ASSOCIATION BETWEEN UNCOUPLING PROTEIN POLYMORPHISMS (UCP2-UCP3) AND ENERGY-METABOLISM OBESITY IN PIMA-INDIANS

The UCP2-UCP3 gene cluster maps to chromosome 11q13 in humans, and pol ymorphisms in these genes may contribute to obesity through effects on energy metabolism. DNA sequencing of UCP2 and UCP3 revealed three pol ymorphisms informative for association studies: an Ala-->Val substitut ion in exon 4 of UCP2, a 45 bp insertion/deletion in the 3'-untranslat ed region of exon 8 of UCP2 and a C-->T silent polymorphism in exon 3 of UCP3. Initially, 82 young (mean age = 30 +/- 7 years), unrelated, f ull-blooded, non-diabetic Pima Indians were typed for these polymorphi sms by direct sequencing. The three sites were in linkage disequilibri um (P < 0.00001). The UCP2 variants were associated with metabolic rat e during sleep (exon 4, P = 0.007; exon 8, P = 0.016) and over 24 h (e xon 8, P = 0.038). Heterozygotes for UCP2 variants had higher metaboli c rates than homozygotes. The UCP3 variant was not significantly assoc iated with metabolic rate or obesity. In a further 790 full-blooded Pi ma Indians, there was no significant association between the insertion /deletion polymorphism and body mass index (BMI). However, when only i ndividuals >45 years of age were considered, heterozygotes (subjects w ith the highest sleeping metabolic rate) had the lowest BMI (P = 0.04) . The location of the insertion/deletion polymorphism suggested a role in mRNA stability; however, it appeared to have no effect on skeletal muscle UCP2 mRNA levels in a subset of 23 randomly chosen Pima Indian s. In conclusion, these results suggest a contribution from UCP2 (or U CP3) to variation in metabolic rate in young Pima Indians which may co ntribute to overall body fat content later in life.