A common promoter variant of the leptin gene is associated with changes inthe relationship between serum leptin and fat mass in obese girls

Mutations in the leptin gene lead to rare obese syndromes of Mendelian inhe ritance in humans and rodents. However, no relevant mutations are found in the coding region of leptin gene DNA in patients with common multifactorial obesity These obese patients tend to have an elevation of serum leptin pro portional to their adiposity but with a rather wide dispersion of leptin le vels for a given body fat content, which in part is attributable to sexual dimorphism. The current study, performed in two independent Caucasian cohor ts of obese girls, shows that a frequent promoter variant of the leptin gen e is associated with changes in the relationship between serum leptin and b ody fatness. Girls of comparable adiposity have different circulating lepti n levels, depending on their genotype at this locus. Girls with the -/- Lep -2,549 genotype have 25% lower mean leptin levels than the girls with othe r genotypes, as reflected by differences in the regression slopes of leptin -to-fat mass. Therefore, genetic factors related to the leptin gene may be important in defining the set point of obese individuals (i.e., the circula ting leptin level for a given degree of body fatness). This definition may be of both physiological and therapeutic relevance, although a phenotypic a ssociation with an individual single-nucleotide polymorphism is not suffici ent to assign function to this particular nucleotide site.