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

Abstract

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 expenditureregulating 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 markeron-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. Copyright © 2009 by The Endocrine Society.