Article Text
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.
- AgRP
- linkage
- obesity
- promoter
- SNP
- AgRP, agouti related protein
- α-MSH, alpha-melanocyte stimulating hormone
- LD, linkage disequilibrium
- MC3R and MC4R, melanocortin receptors 3 and 4
- SNP, single nucleotide polymorphism
- UCP1, uncoupling protein 1