The consumption of fruit and vegetables is associated with a reduced rate of coronary heart disease (CHD) in observational cohorts. The purpose of this study was to assess the strength of this ...association in a meta-analysis. Cohort studies were selected if they reported relative risks (RRs) and 95% CI for coronary heart disease or mortality and if they presented a quantitative assessment of fruit and vegetable intake. The pooled RRs were calculated for each additional portion of fruit and/or vegetables consumed per day, and the linearity of the associations were examined. Nine studies were eligible for inclusion in the meta-analysis that consisted of 91,379 men, 129,701 women, and 5,007 CHD events. The risk of CHD was decreased by 4% RR (95% CI): 0.96 (0.93-0.99), P = 0.0027 for each additional portion per day of fruit and vegetable intake and by 7% 0.93 (0.89-0.96), P < 0.0001 for fruit intake. The association between vegetable intake and CHD risk was heterogeneous (P = 0.0043), more marked for cardiovascular mortality 0.74 (0.75-0.84), P < 0.0001 than for fatal and nonfatal myocardial infarction 0.95 (0.92-0.99), P = 0.0058. Visual inspection of the funnel plot suggested a publication bias, although not statistically significant. Therefore, the reported RRs are probably overestimated. This meta-analysis of cohort studies shows that fruit and vegetable consumption is inversely associated with the risk of CHD. The causal mechanism of this association, however, remains to be demonstrated.
Air pollution impacts health by increasing mortality and the incidence of acute events in unhealthy individuals. In contrast, the acute effects of pollution in healthy individuals are less obvious. ...The present study was designed to evaluate the associations between short-term exposure to air pollution on one hand and lung function, and inflammatory markers on the other in middle-aged, non-smoking adults with no respiratory disease, in two urban areas in northern France.
A sample of 1506 non-smoking adults (aged from 40 to 65) with no respiratory disease was selected from the participants in the 2011–2013 cross-sectional Enquête Littoral Souffle Air Biologie Environnement (ELISABET) survey in two urban areas in the northern France. We evaluated the associations between (i) mean levels of particulate matter with aerodynamic diameter < 10 μm (PM10), nitrogen dioxide (NO2) and ozone (O3) exposure on the day and the day before the study examination for each participant, and (ii) spirometry data and levels of inflammatory markers. Coefficients of multiple linear regression models were expressed (except for the forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio) as the percentage change 95% confidence interval per 10 μg increment in each pollutant.
Levels of PM10, NO2 and O3 exposure were below or only close to the World Health Organization's recommended limits in our two study areas. An increment in NO2 levels was significantly associated with a lower FEV1/FVC ratio (−0.38 −0.64; −0.12), a lower forced expiratory flow between 25% and 75% of FVC (FEF25–75%) (−1.70 −3.15; −0.23), and a lower forced expiratory flow measured at 75% of FVC (FEF75%) (−3.07 −4.92; −1.18). An increment in PM10 levels was associated with lower FEF75% (−1.41 −2.79; −0.01) and a non-significant elevation in serum levels of high-sensitivity C-reactive protein (+3.48 −0.25; 7.36, p = 0.07). Lastly, an increment in O3 levels was associated with a significantly higher blood eosinophil count (+2.41 0.10; 4.77) and a non-significant elevation in fractional exhaled nitric oxide (+2.93 −0.16; 6.13, p = 0.06).
A short-term exposure to air pollution was associated with a subclinical decrement in distal lung function and increment in inflammatory markers in healthy inhabitants of two urban areas in France. If these exploratory results are confirmed, this could suggest that even moderate levels of air pollution could have an impact on respiratory health on the general population, and not solely on susceptible individuals.
•A short-term increase in air pollution was associated with worsened distal lung function.•These associations were observed in non-smoker adults with no respiratory disease.•Levels of pollution were close to the World Health Organization's guideline values.•This association is biologically plausible but needs to be confirmed.•Our results suggest that air pollution may have a health impact in the whole population.
Tau deletion promotes brain insulin resistance Marciniak, Elodie; Leboucher, Antoine; Caron, Emilie ...
The Journal of experimental medicine,
08/2017, Letnik:
214, Številka:
8
Journal Article
Recenzirano
Odprti dostop
The molecular pathways underlying tau pathology-induced synaptic/cognitive deficits and neurodegeneration are poorly understood. One prevalent hypothesis is that hyperphosphorylation, misfolding, and ...fibrillization of tau impair synaptic plasticity and cause degeneration. However, tau pathology may also result in the loss of specific physiological tau functions, which are largely unknown but could contribute to neuronal dysfunction. In the present study, we uncovered a novel function of tau in its ability to regulate brain insulin signaling. We found that tau deletion leads to an impaired hippocampal response to insulin, caused by altered IRS-1 and PTEN (phosphatase and tensin homologue on chromosome 10) activities. Our data also demonstrate that tau knockout mice exhibit an impaired hypothalamic anorexigenic effect of insulin that is associated with energy metabolism alterations. Consistently, we found that tau haplotypes are associated with glycemic traits in humans. The present data have far-reaching clinical implications and raise the hypothesis that pathophysiological tau loss-of-function favors brain insulin resistance, which is instrumental for cognitive and metabolic impairments in Alzheimer's disease patients.
The genetic contribution to dilated perivascular space (dPVS) burden-an emerging MRI marker of cerebral small vessel disease-is unknown. We measured the heritability of dPVS burden and its shared ...heritability with other MRI markers of cerebral small vessel disease.
The study sample comprised 1597 participants from the population-based Three City (3C) Dijon Study, with brain MRI and genome-wide genotyping (mean age, 72.8±4.1 years; 61% women). dPVS burden and lacunar brain infarcts were rated on a semiquantitative scale, whereas an automated algorithm generated white matter hyperintensity volume (WMHV). We estimated dPVS burden heritability and shared heritability with WMHV and lacunar brain infarcts using the genome-wide complex trait analysis tool, on unrelated participants, adjusting for age, sex, intracranial volume, and principal components of population stratification.
dPVS burden was significantly correlated with WMHV and lacunar brain infarcts, the strongest correlation being found between WMHV and dPVS in basal ganglia. Heritability estimates were h
=0.59±0.24 (
=0.007) for dPVS burden, h
=0.54±0.24 (
=0.010) for WMHV, and h
=0.48±0.81 (
=0.278) for lacunar brain infarcts. We found a nonsignificant trend toward shared heritability between dPVS and WMHV (r
=0.41±0.28;
=0.096), which seemed driven by dPVS in basal ganglia (r
=0.72±0.61;
=0.126) and not dPVS in white matter (r
=-0.10±0.36;
=0.393). A genetic risk score for WMHV based on published loci was associated with increased dPVS burden in basal ganglia (
=0.031).
We provide evidence for important genetic contribution to dPVS burden in older community-dwelling people, some of which may be shared with WMHV. Differential heritability patterns for dPVS in white matter and basal ganglia suggest at least partly distinct underlying biological processes.
Few single nucleotide polymorphisms (SNPs) have been reproducibly associated with hepatocellular carcinoma (HCC). Our aim was to test the association between nine SNPs and HCC occurrence. SNPs in ...genes linked to HCC (DEPDC5, GRIK1, KIF1B, STAT4, MICA, DLC1, DDX18) or to liver damage (PNPLA3‐rs738409, TM6SF2‐rs58542926) in GWAS were genotyped in discovery cohorts including 1,020 HCC, 2,021 controls with chronic liver disease and 2,484 healthy individuals and replication was performed in prospective cohorts of cirrhotic patients with alcoholic liver disease (ALD, n = 249) and hepatitis C (n = 268). In the discovery cohort, PNPLA3 and TM6SF2 SNPs were associated with HCC (OR = 1.67 CI95%:1.16–2.40, p = 0.005; OR = 1.45 CI95%:1.08–1.94, p = 0.01) after adjustment for fibrosis, age, gender and etiology. In contrast, STAT4‐rs7574865 was associated with HCC only in HBV infected patients (p = 0.03) and the other tested SNP were not linked with HCC risk. PNPLA3 and TM6SF2 variants were independently associated with HCC in patients with ALD (OR = 3.91 CI95%:2.52–6.06, p = 1.14E‐09; OR = 1.79 CI95%:1.25–2.56, p = 0.001) but not with other etiologies. PNPLA3 SNP was also significantly associated with HCC developed on a nonfibrotic liver (OR = 2.19 CI95%:1.22–3.92, p = 0.007). The association of PNPLA3 and TM6SF2 with HCC risk was confirmed in the prospective cohort with ALD. A genetic score including PNPLA3 and TM6SF2 minor alleles showed a progressive significant increased risk of HCC in ALD patients. In conclusion, PNPLA3‐rs738409 and TM6SF2‐rs58542926 are inherited risk variants of HCC development in patients with ALD in a dose dependent manner. The link between PNPLA3 and HCC on nonfibrotic liver suggests a direct role in liver carcinogenesis.
What's new?
Multiple single nucleotide polymorphisms (SNPs) have been associated with hepatocellular carcinoma (HCC) through genome‐wide association studies (GWAS). Few of these variants, however, have been cross‐validated, raising questions about their relation to HCC. Here, nine SNPs previously linked to HCC or liver damage were selected for investigation in European patients. Two of the variants, PNPLA3 rs738409 and TM6SF2 rs58542926, were found to be associated with HCC risk specifically in patients with alcoholic liver disease. PNPLA3 rs738409 was also associated with HCC in patients with nonfibrotic livers, where it potentially influences liver carcinogenesis via modification of protein function without altering gene expression.
Highlights • We review research on relationship between episodic decline and APOE ε4 in AD. • This relationship was not confirmed by all studies. • These studies present several shortcomings to be ...addressed. • This is to better understand relationship between episodic decline and APOE ε4 in AD.
Although APP metabolism is being intensively investigated, a large fraction of its modulators is yet to be characterized. In this context, we combined two genome-wide high-content screenings to ...assess the functional impact of miRNAs and genes on APP metabolism and the signaling pathways involved. This approach highlighted the involvement of FERMT2 (or Kindlin-2), a genetic risk factor of Alzheimer's disease (AD), as a potential key modulator of axon guidance, a neuronal process that depends on the regulation of APP metabolism. We found that FERMT2 directly interacts with APP to modulate its metabolism, and that FERMT2 underexpression impacts axonal growth, synaptic connectivity, and long-term potentiation in an APP-dependent manner. Last, the rs7143400-T allele, which is associated with an increased AD risk and localized within the 3'UTR of FERMT2, induced a downregulation of FERMT2 expression through binding of miR-4504 among others. This miRNA is mainly expressed in neurons and significantly overexpressed in AD brains compared to controls. Altogether, our data provide strong evidence for a detrimental effect of FERMT2 underexpression in neurons and insight into how this may influence AD pathogenesis.
Systemic sclerosis (SSc) is an orphan, complex, inflammatory disease affecting the immune system and connective tissue. SSc stands out as a severely incapacitating and life-threatening inflammatory ...rheumatic disease, with a largely unknown pathogenesis. We have designed a two-stage genome-wide association study of SSc using case-control samples from France, Italy, Germany, and Northern Europe. The initial genome-wide scan was conducted in a French post quality-control sample of 564 cases and 1,776 controls, using almost 500 K SNPs. Two SNPs from the MHC region, together with the 6 loci outside MHC having at least one SNP with a P<10(-5) were selected for follow-up analysis. These markers were genotyped in a post-QC replication sample of 1,682 SSc cases and 3,926 controls. The three top SNPs are in strong linkage disequilibrium and located on 6p21, in the HLA-DQB1 gene: rs9275224, P = 9.18×10(-8), OR = 0.69, 95% CI 0.60-0.79; rs6457617, P = 1.14×10(-7) and rs9275245, P = 1.39×10(-7). Within the MHC region, the next most associated SNP (rs3130573, P = 1.86×10(-5), OR = 1.36 1.18-1.56) is located in the PSORS1C1 gene. Outside the MHC region, our GWAS analysis revealed 7 top SNPs (P<10(-5)) that spanned 6 independent genomic regions. Follow-up of the 17 top SNPs in an independent sample of 1,682 SSc and 3,926 controls showed associations at PSORS1C1 (overall P = 5.70×10(-10), OR:1.25), TNIP1 (P = 4.68×10(-9), OR:1.31), and RHOB loci (P = 3.17×10(-6), OR:1.21). Because of its biological relevance, and previous reports of genetic association at this locus with connective tissue disorders, we investigated TNIP1 expression. A markedly reduced expression of the TNIP1 gene and also its protein product were observed both in lesional skin tissue and in cultured dermal fibroblasts from SSc patients. Furthermore, TNIP1 showed in vitro inhibitory effects on inflammatory cytokine-induced collagen production. The genetic signal of association with TNIP1 variants, together with tissular and cellular investigations, suggests that this pathway has a critical role in regulating autoimmunity and SSc pathogenesis.
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•Air pollution is associated with the miRNA profile in a large, population sample.•The miRNAs significantly associated with air pollution are involved in inflammation.•miRNAs might ...mediate the effect of air pollution on health.•miRNAs are potential biomarkers of the environmental risk.
MicroRNAs are epigenetic regulatory factors capable of silencing the expression of target genes and might mediate the effects of air pollution on health. The objective of the present population-based study was to investigate the association between microRNA expression and long-term, residential exposure to atmospheric PM10 and NO2.
We included 998 non-smoking adult participants from the cross-sectional ELISABET survey (2010–2014) in the Lille urban area of France. The mean residential annual pollution levels were estimated with an atmospheric dispersion modelling system. Ten microRNAs were selected on the basis of the literature data, together with two housekeeping microRNAs (miR-93-5p and miR-191-5p) and were quantified with RT-qPCRs. Multivariate linear regression models were used to study the association between microRNAs and air pollution. The threshold for statistical significance (after correction for the FDR) was set to p < 0.1.
The mean annual exposure between 2011 and the year of inclusion was 26.4 ± 2.0 µg/m3 for PM10 and 24.7 ± 5.1 µg/m3 for NO2. Each 2 µg/m3 increment in PM10 exposure was associated with an 8.6% increment (95%CI 3.1; 14.3; pFDR = 0.019) in miR-451a expression.
A 5 µg/m3 increment in NO2 exposure was associated with a 5.3% increment (0.7; 10; pFDR = 0.056) in miR451a expression, a 3.6% decrement (95%CI -6.1; −1.1; pFDR = 0.052) in miR-223-3p expression, a 3.8% decrement (95%CI-6.8; −0.7; pFDR = 0.079) in miR-28-3p expression, a 4.3% decrement (95%CI -7.7; −0.8; pFDR = 0.055) in miR-146a-5p expression, and a 4.0% decrement (95% CI−7.4; −0.4; pFDR = 0.059) in miR-23a-5p expression. The difference between the two housekeeping microRNAs miR-93-5p and miR-191-5p was also associated with PM10 and NO2 exposure.
Our results suggest that circulating miRNAs are potentially valuable biomarkers of the effects of air pollution.
Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present genome-wide associations ...of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlight four signalling pathways associated with aortic distensibility (TGF-β, IGF, VEGF and PDGF). We identify distinct sex-specific associations with aortic traits. We develop co-expression networks associated with aortic traits and apply phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggests a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.
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