Background: POMC plays a major role in central body weight regulation. Recently we have shown that a POMC hypermethylation variant is significantly associated with obesity in children and adolescents (Kuehnen et al. PLoS Genetics 2012).
Objective and hypotheses: Here we report about our extended studies to elucidate the mechanism behind the occurrence of the POMC hypermethylation variant in obese individuals.
Method: We tested the POMC DNA methylation in obese adults (n=144), normal weight individuals (n=101), 20 obese monozygotic and 19 obese dizygotic twin pairs and 49 trio families. The DNA methylation was analysed in DNA extracted from peripheral blood cells with a sodium-bisulfite based protocol and pyrosequencing.
Results: We could now reproduce our initial findings in children also in adults and observed a highly significant enrichment of the POMC hypermethylation variant in obese compared to age-and sex matched normal weight individuals. In children-parent-trio families we could found no correlation with maternal but a significant correlation with the paternal DNA methylation level. We excluded a potential impact of genetic variations in cis by sequencing analysis of the complete POMC locus in all individuals. Moreover we identified in monozygotic twins a high grade of DNA methylation concordance, which was completely missing in dizygotic twins. The similarities of the POMC DNA methylation pattern in monozygotic twins -in the light of excluded genetic influence- argue for potential parental effects or rather oocyte specific pre-splitting random re-methylation events.
Conclusion: Taken together the POMC hypermethylation variant represent the strongest factor that is associated with the individual risk for obesity so far since all described genetic variants have shown to have a much lesser impact on the individual BMI compared to the here described POMC locus hypermethylation. In addition the hypermethylation variant seems not to result from primary genetic variation but rather seems to originate from sporadic early embryonic random remethylation difference.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology