This study investigated the role of the ENPP1/PC-1 gene K121Q polymorphism in predicting BMI (kg/m2) in non-diabetic individuals. Three independent samples (n = 631, n = 304, and n = 505) of adult whites were analyzed. Selection criteria were fasting plasma glucose level <126 mg/dL, absence of severe obesity (BMI > or =40 kg/m2), and lack of treatment known to modulate BMI. In Sample 1, BMI values were different in individuals carrying the K121/K121 (KK), K121/Q121 (KQ), and Q121/Q121 (QQ) genotypes (25.5 +/- 4.3, 25.3 +/- 4.1, and 22.8 +/- 2.5 kg/m2, respectively (adjusted p = 0.022); BMI values in Samples 2 and 3 also tended to be different, although the differences, after adjustment for age and sex, did not reach statistical significance. When data were pooled, BMI values were 25.8 +/- 4.4, 25.6 +/- 4.4, and 23.6 +/- 3.3 kg/m2 in KK, KQ, and QQ individuals (adjusted p = 0.029). According to a recessive model, QQ individuals had lower BMI values than KK and KQ individuals combined (23.6 +/- 3.3 kg/m2 vs. 25.7 +/- 4.4 kg/m2; adjusted p = 0.008). These data suggest that the QQ genotype of the ENPP1/PC-1 gene is associated with lower BMI. If similar results are confirmed in prospective studies, the K121Q polymorphism may help identify people at risk for obesity.