A MAJOR QUANTITATIVE TRAIT LOCUS DETERMINING SERUM LEPTIN LEVELS AND FAT MASS IS LOCATED ON HUMAN-CHROMOSOME-2

Obesity is a major predisposing factor for the development of several chronic diseases including non-insulin dependent diabetes mellitus (NI DDM) and coronary heart disease (CHD). Leptin is a serum protein which is secreted by adipocytes(1-4) and thought to play a role in the regu lation of body fat(5-8). Leptin levels in humans have been found to be highly correlated with an individual's total adiposity(8,9). We perfo rmed a genome-wide scan and conducted multipoint linkage analysis usin g a general pedigree-based variance component approach to identify gen es with measurable effects on quantitative variation in leptin levels in Mexican Americans. A microsatellite polymorphism, D2S1788, mapped t o chromosome 2p21 (approximately 74 cM from the tip of the short arm) and showed strong evidence of linkage with serum leptin levels with a lod score of 4.95 (P = 9 x 10(-7)). This locus accounted for 47% of th e variation in serum leptin levels, with a residual additive genetic c omponent contributing an additional 24%. This region contains several potential candidate genes for obesity, including glucokinase regulator y protein (GCKR) and pro-opiomelanocortin (POMC). Our results show str ong evidence of linkage of this region of chromosome 2 with serum lept in levels and indicate that this region could contain an important hum an obesity gene.