title: Association of genetic variation in ENPP1 with obesity-related phenotypes.
abstract: 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.
authors.affiliation: Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA. jenkinsonc@uthscsa.edu
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Jenkinson
authors.forename: Dawn K
authors.initials: DK
authors.lastname: Coletta
authors.forename: Marion
authors.initials: M
authors.lastname: Flechtner-Mors
authors.forename: Shirley L
authors.initials: SL
authors.lastname: Hu
authors.forename: Marcel J
authors.initials: MJ
authors.lastname: Fourcaudot
authors.forename: Lenore M
authors.initials: LM
authors.lastname: Rodriguez
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schneider
authors.forename: Rector
authors.initials: R
authors.lastname: Arya
authors.forename: Michael P
authors.initials: MP
authors.lastname: Stern
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.forename: Ravindranath
authors.initials: R
authors.lastname: Duggirala
authors.forename: Ralph A
authors.initials: RA
authors.lastname: DeFronzo
mesh_terms: 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
chemical_list: D001786:Blood Glucose; D008076:Cholesterol, HDL; D020738:Leptin; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases