Human Molecular Genetics, Vol 7, 1431-1435, Copyright © 1998 by Oxford University Press
K Walder, RA Norman, RL Hanson, P Schrauwen, M Neverova, CP Jenkinson, J Easlick, CH Warden, C Pecqueur, S Raimbault, D Ricquier, MHK Silver, AR Shuldiner, G Solanes, BB Lowell, WK Chung, RL Leibel, R Pratley and E Ravussin
The UCP2-UCP3 gene cluster maps to chromosome 11q13 in humans, and
polymorphisms in these genes may contribute to obesity through effects on
energy metabolism. DNA sequencing of UCP2 and UCP3 revealed three
polymorphisms informative for association studies: an Ala-->Val
substitution in exon 4 of UCP2, a 45 bp insertion/deletion in the 3'-
untranslated 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,
full-blooded, non-diabetic Pima Indians were typed for these polymorphisms
by direct sequencing. The three sites were in linkage disequilibrium ( P
< 0.00001). The UCP2 variants were associated with metabolic rate during
sleep (exon 4, P = 0.007; exon 8, P = 0.016) and over 24 h (exon 8, P =
0.038). Heterozygotes for UCP2 variants had higher metabolic rates than
homozygotes. The UCP3 variant was not significantly associated with
metabolic rate or obesity. In a further 790 full-blooded Pima Indians,
there was no significant association between the insertion/deletion
polymorphism and body mass index (BMI). However, when only individuals
>45 years of age were considered, heterozygotes (subjects with 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 Indians. In conclusion,
these results suggest a contribution from UCP2 (or UCP3) to variation in
metabolic rate in young Pima Indians which may contribute to overall body
fat content later in life.
ARTICLES
Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima indians
Clinical Diabetes and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, 4212 North 16th Street, Room 541, Phoenix, AZ 85016, USA. ken.walder@mailexcite.com
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