Exonic and intronic sequence variation in the human leptin receptor gene (LEPR).

Increased adiposity is a major risk factor for cardiovascular disease and NIDDM (1). Genetic determinants of the degree of adiposity and body fat distribution have been demonstrated by twin and adoption studies, and the heritability (h) of obesity has been estimated to be as high as 0.90 (2). However, the major genes underlying the heritable contribution to body fatness in humans have remained elusive. Rodent models of genetically determined obesity provide excellent candidate genes for evaluation in humans. The linkage of obesity-related phenotypes in humans to genomic regions homologous to rodent leptin (Lep) (3) and leptin receptor (Lepr) (4,5) has been recently demonstrated. The recent cloning of Lepr, which is mutant in the diabetes (Lepr^) mouse and in fatty (Lepr) and Koletsky (Lepr) rats (6-9), the mapping of this gene (LEPR) to Ip32 in humans (10), and the description of the genomic structure of LEPR and two polymorphic intronic microsatellites (11) have provided the necessary reagents for the evaluation of LEPR in the genetics of human obesity. Because the phenotype associated with genetic defects in Lepr in Lepr/Lepr mice and Lepr/Lepr rats is profound early-onset obesity, we sought to identify allelic variations in LEPR, which may be responsible for the genetic variation in adiposity in humans. To maximize the likelihood of the detection of such sequence variants, we examined genomic DNA from a total of 229 obese and lean adults and children, ascertained in medical centers around the U.S. (New York, New York; New Orleans, Louisiana; and Huntington, West Virginia). The study sample was predominantly Caucasian, but also