These data from 10,975 cases and 18,588 controls confirm that individuals carrying the isoleucine allele have a lower risk of obesity compared with noncarriers. However, whereas a previous pooled analysis reported a 31% risk reduction,3
our data based on nearly four times as many individuals show this reduced risk may be around 18%, suggesting the original association was overestimated. Our study reinforces the need for large scale studies to reliably assess gene-disease associations.
Several studies have suggested that the V103I variant may be non-functional. Indeed, the V103I has been shown to possess a normal endogenous agonist ligand profile and normal receptor expression levels at the cell surface.2
However, recent functional studies have revealed that, compared to the wild-type receptor, the infrequent I103 allele is less responsive to agouti-related protein (AGRP).26
AGRP is an endogenous antagonist of the MC4 receptor that stimulates energy intake and promotes weight gain.27-30
Thus the V103I-mediated attenuation in MC4R activation by AGRP might lead to a relatively weaker orexigenic signal; in turn, this may result in a comparatively lower risk of obesity in human populations. Collectively, these findings suggest that the V103I polymorphism may be causally associated with obesity risk. Alternatively, this variant may be in linkage disequilibrium with an unknown functional variant elsewhere in the MC4R gene or in regulatory regions.
Our analysis was potentially limited by a number of factors. We cannot assess the impact of unmeasured genetic or environmental modifiers on the size and direction of the association. However, there is no reported evidence of interdependency. Secondly, because of the infrequency of the V103I polymorphism and the magnitude of the association observed in the current study, we cannot exclude the possibility that this finding is a false positive; however, this explanation is unlikely given the size of our study and the role of this gene in monogenic obesity. Finally, differences in study designs and case definitions may also have distorted the magnitude of the association between the V103I genetic variant and obesity. Despite these differences, we found no statistical evidence of heterogeneity among studies.
In conclusion, in this meta-analysis of 29,563 individuals we confirm that the MC4R V103I genotype protects against common obesity. We estimate that 17% of obesity in the population is attributable to the common homozygous genotype. This polymorphism is the first to be consistently associated with alterations in human obesity at the population level. As such, it provides proof of principle that specific genetic variants may, at least in part, explain susceptibility and resistance to common forms of human obesity. A better understanding of the mechanisms underlying this association will help determine whether changes in MC4R activity have therapeutic potential.