From our study based on obese and nonobese Mexican children, we found a significant contribution of the minor allele of GNPDA2 rs10938397 to increased risk of obesity. The association between GNPDA2 and BMI had firstly been identified in a meta-analysis of several European GWASs performed by the GIANT consortium . Subsequently, the association signal has been confirmed in other populations: in adults from East-Asia [18, 19] and in Chinese children . To our knowledge, the present study is the first confirmation of the GNPDA2 association signal with risk of obesity in the Mexican population.
Furthermore, we found nominal associations between risk of obesity or BMI and the following SNPs: ENPP1 rs7754561, MC4R rs17782313 and NEGR1 rs2815752. Of note, the risk alleles for obesity or increased BMI were the same between Europeans and Mexicans, except for the risk allele of ENPP1 rs7754561 (in Europeans) that showed a protective effect in Mexicans. Although the association between both MC4R and NEGR1 and risk of obesity has been confirmed in a plethora of studies and populations, the ENPP1 association signal with obesity is more controversial . To our knowledge, no other studies demonstrate a protective role of the risk allele of ENPP1 rs7754561. Recently, it has been shown that ENPP1 overexpression in human adipocyte cell lines resulted in defective adipocyte maturation . If confirmed in other Mexican populations, the protective effect of the ENPP1 variant may be due to a loss-of-function of the protein.
We did not find any significant contribution of either NPC1 rs2815752 or FTO rs1421085 to obesity or BMI variation. Therefore, the FTO association signal with obesity which was found in Mexican adults by Villalobos-Comparán and colleagues , was not confirmed in children. Thus, the obesogenic effect of FTO would occur later in the Mexican population than in the Europeans , but as we lack some statistical power, additional genetic studies on Mexican children would be needed.
Importantly, we identified a significant effect of the risk allele of NPC1 rs1805081 on decreased fasting serum insulin levels. NPC1 encodes Niemann Pick disease type C1 protein that mediates intracellular cholesterol trafficking via binding of cholesterol to its N-terminal domain. Very recently, Jelinek and colleagues have reported that Npc1 haploinsufficiency developed abnormal metabolic features (including hyperinsulinemia) and increased susceptibility to weight gain in mice . We could suspect that the variant may have a gain-of-function effect in Mexican children. Of note, we did not report any association between the NPC1 variant and obesity or BMI variation, and this association signal remains quite controversial according to population studies [20, 25, 26].
Furthermore, we identified an effect of the risk allele of MC4R variant and increased fasting plasma glucose levels. To our knowledge, no previous study has shown this association. However, two recent large meta-analyses of GWAS identified a significant association between the MC4R locus and type 2 diabetes risk, in European and Asian populations [27, 28]. Of note, our present association with fasting plasma glucose levels remained significant after adjustment for BMI (data not shown). Altogether, these findings would suggest a potential effect of MC4R polymorphisms on decreased pancreatic beta-cell function.