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Background Neuromedin U (NMU) is a hypothalamic neuropeptide with several functions, considered to be a potential therapeutic target for diabetes mellitus. The aim of this study was to analyse the association between genetic variants in NMU pathway genes and cardiovascular risk, in Italian adults from the general population recruited for the Moli-sani study. Methods A total of 4,039 participants (mean age 55.8±12.1 SD; men 46.1%) were randomly selected from the whole study population (N = 24,325; recruitment years 2005-2010). DNA from blood samples stored in the Moli-sani biobank were genotyped for 14 single nucleotide polymorphisms (SNPs) in the genes encoding for NMU, Neuromedin S (NMS) and their receptors NMUR1 and NMUR2. Cox regression analysis (age, sex, BMI, blood pressure, glucose and lipid levels as covariates) was performed to estimate the associations between SNPs and fatal or non-fatal CVD events (validated myocardial infarction or stroke), identified from death certificates and electronic records during a median follow-up of 4.5 years. A genetic score was then computed. Results CVD events (N = 93) were associated with mutant alleles in the NMU SNP rs55796004 (HR = 1.94; 95%CI:1.08-3.48) and rs4856020 (HR = 0.52; 95%CI: 0.29-0.94) and in the NMS SNP rs12474526 (HR = 0.48, 95%CI:0.28-0.81), independently from CVD risk factors. A SNP in NMUR1 showed a borderline association (rs6754952, HR = 0.74; 95%CI:0.54-1.00). The derived genetic score was associated with CVD incidence with a HR of 1.57 (95%CI:1.25-1.96, per 1 score SD). A HR of 7.33 (95%CI:1.68-32.01) was found comparing the last vs the 1st decile of the genetic score. Conclusions Italian adults carrying variants in NMU pathway genes are at increased CVD risk. Intermediate phenotypes, mediating this association independent of classical risk factors, are unknown and should be investigated. Once confirmed, these results could be useful to improve CVD risk assessment and to plan cost-effective interventions. Key messages Polymorphisms in NMU pathway genes are associated with CVD risk independently of classical CVD risk factors, suggesting a potential clinical utility in CVD prediction when added to CVD risk algorithms. The unknown phenotype mediating the association between NMU genes polymorphisms and CVD development could be the neglected CVD risk factor potentially explaining the unpredicted CVD fraction.

Variants in Neuromedin U pathway genes and risk of cardiovascular disease in an Italian population