Reference
Complete the bibliographic reference for the article according to AJE format.

Esterbauer H, Schneitler C, Oberkofler H, Ebenbichler C, Paulweber B, Sandhofer F, Ladurner G, Hell E, Strosberg AD, Patsch JR, Krempler F, Patsch W.  A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans.  Nat Genet. 2001 Jun;28(2):178-83.

Category of HuGE information
Specify the types of information (from the list below) available in the article:

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

1. Prevalence of gene variant
2. Gene-disease association

Study hypotheses or purpose
The authors study hypotheses or main purpose for conducting the study.

Hypothesis: Uncoupling protein-2 (UCP2) is a member of the mitochondrial transporter family that is expressed in many tissues, including adipose tissue. Because it uncouples proton entry in the mitochondrial matrix from ATP synthesis, polymorphisms at this gene locus may be associated with obesity.

Gene(s)
Identification of the following:

1. Gene name
2. Chromosome location
3. Gene product/function
4. Alleles
5. OMIM #

1. Gene : UCP2
2. Chromosome location: 11q13
3. Gene product/function: A mitochondrial transporter protein that creates proton leaks across the inner mitochondrial membrane thus uncoupling oxidative phosphorylation from ATP synthesis.
4. Alleles: -866G/A
5. OMIM #: 601693

Environmental factor(s)
Identification of the major environmental factors studied (infectious, chemical, physical, nutritional, and behavioral)

Health outcome(s)
Identification of the major health outcome(s) studied

1. Obesity where BMI>30kg/m 2

1. Case-control
2. Cohort 
3. Cross-sectional
4. Descriptive or case series
5. Clinical trial
6. Population screening

Case definition
For study designs 2, 3, and 6, the following are defined, where available:

1. Case selection criteria
2. Exclusion criteria
3. Gender
4. Race/ethnicity
5. Age
6. Time period
7. Geographic location
8. Number of participants

1. Case definition: Unrelated, obese subjects (BMI>30kg/m 2) referred for weight-reducing surgery or a conservative weight-reduction program.
2. Exclusion criteria: not specified
3. Gender: 68 male; 272 female
4. Race/ethnicity: Caucasian Europeans, mainly of Bavarian and Austrian German Descent
5. Age: 30-55 years
6. Time period: not specified
7. Geographic location: not specified
8. Number of participants: 340

Control definition  
For study design 1, the following are defined, if available.

1. Control selection criteria
2. Matching variables
3. Exclusion criteria 
4. Gender
5. Race/ethnicity
6. Age
7. Time period
8. Geographic location
9. Number of participants

1. Control definition: Healthy, unrelated, never-obese (BMI<30) and mostly health care workers 
2. Matching variables: age, sex, geography
3. Exclusion criteria: not specified
4. Gender: 64 male; 192 female
5. Race/ethnicity: Caucasian Europeans, mainly of Bavarian and Austrian German descent
6. Age: 30-55
7. Time period: not specified
8. Geographic location: not specified
9. Number of participants: 256

Cohort definition  
For study designs 2, 3, and 6, the following are defined, if available. 

1. Cohort selection criteria 
2. Exclusion criteria
3. Gender
4. Race/ethnicity
5. Age
6. Time period
7. Geographic location
8. Number of participants

1. Cross-sectional selection criteria : Unrelated participants of SAPHIR, a population-based prospective study investigating genetic factors and atherosclerosis who responded to invitations from their physicians or announcements in the local press.
2. Exclusion criteria: not specified
3. Gender: 447 male; 344 female
4. Race/ethnicity: Caucasian Europeans, mainly of Bavarian and Austrian German descent
5. Age: 40-63 years
6. Time period: not specified
7. Geographic location: greater Salzburg
8. Number of participants: 791

1. Environmental factor
2. Exposure assessment
3. Exposure definition
4. Number of participants with exposure data (%
   of total eligible)

1. Environmental factor 1:  none
2. Exposure assessment: 
3. Exposure definition: 
4. Participants with exposure data:

1. Gene
2. DNA source
3. Methodology
4. Number of participants genotyped (% of total eligible) 

1. Gene:   UCP2
2. DNA source: white blood cells
3. Methodology: DNA isolated using QIAamp Blood Kit (Qiagen); Genome Walker kit (Clontech) used to sequence UCP2 promoter region; promoter polymorphisms and phases identified by cloning PCR products from 12 alleles into pGEM-T (Promega) and sequencing clones from both sides by dye-terminator cycle sequencing using an ABI PRISM TM 310 Genetic Analyzer (Applied Biosystems); five promoter polymorphisms genotyped using restriction isotyping of PCR products.
4. Participants genotyped: all individuals from case-control and cross-sectional study  

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

2. Gene-disease association  

Case-control

* adjusted for age and gender 

Cross-sectional**

*adjusted for age and gender
** individuals with BMI of 29-31 were excluded to reduce misclassification

Based on results of the case-control analysis, a modest but significant reduction in obesity prevalence was associated with the less common allele (-866 A) of the UCP2 gene locus. This association was confirmed in a cross- sectional study of 791 subjects from the same geographic area. Although the effect was modest, the prevalence of the more common allele (~63%) suggests that it may account for 15% of obesity in this population.  

Comments
Provide additional insight, including methodologic issues and/or concerns about the study

Other polymorphic sites within the promoter region were not found to be associated with obesity as shown in the table below:

The authors estimated the population-attributable risk of the –866 G/A genotype as 14.7% (CI, -5 to 43%) based on the cross-sectional data. It should be kept in mind that although the original study population (SAPHIR) was population-based, those that participated in the current analysis were self-selected. Additionally, the controls used for the case–control study were not sampled from the same population as the cases.