Haplotypes, Genotypes, and DNA Methylation Levels of Neuromedin U Gene Are Associated with Cardio-Metabolic Parameters: Results from the Moli-sani Study

<b>Background/Objectives:</b> Neuromedin U (NMU) is a highly conserved gene encoding a neuropeptide involved in the regulation of feeding behavior and energy homeostasis. We aimed to analyze the association between <i>NMU</i> genetic and epigenetic variations and cardio-metabolic parameters in an Italian population to identify the role of these variants in cardio-metabolic risk. <b>Methods:</b> A total of 4028 subjects were randomly selected from the Moli-sani study cohort. <i>NMU</i> haplotypes were estimated using seven SNPs located in the gene body and in the promoter region; DNA methylation levels in the promoter region, previously associated with lipid-related variables in the same population, were also used. <b>Results</b>: Among the haplotypes inferred, the haplotype carrying the highest number of minor variants (frequency 16.6%), when compared with the most frequent haplotype, was positively associated with insulin levels, HOMA-IR, and diastolic blood pressure, and negatively with HDL-cholesterol. The multivariable analysis that considered methylation levels along with their interactions with SNPs showed that increased methylation levels in two close CpG sites were associated with higher levels of lipid-related variables. <b>Conclusions</b>: This study supports a role for NMU as a regulator of human metabolism. This finding suggests that NMU could be a potential target for preventive interventions against coronary and cerebrovascular diseases, and that <i>NMU</i> genetic and epigenetic variability may serve as a biomarker for cardio-metabolic risk.