Neuromedin U gene pathway in the control of obesity and other hypothalamus-regulated phenotypes in an Italian population

Rationale. Neuromedin U (NMU) is a hypothalamic neuropeptide that regulates metabolic phenotypes. Our preliminary analyses in European children suggested that NMU gene plays an important role in adiposity and bone health. Objectives. This project aims at investigating the associations between hypothalamus-regulated phenotypes and NMU pathway genes, by: (i) exploring in adults and elderly subjects possible associations between polymorphisms in NMU pathway genes and adiposity, insulin resistance, blood pressure and bone health; (ii) verifying gene-gene interaction effects; (iii) identifying regions with aberrant methylation in the genes confirmed for associations. Methods. The Moli-sani project population of 24,600 subjects, aged 35-99 years, recruited from the general population will be studied. A two-step approach will be set-up to identify and replicate associations, considering false discovery rate correction. Twelve NMU pathway genes will be selected among those mostly associated with adiposity or related phenotypes in GWAs studies or with strong functional data on encoded proteins. Beside NMU, genes directly related to NMU function and genes, strongly associated with phenotypes downstream to NMU in GWAs meta-analyses will be selected. A random sample of 3,000 adults and 2,000 elderly recruited within the Moli-sani project will be genotyped, expecting to identify at least 2 associated SNPs. Significantly associated SNPs will be replicated in an additional random sample of 3,000 adults/elderly from the Moli-sani study. Among the 12 genes of the NMU pathways investigated, those with CpG islands or transcription factor binding site known to have reduced binding activity when methylated will be selected. Then methylation will be measured in a subgroup of 500 subjects selected among those with extreme values of BMI. Finally, associated CpG areas will be replicated in the whole sample. Implication on public health. Obesity is a growing epidemics worldwide and a severe risk factor against disease-less ageing. Genome and epigenome analyses will allow identifying the genes involved in its development . The identification of underlying mechanisms may offer novel insights into the pathogenesis of obesity and other metabolic disorders and provide targets for intervention or identify biomarkers for risk assessment. Genetic markers in NMU and other CNS-related genes could be useful for planning therapy of metabolic diseases and to recognize subjects with potential adverse effects on bone parameters, thus contributing to the prevention of chronic disease associated with ageing. Anyway, delving into specific CNS genes involved in different phenotypes could contribute to find out new biomarkers for risk assessment and therapy planning, as well as novel specific targets for preventive or therapeutic interventions. The Project will be done at IRCCS Istituto Neurologico Mediterraneo NEUROMED (Pozzilli - IS) in collaboration with the EPIMED Research Center - University of Insubria, Varese