The-2548G/A polymorphism in the human leptin gene promoter region is associated with plasma free leptin levels; interaction with adiposity and gender in healthy subjects

Abstract

A common -2548G/A promoter variant of the human leptin gene has recently been shown to be associated with variations in circulating leptin levels but available data are still conflicting. The aim of this study was to explore potential associations between the -2548G/A polymorphism and adiposity-related variables, plasma total leptin levels, as well as soluble leptin receptor (sOB-R) levels and free leptin in a group of healthy Greek subjects. One hundred eighteen consecutively enrolled subjects [62 females, 56 males; mean age+/-SD: 17.7+/-1.8 years; body mass index (BMI) range: 15.4-35.9 kg/m2] were genotyped for the -2548G/A polymorphism and their BMI, fat free mass, % fat mass, fasting plasma total leptin and sOB-R levels were determined. The ratio leptin/sOB-R was used as an index of free leptin. No significant differences in genotype and allele frequencies of the -2548G/A polymorphism were detected between normal weight and overweight subjects, and no association was found between this polymorphism and BMI, fat mass or plasma total leptin levels. However, the -2548G/A polymorphism was found to be associated with circulating free leptin levels in a gender specific manner. More specifically, compared to carriers of the -2548G allele, female subjects with the A/A genotype had higher age and fat mass adjusted mean (+/-SE) plasma concentrations of sOB-R (32.9+/-7.2 vs. 25.6+/-3.8 ng/ml, P=0.05), and significantly lower (approx. 50%) leptin/sOB-R values (0.74+/-0.25 vs. 1.42+/-0.13, P=0.02). Furthermore, multiple regression analysis revealed that, after adjustment to fat mass, the -2548G/A genotype and gender are significantly associated with free leptin index in the entire study sample. Similar regression models revealed a significant interaction of gender and genotype when considered in addition to fat mass, or fat mass and genotype when considered in addition to gender, as predictors of free leptin index. In conclusion, the common -2548G/A promoter variant of the human leptin gene is associated with plasma free leptin levels through an interaction with adiposity and gender in healthy subjects.