A major quantitative trait locus (QTL) determining
leptin levels has been linked to the
proopiomelanocortin (
POMC) region on chromosome 2. Most studies, based on under 350 lean or obese subjects, have shown no association between
POMC SNP 8246 C/T and serum
leptin, but significant associations have been reported with RsaI 8246 C/T SNP haplotypes. We have investigated association of four
POMC SNPs with body composition and serum
leptin in 2758 normal Caucasian female subjects (mean age 47.4+/-12.5 years), from the St Thomas' UK Adult Twin Registry (Twins UK): RsaI and 51 G/C in the
5'UTR and 8246 C/T and 7965 C/T in the
3'UTR. Under the recessive model, the 8246 T allele (freq. 0.18) was significantly associated with higher mean BMI (P=0.032) and total fat (P=0.046, both after age adjustment). Significant associations were maintained in sib-TDT with waist (P=0.049), total fat (P=0.037) and emerged with serum
leptin (P=0.016). Initial significant associations between RsaI (-) allele (freq. 0.30) and higher waist (P=0.04) or % central fat (P=0.02) were not maintained in sib-TDT. No significant associations were found between body composition or serum
leptin and RsaI/8246 C/T haplotype and none with 51 G/C (freq. 0.01) or 7965 C/T (freq. 0.004). There was minimal pairwise LD between the four loci, apart from RsaI and 8246 C/T (D'=-0.78 (P<0.0001)). Associations of BMI, weight and total fat with SNPs in regions flanking the
POMC gene in this powerful study suggest that regulation of
POMC expression may be influential in determining
body weight.