The role of neuromedin U in adiposity regulation. Haplotype analysis in European children from the IDEFICS Cohort

Background and aims: Neuromedin U (NMU) is a hypothalamic neuropeptide with important roles in several metabolic processes, recently suggested as potential therapeutic target for obesity. We analysed the associations between NMU gene variants and haplotypes and body mass index (BMI) in a large sample of European children. Methods and results: From a large European multi-center study on childhood obesity, 4,528 children (2.0–9.9 years, mean age 6.0±1.8 SD; boys 52.2%) were randomly selected, stratifying by age, sex and country, and genotyped for tag single nucleotide polymorphisms (SNPs; rs6827359, T:C; rs12500837, T:C; rs9999653,C:T) of NMU gene, then haplotypes were inferred. Regression models were applied to estimate the associations between SNPs or haplotypes and BMI as well as other anthropometric measures. BMI was associated with all NMU SNPs (p<0.05). Among five haplotypes inferred, the haplotype carrying the minor alleles (CCT, frequency = 22.3%) was the only associated with lower BMI values (beta = -0.16, 95%CI:-0.28,-0.04, p = 0.006; z-score, beta = -0.08, 95%CI:-0.14,-0.01, p = 0.019) and decreased risk of overweight/obesity (OR = 0.81, 95%CI:0.68,0.97, p = 0.020) when compared to the most prevalent haplotype (codominant model). Similar significant associations were also observed using the same variables collected after two years’ time (BMI, beta = -0.25, 95%CI:-0.41,-0.08, p = 0.004; z-score, beta = -0.10, 95%CI:-0.18,-0.03, p = 0.009; overweight/obesity OR = 0.81, 95%CI:0.66,0.99, p = 0.036). The association was age-dependent in girls (interaction between CCT haplotypes and age, p = 0.008), more evident between 7 and 9 years of age. The CCT haplotype was consistently associated with lower levels of fat mass, skinfold thickness, hip and arm circumferences both at T0 and at T1, after adjustment for multiple testing (FDR-adjusted p<0.05). Conclusions: This study shows an association between a NMU haplotype and anthropometric indices, mainly linked to fat mass, which appears to be age- and sex-specific in children. Genetic variations within or in linkage with this haplotype should be investigated to identify functional variants responsible for the observed phenotypic variation

The role of neuromedin U in adiposity regulation. Haplotype analysis in European children from the IDEFICS Cohort

BACKGROUND AND AIMS: Neuromedin U (NMU) is a hypothalamic neuropeptide with important roles in several metabolic processes, recently suggested as potential therapeutic target for obesity. We analysed the associations between NMU gene variants and haplotypes and body mass index (BMI) in a large sample of European children. METHODS AND RESULTS: From a large European multi-center study on childhood obesity, 4,528 children (2.0–9.9 years, mean age 6.0±1.8 SD; boys 52.2%) were randomly selected, stratifying by age, sex and country, and genotyped for tag single nucleotide polymorphisms (SNPs; rs6827359, T:C; rs12500837, T:C; rs9999653,C:T) of NMU gene, then haplotypes were inferred. Regression models were applied to estimate the associations between SNPs or haplotypes and BMI as well as other anthropometric measures. BMI was associated with all NMU SNPs (p<0.05). Among five haplotypes inferred, the haplotype carrying the minor alleles (CCT, frequency = 22.3%) was the only associated with lower BMI values (beta = -0.16, 95%CI:-0.28,-0.04, p = 0.006; z-score, beta = -0.08, 95%CI:-0.14,-0.01, p = 0.019) and decreased risk of overweight/obesity (OR = 0.81, 95%CI:0.68,0.97, p = 0.020) when compared to the most prevalent haplotype (codominant model). Similar significant associations were also observed using the same variables collected after two years’ time (BMI, beta = -0.25, 95%CI:-0.41,-0.08, p = 0.004; z-score, beta = -0.10, 95%CI:-0.18,-0.03, p = 0.009; overweight/obesity OR = 0.81, 95%CI:0.66,0.99, p = 0.036). The association was age-dependent in girls (interaction between CCT haplotypes and age, p = 0.008), more evident between 7 and 9 years of age. The CCT haplotype was consistently associated with lower levels of fat mass, skinfold thickness, hip and arm circumferences both at T0 and at T1, after adjustment for multiple testing (FDR-adjusted p<0.05). CONCLUSIONS: This study shows an association between a NMU haplotype and anthropometric indices, mainly linked to fat mass, which appears to be age- and sex-specific in children. Genetic variations within or in linkage with this haplotype should be investigated to identify functional variants responsible for the observed phenotypic variation

Allele frequencies and Hardy-Weinberg equilibrium of the <i>NMU</i> SNPs (n = 4,528 with at least one SNP successfully genotyped; T0).

<p>Allele frequencies and Hardy-Weinberg equilibrium of the <i>NMU</i> SNPs (n = 4,528 with at least one SNP successfully genotyped; T0).</p

Haplotype frequencies in the whole sample and stratified for BMI categories (n = 4,528 with at least one SNP successfully genotyped; T0).

<p>Haplotype frequencies in the whole sample and stratified for BMI categories (n = 4,528 with at least one SNP successfully genotyped; T0).</p

Associations between <i>NMU</i> genotypes and haplotypes and BMI, other anthropometric parameters and BMI categories.

<p>Associations between <i>NMU</i> genotypes and haplotypes and BMI, other anthropometric parameters and BMI categories.</p

BMI (crude values and <i>z</i>-scores) age trend with 95% confidence intervals by haplotypes (CCT/x, red, vs carriers of the most prevalent haplotype, TTC, blue) in boys and girls.

<p>The graphs were drawn pooling T0 (2–10 years) and T1 (4–12 years) data to have a single comprehensive view. All children contributed with their measures weighted by haplotype posterior probabilities. Each BMI value of children contributing with both T0 and T1 measures was also weighted 0.5, to take into account the effect of repeated observations in the same subject. Local regression method implies that statistical power decreases at extreme x values (larger confidence intervals).</p

Anthropometric characteristics of N = 4,528 children with genotype data recruited at baseline of the IDEFICS study.

<p>Anthropometric characteristics of N = 4,528 children with genotype data recruited at baseline of the IDEFICS study.</p

Reduced mortality risk by a polyphenol-rich diet: An analysis from the Moli-sani study

Objectives: The effect of the polyphenol content of the human diet on mortality risk is not yet fully understood. The aim of this study was to evaluate the association of a polyphenol-rich diet with mortality rate and a possible mediation effect by inflammation, in what we believe to be a novel, holistic approach. Methods: We analyzed 21 302 participants (10 980 women and 10 322 men, aged 6535 y) from the Moli-sani cohort. The participants were followed up for a median of 8.3 y. The European Prospective Investigation into Cancer and Nutrition food frequency questionnaire (FFQ) was used for dietary assessment. Flavonol, flavone, flavanone, flavanol, anthocyanin, isoflavone, and lignan intakes were calculated using European Food Information Resource\u2014Bioactive Substances in Food Information Systems and the polyphenol antioxidant content (PAC)-score was constructed to assess the total content of these nutrients in the diet. Results: Participants included in the highest quintile of intake of various polyphenol classes and subclasses presented a significant lower all-cause mortality risk compared with those in the lowest group of consumption (hazard ratio [HR] &lt; 1; P &lt; 0.05). Cox regression analyses adjusted for potential confounders indicated that participants in higher quintiles of PAC-score had lower all-cause mortality risk (HR &lt;1; P &lt; 0.05). When cause-specific mortality rates were considered, similar effects were observed for cardiocerebrovascular and cancer mortality (HR &lt;1; P &lt; 0.05). Conclusions: The polyphenol content of the diet was associated with reduced mortality risk in a Mediterranean population, possibly through an antiinflammatory mechanism

Mean platelet volume is associated with lower risk of overall and non-vascular mortality in a general population: Results from the Moli-sani study

Larger mean platelet volume (MPV) has been associated with adverse health outcomes in high-risk populations or patients with cardiovascular disease (CVD). We tested the association of MPV with mortality in a prospective cohort study including 17,402 subjects randomly recruited from an adult general population within the Moli-sani study (2005-2010). Two distinct subgroups (with or without CVD at baseline) were subsequently analysed. Hazard ratios (HR) were calculated using multivariable Cox-proportional hazard models. Over a median follow up of eight years (137,547 person-years), 925 all-cause deaths occurred (330 vascular, 351 cancer and 244 other deaths). In a multivariable model, the highest MPV quintile (mean MPV=10.0 fL), as compared to the lowest one, was associated with reduced risk of overall mortality (HR=0.79; 95 % confidence interval 0.64-0.98), cancer death (HR=0.70; 0.49-1.00) and death from other non-vascular/non cancer causes (HR=0.55; 0.36-0.84) but not with vascular mortality. The inverse association with overall death appeared even stronger in the subgroup without CVD at baseline (HR=0.64; 0.50-0.81). In contrast, within 920 subjects reporting a previous CVD event, larger MPV was associated with higher risk of total mortality (HR=1.69; 1.05-2.72; p for interaction=0.048) and with a trend of risk for other cause-specific deaths. In conclusion, larger MPV is associated with lower risk of overall and non-vascular death in subjects apparently free from CVD, but appears to be a predictive marker of death in patients with CVD history. The latter is a likely effect modifier of the association between MPV and death