title: Functional dimorphism of two hAgRP promoter SNPs in linkage disequilibrium.
abstract: The agouti related protein (AgRP) exerts its anabolic effects on food intake by antagonising the alpha-melanocyte stimulating hormone (alpha-MSH) at its receptors, melanocortin receptors 3 and 4 (MC3R and MC4R). A single nucleotide polymorphism (SNP) in the promoter of the human AgRP (hAgRP), -38C>T, was associated with low body fatness. The -38T allele that was associated with low body fatness also resulted in lower promoter activity. Here we report a novel SNP, -3019G>A, again in the promoter of hAgRP, which is in complete linkage disequilibrium (LD) with the -38C>T SNP (linked alleles: -3019A/-38T and -3019G/-38C). Functional analyses in a human adrenal and two mouse hypothalamus cell lines showed that the -3019A allele had significantly higher promoter activity. Hence, the two linked alleles (-3019A and -38T) had opposite effects on promoter function and yet they were both associated with low body fatness. The region encompassing the -38C>T SNP had approximately 1000-fold higher activity than the region encompassing the -3019G>A SNP, potentially determining the net functional effect between these two SNPs.
authors.affiliation: Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
authors.forename: F
authors.initials: F
authors.lastname: Bai
authors.forename: T
authors.initials: T
authors.lastname: Rankinen
authors.forename: C
authors.initials: C
authors.lastname: Charbonneau
authors.forename: D D
authors.initials: DD
authors.lastname: Belsham
authors.forename: D C
authors.initials: DC
authors.lastname: Rao
authors.forename: C
authors.initials: C
authors.lastname: Bouchard
authors.forename: G
authors.initials: G
authors.lastname: Argyropoulos
mesh_terms: D054369:Agouti-Related Protein; D000818:Animals; D002460:Cell Line; D005260:Female; D005787:Gene Frequency; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D015810:Linkage Disequilibrium; D008297:Male; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: C515198:AGRP protein, human; D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins