Normal variation in leptin levels is associated with polymorphisms in the proopiomelanocortin gene, POMC

We previously reported that our genome-scanning initiative had detected a h ighly significant linkage (log odds ratio = 4.95; P = 9 x 10(-7)) between a quantitative trait locus (QTL) on chromosome 2 and leptin levels in Mexica n American families. We now have typed additional microsatellite markers in this region, increasing this log odds ratio score to 7.46 (P = 2 x 10(-9)) . This region of chromosome 2 contains a strong positional candidate gene, POMC. The POMC gene codes for POMC, the prohormone from which alpha MSH, AC TH, and beta-endorphin are derived. Studies by others have shown that POMC- derived products are involved in the regulation of appetite and obesity. We have used polymorphisms in POMC to map its location within the 95% confide nce interval of the peak for the linkage signal for the QTL. We also constr ucted POMC haplotypes using these polymorphisms and have found a significan t association with normal variation in leptin levels (P = 0.001). We conclu de that variation in POMC is associated with normal variation in serum lept in levels, providing further evidence that POMC may be the leptin QTL previ ously identified in Mexican American families.