The Health Outcome

Obesity is a major contributor to illnesses including cardiovascular disease, diabetes, gallbladder disease, arthritis, respiratory disease, and some cancers. In the U.S. , 26% of adults are obese according the 1999 National Health and Nutrition Examination Survey (NHANES). There is strong evidence from family studies that bodyweight is regulated by genetic factors but the search for genes that cause obesity has been unsuccessful so far using the candidate gene approach or linkage studies in obese families.

The Finding

Esterbauer et al. have reported finding a polymorphism in the promoter region of a gene encoding the uncoupling protein-2 (UCP2) that is associated with obesity. The association was found in a case-control study and was replicated in a cross-sectional study in Salzburg , Austria (1). A detailed abstraction of this article is available online as part of the HuGENet™ e-journal club (2). The case-control study included obese individuals (cases) who had been referred for weight-reducing surgery or a conservative weight-reduction program. The controls were healthy, never-obese individuals who were mostly health care workers. The cross-sectional study included participants from the Salzburg Atherosclerosis Prevention Program (SAPHIR), a population-based prospective study investigating genetic factors in cardiovascular disease. All study participants were genotyped to evaluate polymorphisms within the UCP2 promoter region, and one deletion/insertion polymorphism within exon 8 of the gene. Genotype distributions for the –866 G/A polymorphism differed significantly between the obese cases and never-obese controls. The authors suggest that since the estimated risks due to G/A-heterozygous (OR = 0.61) and A/A-homozygous (OR = .60) were very similar, the at-risk allele (G) has a recessive effect. In the cross-sectional study when the obese and non-obese participants were compared, the OR for the A/A genotype was 0.66 and the OR for the G/A genotype was 0.58. Two additional polymorphisms studied (-1957 G/A and 45nt-del/ins) were found to have no association with obesity. Using data from the cross-sectional study the researchers determined that the population attributable risk for the more common risk allele accounted for 15% of obesity in the population studied.

Public Health Implications

The implications of this study for the prevention and treatment of obesity are presently unclear. While the allele associated with obesity in this study appears common, potential confounding and selection bias resulting from the lack of comparability of cases and controls can affect inference. The authors describe the effect of UCP2 at the molecular level thus providing evidence for the biologic plausibility of their finding. What is now needed is prevalence data on the –866 G/A polymorphism in a large heterogeneous population and studies replicating the association of this polymorphism with obesity.

References

1. Esterbauer H, et al. 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
2. Esterbauer H, et al. electronic journal club abstraction form