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.
BACKGROUND
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.


METHODS
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.
Shih
Pei-An Betty
PA
Department of Medicine and Pharmacology, Institute for Genomic Medicine, University of California, San Diego 92093-0838, USA.
Wang
Lei
L
Chiron
Stephane
S
Wen
Gen
G
Nievergelt
Caroline
C
Mahata
Manjula
M
Khandrika
Srikrishna
S
Rao
Fangwen
F
Fung
Maple M
MM
Mahata
Sushil K
SK
Hamilton
Bruce A
BA
O'Connor
Daniel T
DT
D020413:3' Untranslated Regions / Q000235:genetics*; D004200:Diseases in Twins / Q000235:genetics; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006331:Heart Diseases / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D007674:Kidney Diseases / Q000235:genetics; D024821:Metabolic Syndrome / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D019894:Peptide YY / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014427:Twins / Q000235:genetics
D020413:3' Untranslated Regions; D019894:Peptide YY