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

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 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 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 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 ( < 0.0001), and genetic pleiotropy was noted between plasma PYY and body mass index (BMI) ( = 0.03). A haplotype extending from the proximal promoter (A-23G, rs2070592) to the 3′-UTR (C+1134A, rs162431) predicted not only plasma PYY ( = 0.009) but also other metabolic syndrome traits. Functional studies with transfected luciferase reporters confirmed regulatory roles in altering gene expression for both ′-UTR C+1134A ( < 0.001) and promoter A-23G ( = 0.0016).

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