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J Clin Endocrinol Metab. 2009 Nov;94(11):4557-66. doi: 10.1210/jc.2009-0465. Epub 2009 Oct 9.

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.

Author information

1
Department of Medicine and Pharmacology, Institute for Genomic Medicine, University of California, San Diego 92093-0838, USA.

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 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.

PMID:
19820027
PMCID:
PMC2775651
DOI:
10.1210/jc.2009-0465
[Indexed for MEDLINE]
Free PMC Article

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