APPLIED NUTRITIONAL INVESTIGATION Higher Obesity Risk Associated With the Exon-8 Insertion of the UCP2 Gene in a Spanish Case-Control Study Amelia Marti, PhD, M a Soledad Corbala ´n, PhD, Luis Forga L., PhD, MD, Miguel A. Martinez-Gonza ´lez, PhD, MD, and J. Alfredo Martinez, PhD From the Departments of Physiology and Nutrition and Department of Epidemiology and Public Health, University of Navarra, and the Hospital of Navarra, Pamplona, Spain OBJECTIVE: We conducted a case-control study to examine the association between the risk of obesity and the exon-8 insertion allele in the UCP2 gene. METHODS: The case series included 157 subjects with a body mass index greater than 30 kg/m 2 (obesity) and no other major disease except for type 2 diabetes; the control series consisted of 150 healthy subjects with a body mass index less than 25 kg/m 2 . In total, 307 subjects between ages 20 and 60 y were screened for the exon-8 insertion allele in the UCP2 gene. RESULTS: The association between risk of obesity and the UCP2 insertion allele was estimated using multivariate logistic regression. Obesity risk among carriers of the UCP2 insertion allele was slightly higher than among non-carriers (unadjusted odds ratio, 1.42; 95% confidence interval, 0.90 to 2.23); however, when the model was adjusted for sex, age, physical activity, and sedentary lifestyle (hours spent sitting down), a statistically significant odds ratio of obesity (1.94; 95% confidence interval, 1.14 to 3.30; P = 0.01) for carriers of the UCP2 insertion allele was found. CONCLUSIONS: We found a greater risk of developing obesity among individuals carrying the exon-8 insertion allele in the UCP2 gene, independent of sex, age, physical activity, and sedentary lifestyle, which may partly explain some discrepancies found in the literature. Nutrition 2004;20:498 –501. ©Elsevier Inc. 2004 KEY WORDS: case-control study, obesity, UCP2, exon-8 insertion, physical activity INTRODUCTION Several UCP2 gene variants have been reported in human studies: a G/A mutation in the promoter region -866G/A, 1,2 a valine-for- alanine substitution at amino acid 55 in exon-4 (Ala55Val), 3,4 and a 45 base-pair insertion and deletion in the untranslated region of exon-8. 5–9 The association between these polymorphisms of the UCP2 and various aspects of obesity has been studied intensively. From the literature, it seems that allele-G in the promoter region of UCP2 increases obesity risk but affords relative protection against type 2 diabetes, 1,2 and the Ala55Val polymorphism has been associated with increased exercise efficiency. 3,4 However, results have been inconsistent in different populations concerning the exon-8 insertion allele of the UCP2 gene. Although no association with obesity was observed in a number of studies conducted in several populations, 5–10 significant associations between the exon-8 insertion of the UCP2 gene and body mass index (BMI), fat mass, or obesity were found with P values of 0.01, 11 0.001, 12,13 0.002, 14 and 0.005. 15 A sixth study reported an association of the exon-8 insertion allele with sleeping metabolic rate (P = 0.007). 16 We conducted a case-control study in Spanish subjects to evaluate the association between obesity risk and the 45 base-pair insertion and deletion allele of exon-8 in the UCP2 gene after controlling for several factors associated with obesity risk. MATERIALS AND METHODS Study Population The study population consisted of 307 Spanish subjects ages 20 to 60 y who were selected between January 1999 and June 2000. The study was based on a case-control design. Cases (BMI  30 kg/m 2 ) were recruited from the Endocrinology Department at Navarra Hospital. Controls (BMI  25 kg/m 2 ), recruited from the Occupational Medicine Department at the same hospital, were healthy, with no hormonal treatment or endocrine disorders, and had a blood pressure below 120/90 mmHg. Face-to-face interviews were conducted with all participants, during which they also completed a questionnaire about their leisure-time physical activities to ascertain the nature of physical activity participation. According to the instructions of the Com- pendium of Physical Activities and Paffenbarger’s question- naire, 17,18 leisure-time physical activity for each subject is mea- sured by using participants’ answers regarding their participation in the following activities: athletics, cycling, dancing, equestrian sports, fishing, football, gardening, hill walking, climbing, aero- bics, jogging, martial arts, racquet sports, rowing, canoeing, skiing, skating, swimming, team sports, walking, and water sports. Par- ticipants expressed the number of weekly hours they practiced in each activity, and metabolic equivalents were assigned to each activity and a composite value for total weekly metabolic equiv- alent hours per participant was determined. In addition, a sedentary This work was supported by grants from the Navarra Government and Lı ´nea Especial: Nutricio ´n y Obesidad, University of Navarra. Correspondence to: Amelia Marti del Moral, PhD, Department of Physiology and Nutrition, C/Irunlarrea s/n, University of Navarra, 31080 Pamplona, Spain. E-mail: amarti@unav.es 0899-9007/04/$30.00 Nutrition 20:498 –501, 2004 ©Elsevier Inc., 2004. Printed in the United States. All rights reserved. doi:10.1016/j.nut.2004.03.019