Abstract
The agouti related protein (AgRP) exerts its anabolic effects on food intake by antagonising the alpha-melanocyte stimulating hormone (α-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.
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