Association of genetic variation in ENPP1 with obesity-related phenotypes.
Ectonucleotide pyrophosphatase phosphodiesterase (ENPP1) is a positional candidate gene at chromosome 6q23 where we previously detected strong linkage with fasting-specific plasma insulin and obesity in Mexican Americans from the San Antonio Family Diabetes Study (SAFDS). We genotyped 106 single-nucleotide polymorphisms (SNPs) within ENPP1 in all 439 subjects from the linkage study, and measured association with obesity and metabolic syndrome (MS)-related traits. Of 72 polymorphic SNPs, 24 were associated, using an additive model, with at least one of eight key metabolic traits. Three traits were associated with at least four SNPs. They were high-density lipoprotein cholesterol (HDL-C), leptin, and fasting plasma glucose (FPG). HDL-C was associated with seven SNPs, of which the two most significant P values were 0.0068 and 0.0096. All SNPs and SNP combinations were analyzed for functional contribution to the traits using the Bayesian quantitative-trait nucleotide (BQTN) approach. With this SNP-prioritization analysis, HDL-C was the most strongly associated trait in a four-SNP model (P=0.00008). After accounting for multiple testing, we conclude that ENPP1 is not a major contributor to our previous linkage peak with MS-related traits in Mexican Americans. However, these results indicate that ENPP1 is a genetic determinant of these traits in this population, and are consistent with multiple positive association findings in independent studies in diverse human populations.
Jenkinson
Christopher P
CP
Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA. jenkinsonc@uthscsa.edu
Coletta
Dawn K
DK
Flechtner-Mors
Marion
M
Hu
Shirley L
SL
Fourcaudot
Marcel J
MJ
Rodriguez
Lenore M
LM
Schneider
Jennifer
J
Arya
Rector
R
Stern
Michael P
MP
Blangero
John
J
Duggirala
Ravindranath
R
DeFronzo
Ralph A
RA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001499:Bayes Theorem; D001786:Blood Glucose / Q000032:analysis; D008076:Cholesterol, HDL / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D005215:Fasting / Q000097:blood; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D020738:Leptin / Q000097:blood; D008297:Male; D024821:Metabolic Syndrome / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D017058:Mexican Americans / Q000235:genetics; D008875:Middle Aged; D008957:Models, Genetic; D009765:Obesity / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D010641:Phenotype; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000235:genetics*; D012307:Risk Factors; D013781:Texas / Q000453:epidemiology
D001786:Blood Glucose; D008076:Cholesterol, HDL; D020738:Leptin; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases