Association Between Variants in the LEP Gene and Its Receptor (LEPR) with Birth Weight and Pre-Diabetic Phenotypes in Young Healthy Twins.

Leptin acts as a satiety signal regulating food intake and energy expenditure. The relation between variants in the leptin (LEP; 19 G>A) gene and its receptor (LEPR; Q223R and K109R) with obesity and type 2 diabetes has been studied extensively, but results are inconclusive and the relation remains unclear. In a population-based association study, we examined the effect of these variants on pre-diabetic phenotypes measured in young healthy twins. In this study, 396 monozygotic and 230 dizygotic twins (286 men and 340 women, mean age 25 years) were recruited from the East Flanders Prospective Twin Survey. Several diabetes-related traits were measured, including birth weight, adult body composition, fasting concentrations of cholesterol (LDL and HDL), triglycerides, free fatty acids, leptin, insulin and glucose. Genotyping was performed using Pyrosequencing. Linear mixed models, including a random effect term for twin pair membership, were used to evaluate associations between the variants and the measured traits. When appropriate, traits were adjusted for covariates including sex, (gestational) age, height and fat. Subjects carrying the 19 G allele of LEP had higher HDL-cholesterol levels compared to 19 A homozygotes (GX vs AA (95% CI): 1.62 (1.58-1.66) vs 1.49 (1.40-1.58) mmol/1;p=0.008). The K109R variant in the LEPR was associated with birth weight (KK, KR and RR (95% CI): 2507 (2462-2553), 2577 (2519-2536) and 2762 (2643-2882) gram; p=0.0002). Also the Q223R variant in the LEPR showed association with birth weight (QQ, QR and RR (95% CI): 2493 (2431-2554), 2542 (2492-2591) and 2670 (2583-2756) gram; p=0.002). These results indicate that genetic variation in the LEP gene affects HDL-cholesterol levels. Furthermore, this study suggests a possible role for the LEPR in explaining the inverse relationship between birth weight and the development of metabolic diseases in adult life. [ABSTRACT FROM AUTHOR]