Submitted to: Obesity
Publication Type: Peer reviewed journal
Publication Acceptance Date: 10/13/2008
Publication Date: 12/18/2008
Citation: Lai, C., Parnell, L.D., Garcia-Bailo, B., Tucker, K., Ordovas, J.M. 2008. WDTC1, an ortholog of Drosphilia adipose gene, associates with human obesity. Obesity. 17(3):593-600. Interpretive Summary: Obesity, a major characteristic of metabolic syndrome, is associated with increased risk of type 2 diabetes and coronary heart disease, afflictions which are both at epidemic levels and burden healthcare systems worldwide. Adipose (adp) is an obesity gene in the fruit fly and plays a crucial role in fat metabolism. Its function is evolutionarily conserved from insects to mammals. Mutants of the adp gene in both flies and mice are obese and insulin resistant. Even though the human version of this gene is known (termed WDTC1), its association with obesity in humans remains to be determined. In this study, we investigated the correlation between WDTC1 genetic variation and obesity in an adult Puerto Rican population living in the Greater Boston metropolitan area. Our results demonstrated that two points of genetic variation, termed single nucleotide polymorphisms or SNPs, within the WDTC1 gene were strongly associated with obesity. Individuals who carry the common version of one SNP, a T nucleotide and who represent about 96% of the population, have significantly higher body mass index (BMI) than the non-carriers. Conversely, individuals who carry a C at this position on chromosomes inherited from both parents were leaner and were 75% less likely to be overweight or obese compared to those individuals who carry a T at this position on chromosomes inherited from both parents. Additionally, we have determined that at some point in recent human history there was a strong selection favoring on the genetic variation at this gene that associates with obesity. We conclude that variation within the WDTC1 gene represents one of the major risk factors contributing to the severe health disparity in this Puerto Rican population.
Technical Abstract: Obesity, a major characteristic of metabolic syndrome, is associated with increased risk of type 2 diabetes and coronary heart disease, and is a major healthcare burden worldwide. The prevalence of obesity has reached epidemic proportions. Adipose (adp) is an obesity gene in Drosophila and plays a crucial role in fat metabolism. Its function is evolutionarily conserved from flies to mammals; adp mutants both in flies and mice are obese and insulin resistant. WDTC1 has been identified as its mammalian ortholog. Whether WDTC1is associated with obesity in humans, however, remains to be determined. In this study, we investigated the correlation between WDTC1 genetic variation and obesity in an adult Puerto Rican population living in the Greater Boston metropolitan area. This population is at high risk for obesity, diabetes, depression, and hypertension. Our results demonstrated that two single nucleotide polymorphisms (SNPs) at the WDTC1 locus were strongly associated with obesity. The carriers (TT and CT) of the major allele i22835T, representing about 96% of the population, had significantly higher mean BMI (33.1 and 32.6) than non-carriers (30.0). Conversely, the homozygous subjects of the minor allele i22835C were leaner and were 75% less likely to be overweight or obese (OR=0.25, P=0.002) compared to the homozygous carriers of the major allele. Furthermore, haplotype analysis based on the two SNPs supported these findings. This WDTC1 variant associated with obesity is likely to have experienced strong positive selection in human history, when food adequacy was variable. Given the high frequency of the major allele in this population, we suggest that WDTC1 variation may be an important risk factor contributing to health disparities in this population.