This Article Full Text Full Text (PDF) Supplemental Data Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Google Scholar Articles by Shih, P.-a. B. Articles by O'Connor, D. T. PubMed PubMed Citation Articles by Shih, P.-a. B. Articles by O'Connor, D. T. Related Collections Metabolism

Peptide YY (PYY) Gene Polymorphisms in the 3'-Untranslated and Proximal Promoter Regions Regulate Cellular Gene Expression and PYY Secretion and Metabolic Syndrome Traits in Vivo

Departments of Medicine and Pharmacology, Institute for Genomic Medicine, University of California, San Diego, and Veterans Affairs San Diego Healthcare System, San Diego, California 92093-0838

Address all correspondence and requests for reprints to: Daniel T. O'Connor, M.D., Department of Medicine (0838), University of California, San Diego, School of Medicine and Veterans Affairs San Diego Healthcare System, 9500 Gilman Drive, La Jolla, California 92093-0838. E-mail: doconnor{at}ucsd.edu (http://hypertension.ucsd.edu/).

Rationale: Obesity is a heritable trait that contributes to hypertension and subsequent cardiorenal disease risk; thus, the investigation of genetic variation that predisposes individuals to obesity is an important goal. Circulating peptide YY (PYY) is known for its appetite and energy expenditure-regulating properties; linkage and association studies have suggested that PYY genetic variation contributes to susceptibility for obesity, rendering PYY an attractive candidate for study of disease risk.

Design: To explore whether common genetic variation at the human PYY locus influences plasma PYY or metabolic traits, we systematically resequenced the gene for polymorphism discovery and then genotyped common single-nucleotide polymorphisms across the locus in an extensively phenotyped twin sample to determine associations. Finally, we experimentally validated the marker-on-trait associations using PYY 3'-untranslated region (UTR)/reporter and promoter/reporter analyses in neuroendocrine cells.

Results: Four common genetic variants were discovered across the locus, and three were typed in phenotyped twins. Plasma PYY was highly heritable (P < 0.0001), and genetic pleiotropy was noted between plasma PYY and body mass index (BMI) (P = 0.03). A PYY haplotype extending from the proximal promoter (A-23G, rs2070592) to the 3'-UTR (C+1134A, rs162431) predicted not only plasma PYY (P = 0.009) but also other metabolic syndrome traits. Functional studies with transfected luciferase reporters confirmed regulatory roles in altering gene expression for both 3'-UTR C+1134A (P < 0.001) and promoter A-23G (P = 0.0016).

Conclusions: Functional genetic variation at the PYY locus influences multiple heritable metabolic syndrome traits, likely conferring susceptibility to obesity and subsequent cardiorenal disease.