Genetic variation at the leptin receptor gene locus may play an important role in the pathophysiology of human obesity, a leptin-resistant state. Previous studies exploring potential associations between leptin receptor gene polymorphisms and obesity have reported conflicting results. The aim of this study was to evaluate a genetically homogeneous population for associations between body composition variables and three common leptin receptor gene polymorphisms (K109R, Q223R, and K656N) that have potential functional significance as well as to assess the contributions of these polymorphisms to the variability of obesity. One hundred and eighteen consecutively enrolled subjects (62 women: mean age, 17.5 +/- 1.6 yr; body mass index range, 16.2-30.1; 56 men: mean age, 17.8 +/- 1.8 yr; body mass index range, 15.4-35.9) were genotyped for the three polymorphisms, and their body mass index, sum of 4 skinfolds, fat-free mass, percent fat mass, serum leptin levels, caloric intake, fat intake, and exercise patterns were determined. Allele frequencies were estimated by the gene-counting method, and genotype distributions between 89 normal weight (body mass index, < or =25 kg/m(2)) and 29 overweight-obese (body mass index, >25 kg/m(2)) subjects were compared using chi(2) test (using codominant, dominant, and recessive models). Analysis of covariance was also performed to evaluate associations between the polymorphisms and body composition variables after controlling for potential confounders. For the Q223R polymorphism, there was a higher prevalence of the R223 allele in the homozygous form among overweight-obese subjects vs. normal weight subjects (20.7% vs. 4.5%; P = 0.01). Furthermore, simple and multiple regression analyses revealed that the R223 allele in the homozygous form is a significant predictor of both body mass index (P = 0.015) and percent fat mass (P = 0.02) even after adjusting for age and gender and explains 4.5% of the variance in percent fat mass and 5% of the variance in body mass index. There was no significant difference in allele frequencies or genotype distributions for the K109R or K656N polymorphisms. These findings support the hypothesis that the Q223R polymorphism (but not the K109R or K656N polymorphism) of the leptin receptor gene is associated with obesity and predicts a small percentage of body weight and body composition variability in a genetically homogeneous population.