The CART gene and human obesity - Mutational analysis and population genetics

The cocaine- and amphetamine-regulated transcript (CART) peptide is a recen tly characterized neuropeptide implicated in the control of appetite. We hy pothesized that genetic variation in CART may contribute to human obesity. The entire coding region of CART was determined by nucleotide sequencing in 91 unrelated subjects with severe early-onset obesity. A novel amino acid change, Ser66Thr, was found in 2 probands and in 0 of 100 control subjects but did not cosegregate with obesity in family studies. Two common polymorp hisms were found in the 3'-untranslated region (A1475G and Delta A1457). An effect of these polymorphisms on body composition and intermediate phenoty pes related to obesity was examined in a large Caucasian population in the U.K. Neither polymorphism showed any significant relationship with obesity; however, men heterozygous for the A1475G variant had significantly lower w aist-to-hip ratio (WHR), fasting plasma insulin, and fasting triglycerides. Regression analysis indicated that the effects on insulin and triglyceride s were likely to be secondary to the effects on WHR. Thus, we have conducte d the first systematic study of the CART gene in human obesity and although no clear association with obesity was found, the data suggest that genetic variation in the CART locus might influence fat distribution and variables related to syndrome X.