Walder K, Norman R A, Hanson R L, Schrauwen P, Neverova M, Jenkinson C P, Easlick J, Warden C H, Pecqueur C, Raimbault S, Ricquier D, Silver M H, Shuldiner A R, Solanes G, Lowell B B, Chung W K, Leibel R L, Pratley R, Ravussin E
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.
Hum Mol Genet. 1998 Sep;7(9):1431-5. doi: 10.1093/hmg/7.9.1431.
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.
UCP2 - UCP3基因簇定位于人类染色体11q13，这些基因的多态性可能通过影响能量代谢而导致肥胖。对UCP2和UCP3进行DNA测序发现了三个对关联研究有意义的多态性：UCP2第4外显子中的丙氨酸（Ala）到缬氨酸（Val）的替换、UCP2第8外显子3'非翻译区的45bp插入/缺失以及UCP3第3外显子中的C到T沉默多态性。最初，通过直接测序对82名年轻（平均年龄 = 30±7岁）、无亲缘关系、纯种、非糖尿病的皮马印第安人进行了这些多态性分型。这三个位点处于连锁不平衡状态（P < 0.00001）。UCP2变体与睡眠期间的代谢率相关（第4外显子，P = 0.007；第8外显子，P = 0.016）以及24小时内的代谢率相关（第8外显子，P = 0.038）。UCP2变体的杂合子比纯合子具有更高的代谢率。UCP3变体与代谢率或肥胖无显著关联。在另外790名纯种皮马印第安人中，插入/缺失多态性与体重指数（BMI）之间无显著关联。然而，当仅考虑年龄大于45岁的个体时，杂合子（睡眠代谢率最高的受试者）的BMI最低（P = 0.04）。插入/缺失多态性的位置表明其在mRNA稳定性中起作用；然而，在随机选择的23名皮马印第安人亚组中，它似乎对骨骼肌UCP2 mRNA水平没有影响。总之，这些结果表明UCP2（或UCP3）对年轻皮马印第安人代谢率的变化有影响，这可能在以后的生活中导致总体脂肪含量增加。
