RT Journal Article
SR Electronic
T1 Functional dimorphism of two hAgRP promoter SNPs in linkage disequilibrium
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 350
OP 353
DO 10.1136/jmg.2003.014092
VO 41
IS 5
A1 Bai, F
A1 Rankinen, T
A1 Charbonneau, C
A1 Belsham, D D
A1 Rao, D C
A1 Bouchard, C
A1 Argyropoulos, G
YR 2004
UL http://jmg.bmj.com/content/41/5/350.abstract
AB 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.