta-analysis of the present and published studies revealed an association with type 2 diabetes (odds ratio per Q allele, 1.17 [95% CI 1.10-1.25], p=1x10(-6)). In case-control studies comparing subjects of different BMI strata, we observed a putative association of the codon 121 QQ genotype with being overweight (BMI>25 kg/m(2); odds ratio 1.63 [95% CI 1.09-2.46], p=0.015), an association not observed when comparing other levels of BMI or when analysing BMI as a quantitative trait.


CONCLUSIONS
In a meta-analysis, the ENPP1 codon 121 Q allele associates with type 2 diabetes. However, a similar association was not found in the present study of Danish white subjects. The effect of this variant on obesity in Danish subjects is contentious and further study is needed.
Grarup
N
N
Steno Diabetes Center and Hagedorn Research Institute, Niels Steensens Vej 2-6, NSP1.14, 2820, Gentofte, Copenhagen, Denmark. ngrp@steno.dk
Urhammer
S A
SA
Ek
J
J
Albrechtsen
A
A
Glümer
C
C
Borch-Johnsen
K
K
Jørgensen
T
T
Hansen
T
T
Pedersen
O
O
D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D016022:Case-Control Studies; D015331:Cohort Studies; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D005951:Glucose Tolerance Test; D005973:Glutamine / Q000235:genetics; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008239:Lysine / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000235:genetics*; D016017:Odds Ratio; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D011110:Polymorphism, Genetic; D011755:Pyrophosphatases / Q000235:genetics*; D012044:Regression Analysis; D044465:White People / Q000235:genetics*
D001786:Blood Glucose; D005973:Glutamine; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases; D008239:Lysine