Publications by authors named "Maria G Stathopoulou"

52 Publications

Epigenome-wide association study detects a novel loci associated with central obesity in healthy subjects.

BMC Med Genomics 2021 09 23;14(1):233. Epub 2021 Sep 23.

INSERM UMR U1122, IGE-PCV, Faculté de Pharmacie, Université de Lorraine, 30 Rue Lionnois, 54000, Nancy, France.

Background And Aims: Central obesity is a condition that poses a significant risk to global health and requires the employment of novel scientific methods for exploration. The objective of this study is to use DNA methylation analysis to detect DNA methylation loci linked to obesity phenotypes, i.e. waist circumference and waist-to-hip ratio adjusted for BMI.

Methods And Results: Two-hundred and ten healthy European participants from the STANISLAS Family Study (SFS), comprising 73 nuclear families, were comprehensively assessed for methylation status using Illumina Infinium HumanMethylation450 BeadChip. An epigenome-wide association study was performed, which identified a CpG site cg16170243 located on chromosome 18q21.2 significantly associated with waist circumference, after adjusting for BMI (β = 2.32, SE = 0.41, P = 0.048). Cg16170243 corresponds to a 50 bp-length human methylation oligoprobe located within the AC090241.2 gene that overlaps ST8SIA5 gene. No significant association was observed with waist-to-hip ratio adjusted for BMI (P > 0.05).

Conclusions: A novel association between DNA methylation and WC was identified, which is demonstrating that epigenetic mechanisms may have a significant impact on waist circumference ratio in healthy individuals. Further studies are warranted to address the causal effects of this association.
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http://dx.doi.org/10.1186/s12920-021-01077-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459469PMC
September 2021

Paternal High-Protein Diet Programs Offspring Insulin Sensitivity in a Sex-Specific Manner.

Biomolecules 2021 05 18;11(5). Epub 2021 May 18.

Université de Paris, BFA, UMR 8251, CNRS, Team "Biologie et Pathologie du Pancréas Endocrine", 75013 Paris, France.

The impact of maternal nutrition on offspring is well documented. However, the implication of pre-conceptional paternal nutrition on the metabolic health of the progeny remains underexplored. Here, we investigated the impact of paternal high-protein diet (HPD, 43.2% protein) consumption on the endocrine pancreas and the metabolic phenotype of offspring. Male Wistar rats were given HPD or standard diet (SD, 18.9% protein) for two months. The progenies (F1) were studied at fetal stage and in adulthood. Body weight, glycemia, glucose tolerance (GT), glucose-induced insulin secretion in vivo (GIIS) and whole-body insulin sensitivity were assessed in male and female F1 offspring. Insulin sensitivity, GT and GIIS were similar between F1 females from HPD (HPD/F1) and SD fathers (SD/F1). Conversely, male HPD/F1 exhibited increased insulin sensitivity ( < 0.05) and decreased GIIS ( < 0.05) compared to male SD/F1. The improvement of insulin sensitivity in HPD/F1 was sustained even after 2 months of high-fat feeding. In male HPD/F1, the β cell mass was preserved and the β cell plasticity, following metabolic challenge, was enhanced compared to SD/F1. In conclusion, we provide the first evidence of a sex-specific impact of paternal HPD on the insulin sensitivity and GIIS of their descendants, demonstrating that changes in paternal nutrition alter the metabolic status of their progeny in adulthood.
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http://dx.doi.org/10.3390/biom11050751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157381PMC
May 2021

Nutrigenetic Interactions Might Modulate the Antioxidant and Anti-Inflammatory Status in Mastiha-Supplemented Patients With NAFLD.

Front Immunol 2021 7;12:683028. Epub 2021 May 7.

EA_1122, IGE-PCV, Université de Loraine, Nancy, France.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease with no therapeutic consensus. Oxidation and inflammation are hallmarks in the progression of this complex disease, which also involves interactions between the genetic background and the environment. Mastiha is a natural nutritional supplement known to possess antioxidant and anti-inflammatory properties. This study investigated how a 6-month Mastiha supplementation (2.1 g/day) could impact the antioxidant and inflammatory status of patients with NAFLD, and whether genetic variants significantly mediate these effects. We recruited 98 patients with obesity (BMI ≥ 30 kg/m) and NAFLD and randomly allocated them to either the Mastiha or the placebo group for 6 months. The anti-oxidative and inflammatory status was assessed at baseline and post-treatment. Genome-wide genetic data was also obtained from all participants, to investigate gene-by-Mastiha interactions. NAFLD patients with severe obesity (BMI > 35kg/m) taking the Mastiha had significantly higher total antioxidant status (TAS) compared to the corresponding placebo group (P value=0.008). We did not observe any other significant change in the investigated biomarkers as a result of Mastiha supplementation alone. We identified several novel gene-by-Mastiha interaction associations with levels of cytokines and antioxidant biomarkers. Some of the identified genetic loci are implicated in the pathological pathways of NAFLD, including the lanosterol synthase gene ( associated with glutathione peroxidase activity (Gpx) levels, the mitochondrial pyruvate carrier-1 gene ( and the sphingolipid transporter-1 gene () associated with hemoglobin levels, the transforming growth factor-beta-induced gene () and the micro-RNA 129-1 ( associated with IL-6 and the granzyme B gene () associated with IL-10 levels. Within the MAST4HEALTH randomized clinical trial (NCT03135873, www.clinicaltrials.gov) Mastiha supplementation improved the TAS levels among NAFLD patients with severe obesity. We identified several novel genome-wide significant nutrigenetic interactions, influencing the antioxidant and inflammatory status in NAFLD.

Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03135873.
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http://dx.doi.org/10.3389/fimmu.2021.683028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138178PMC
May 2021

Systemic CLIP-seq analysis and game theory approach to model microRNA mode of binding.

Nucleic Acids Res 2021 06;49(11):e66

Inserm U1065, C3M, Team Control of Gene Expression (10), Nice, France.

microRNAs (miRNAs) associate with Ago proteins to post-transcriptionally silence gene expression by targeting mRNAs. To characterize the modes of miRNA-binding, we developed a novel computational framework, called optiCLIP, which considers the reproducibility of the identified peaks among replicates based on the peak overlap. We identified 98 999 binding sites for mouse and human miRNAs, from eleven Ago2 CLIP-seq datasets. Clustering the binding preferences, we found heterogeneity of the mode of binding for different miRNAs. Finally, we set up a quantitative model, named miRgame, based on an adaptation of the game theory. We have developed a new algorithm to translate the miRgame into a score that corresponds to a miRNA degree of occupancy for each Ago2 peak. The degree of occupancy summarizes the number of miRNA-binding sites and miRNAs targeting each binding site, and binding energy of each miRNA::RNA heteroduplex in each peak. Ago peaks were stratified accordingly to the degree of occupancy. Target repression correlates with higher score of degree of occupancy and number of miRNA-binding sites within each Ago peak. We validated the biological performance of our new method on miR-155-5p. In conclusion, our data demonstrate that miRNA-binding sites within each Ago2 CLIP-seq peak synergistically interplay to enhance target repression.
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http://dx.doi.org/10.1093/nar/gkab198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216473PMC
June 2021

Effect of Mastiha supplementation on NAFLD: The MAST4HEALTH Randomised, Controlled Trial.

Mol Nutr Food Res 2021 05 16;65(10):e2001178. Epub 2021 Apr 16.

Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy.

Scope: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease with poor therapeutic strategies. Mastiha possesses antioxidant/anti-inflammatory and lipid-lowering properties. The authors investigate the effectiveness of Mastiha as a nonpharmacological intervention in NAFLD.

Methods And Results: Ninety-eight patients with NAFLD in three countries (Greece, Italy, Serbia) are randomly allocated to either Mastiha or Placebo for 6 months, as part of a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The authors assess NAFLD severity via magnetic resonance imaging (MRI) scanning and LiverMultiScan technique and evaluate the effectiveness of Mastiha through medical, anthropometric, biochemical, metabolomic, and microbiota assessment. Mastiha is not superior to Placebo on changes in iron-corrected T1 (cT1) and Liver Inflammation Fibrosis score (LIF) in entire patient population; however, after BMI stratification (BMI ≤ 35 kg m and BMI > 35 kg m ), severely obese patients show an improvement in cT1 and LIF in Mastiha versus Placebo. Mastiha increases dissimilarity of gut microbiota, as shown by the Bray-Curtis index, downregulates Flavonifractor, a known inflammatory taxon and decreases Lysophosphatidylcholines-(LysoPC) 18:1, Lysophosphatidylethanolamines-(LysoPE) 18:1, and cholic acid compared to Placebo.

Conclusion: Mastiha supplementation improves microbiota dysbiosis and lipid metabolite levels in patients with NAFLD, although it reduces parameters of liver inflammation/fibrosis only in severely obese patients.
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http://dx.doi.org/10.1002/mnfr.202001178DOI Listing
May 2021

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Hum Mol Genet 2021 04;30(5):393-409

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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http://dx.doi.org/10.1093/hmg/ddab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098112PMC
April 2021

Prediction of coronary heart disease incidence in a general male population by circulating non-coding small RNA sRNY1-5p in a nested case-control study.

Sci Rep 2021 01 19;11(1):1837. Epub 2021 Jan 19.

Inserm U1065, C3M, Team Control of Gene Expression (10), Université Côte D'Azur, Nice, France.

During the development of atherosclerotic lesion, s-RNYs (small RNAs of about 24/34 nucleotides) are derived by the processing of long Ro-associated non-coding RNAs (RNYs) in macrophages. The levels of serum s-RNYs have been found significantly upregulated in patients with coronary heart disease (CHD) compared to age-matched CHD-free individuals. The present study aimed to examine the predictive value of serum s-RNYs for CHD events in the general male population. Within the frame of nested-case-control study, the GENES study, we measured the absolute expression of a RNY-derived small RNA, the s-RNY1-5p, in the serum of individuals (without CHD at baseline) who encountered a CHD event within 12 years of follow-up (n = 30) (Cases) and compared them to individuals who remained event-free (Controls) (n = 30). The expression of s-RNY1-5p in serum was significantly upregulated in Cases compared to Controls (p = 0.027). The proportion of CHD event-free was significantly higher among individuals with serum s-RNY1-5p below the median value (631 molecules/mL). In a multivariable model adjusted for age, smoking, hypertension, diabetes and dyslipidemia, the risk of CHD events increased more than fourfold in individuals with serum s-RNY1-5p above the median value (HR, 4.36; 95% CI 1.22-15.60). A positive association with CHD events was also observed when considering s-RNY1-5p as a continuous variable (p = 0.022). Based on our results, we conclude that serum s-RNY1-5p is an independent predictor of CHD events in a general male population and might be a relevant biomarker for early detection of cardiovascular diseases.
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http://dx.doi.org/10.1038/s41598-021-81221-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815790PMC
January 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Increased risk of hypercholesterolemia in a French and Lebanese population due to an interaction between rs2569190 in CD14 and gender.

Clin Chim Acta 2020 Oct 13;509:172-176. Epub 2020 Jun 13.

Université de Lorraine, IGE-PCV, F-54000 Nancy, France. Electronic address:

Rationale: Since identifying gender-specific genetic associations may have a significant impact on public health, we studied the interaction between rs2569190 in CD14 (cluster of differentiation 14) and gender in relation to the lipid traits in two independent populations.

Methods: We first tested the interaction in a discovery population (SFS, n = 956), then replicated it in an independent population (LGP, n = 460), followed by a meta-analysis (n = 1,416). Finally, stratification according to gender was conducted to test the association between rs2569190 and lipid traits. Binary multiple logistic regression models were used while correcting for many confounders. Power calculations were also performed.

Results: An interaction between rs2569190 and gender, which increased the risk of total cholesterol levels in SFS, was found (OR = 2.151 and P = 0.05). This interaction was further replicated in the LGP (OR = 1.353 and P < 0.001), and the meta-analysis showed an overall significant interaction (OR = 1.436 and P = 0.02). Similarly, the meta-analysis showed an overall significant positive effect (OR = 1.204 and P = 0.004) for low-density lipoprotein cholesterol levels. Overall, 1,416 patients were evaluated, and the statistical heterogeneity was low, with I estimates ranging between 0% and 22.2%. In contrast, rs2569190 in CD14 did not show any significant interaction with gender influencing high-density lipoprotein levels and triglycerides levels in both populations.

Conclusion: An interaction between rs2569190 in CD14 and gender increased the risk of hypercholesterolemia in two independent populations with a gender-specific effect in males.
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http://dx.doi.org/10.1016/j.cca.2020.06.020DOI Listing
October 2020

Epigenome-wide association study in healthy individuals identifies significant associations with DNA methylation and PBMC extract VEGF-A concentration.

Clin Epigenetics 2020 06 5;12(1):79. Epub 2020 Jun 5.

IGE-PCV, Inserm, Université de Lorraine, F-54000, Nancy, France.

Introduction: Vascular endothelial growth factor A (VEGF-A) is a chemokine that induces proliferation and migration of vascular endothelial cells and is essential for both physiological and pathological angiogenesis. It is known for its high heritability (> 60%) and involvement in most common morbidities, which makes it a potentially interesting biomarker. Large GWAS studies have already assessed polymorphisms related to VEGF-A. However, no previous research has provided epigenome-wide insight in regulation of VEGF-A.

Methods: VEGF-A concentrations of healthy participants from the STANISLAS Family Study (n = 201) were comprehensively assessed for association with DNA methylation. Genome-wide DNA methylation profiles were determined in whole blood DNA using the 450K Infinium BeadChip Array (Illumina). VEGF-A concentration in PBMC extracts was detected using a high-sensitivity multiplex Cytokine Array (Randox Laboratories, UK).

Results: Epigenome-wide association analysis identified 41 methylation sites significantly associated with VEGF-A concentrations derived from PBMC extracts. Twenty CpG sites within 13 chromosomes reached Holm-Bonferroni significance. Significant values ranged from P = 1.08 × 10 to P = 5.64 × 10.

Conclusion: This study exposed twenty significant CpG sites linking DNA methylation to VEGF-A concentration. Methylation detected in promoter regions, such as TPX2 and HAS-1, could explain previously reported associations with the VEGFA gene. Methylation may also help in the understanding of the regulatory mechanisms of other genes located in the vicinity of detected CpG sites.
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http://dx.doi.org/10.1186/s13148-020-00874-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273671PMC
June 2020

Variants Associated with Short Leukocyte Telomeres: Implication of Higher Early Life Leukocyte Telomere Attrition as Assessed by the Blood-and-Muscle Model.

Cells 2020 05 31;9(6). Epub 2020 May 31.

Université de Lorraine, Inserm, DCAC, F-54000 Nancy, France.

Short leukocyte telomere length (LTL) is associated with atherosclerotic cardiovascular disease (ASCVD). Mendelian randomisation studies, using single nucleotide polymorphisms (SNPs) associated with short LTL, infer a causal role of LTL in ASCVD. Recent results, using the blood-and-muscle model, indicate that higher early life LTL attrition, as estimated by the ratio between LTL and skeletal muscle telomere length (MTL), rather than short LTL at conception, as estimated by MTL, should be responsible of the ASCVD-LTL connection. We combined LTL and MTL measurements and SNPs profiling in 402 individuals to determine if 15 SNPs classically described as associated with short LTL at adult age were rather responsible for higher LTL attrition during early life than for shorter LTL at birth. Two of these SNPs (rs12696304 and rs10936599) were associated with LTL in our cohort ( = 0.027 and = 0.025, respectively). These SNPs, both located on the gene, were associated with the LTL/MTL ratio ( = 0.007 and = 0.037, respectively), but not with MTL ( = 0.78 and = 0.32 respectively). These results suggest that SNPs located on genes coding for telomere maintenance proteins may contribute to a higher LTL attrition during the highly replicative first years of life and have an impact later on the development of ASCVD.
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http://dx.doi.org/10.3390/cells9061360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349705PMC
May 2020

Obesity status modifies the association between rs7556897T>C in the intergenic region SLC19A3-CCL20 and blood pressure in French children.

Clin Chem Lab Med 2020 10;58(11):1819-1827

Research Unit EA_1122; IGE-PCV - Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire, Université de Lorraine, Faculté de Pharmacie, Nancy, France.

Background Growing evidence reports an association between inflammatory markers, obesity and blood pressure (BP). Specifically, the intergenic single nucleotide polymorphism (SNP) rs7556897T > C (MAF = 0.34) located between SLC19A3 and the CCL20 was shown to be associated with chronic inflammatory diseases. In addition, CCL20 expression was found increased in pancreatic islets of obese rodents and human pancreatic β cells under the influence of inflammation. In this study, we hypothesized that SNP rs7556897 could affect BP levels, thus providing a link between inflammation, BP and obesity. Methods BP was measured under supine position with a manual sphygmomanometer; values reported were the means of three readings. We analyzed rs7556897 in 577 normal weight and 689 obese French children. Using real-time polymerase chain reaction (PCR), we quantified CCL20 and SLC19A3 expression in adipose tissue and peripheral blood mononuclear cells (PBMCs) of normal weight and overweight children. Results The rs7556897C allele was negatively associated with diastolic BP in normal weight children (β = -0.012 ± 0.004, p = 0.006) but positively associated in obese children (β = 2.178 ± 0.71, p = 0.002). A significant interaction between rs7556897T > C and the obesity status (obese or normal weight) was detected (β = 3.49, p = 9.79 × 10-5) for BP in a combined population analysis. CCL20 mRNA was only expressed in the adipose tissue of overweight children, and its expression levels were 10.7×  higher in PBMCs of overweight children than normal weight children. Finally, CCL20 mRNA levels were positively associated with rs7556897T > C in PBMCs of 58 normal weight children (β = 0.43, p = 0.002). SLC19A3 was not expressed in PBMCs, and in adipose tissue, it showed same levels of expression in normal weight and overweight children. The gene expression results may highlight a specific involvement of CCL20 via communicating obesity/inflammation pathways that regulate BP. Conclusions Childhood obesity reverses the effect of rs7556897T > C on diastolic BP, possibly via the modulation of CCL20 expression levels.
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http://dx.doi.org/10.1515/cclm-2019-0292DOI Listing
October 2020

Telomere length determinants in childhood.

Clin Chem Lab Med 2020 01;58(2):162-177

University of Lorraine, Inserm, IGE-PCV, Nancy, France.

Telomere length (TL) is a dynamic marker that reflects genetic predispositions together with the environmental conditions of an individual. It is closely related to longevity and a number of pathological conditions. Even though the extent of telomere research in children is limited compared to that of adults, there have been a substantial number of studies providing first insights into child telomere biology and determinants. Recent discoveries revealed evidence that TL is, to a great extent, determined already in childhood and that environmental conditions in adulthood have less impact than first believed. Studies have demonstrated that large inter-individual differences in TL are present among newborns and are determined by diverse factors that influence intrauterine development. The first years of child growth are associated with high cellular turnover, which results in fast shortening of telomeres. The rate of telomere loss becomes stable in early adulthood. In this review article we summarise the existing knowledge on telomere dynamics during the first years of childhood, highlighting the conditions that affect newborn TL. We also warn about the knowledge gaps that should be filled to fully understand the regulation of telomeres, in order to implement them as biomarkers for use in diagnostics or treatment.
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http://dx.doi.org/10.1515/cclm-2019-0235DOI Listing
January 2020

Peripheral blood mononuclear cells extracts VEGF protein levels and VEGF mRNA: Associations with inflammatory molecules in a healthy population.

PLoS One 2019 16;14(8):e0220902. Epub 2019 Aug 16.

Université de Lorraine, Inserm, IGE-PCV, Nancy, France.

Background: Vascular endothelial growth factor (VEGF) is a signal protein, implicated in various physiological and pathophysiological processes together with other common inflammatory biomarkers. However, their associations have not yet been fully elucidated. In the present study, we investigated associations between VEGF and four specific VEGF mRNA isoforms with levels of 11 inflammation molecules, derived from peripheral blood mononuclear cells (PBMCs) extracts.

Methods: Healthy participants from the STANISLAS Family Study (n = 285) were included. Levels of VEGF (four mRNA isoforms and protein levels) and inflammatory molecules (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, INF-γ, TNF-α, MCP-1, EGF) were measured in PBMCs extracts. Multiple regression analyses were performed, adjusted for age and gender.

Results: The analyses revealed significant associations between VEGF protein levels and levels of IL-4 (β = 0.028, P = 0.013), MCP-1 (β = 0.015, P<0.0001) and EGF (β = 0.017, P<0.0001). Furthermore, mRNA isoform VEGF165 was associated with MCP-1 and IL-1α (P = 0.002 and P = 0.008, respectively); and mRNA isoform VEGF189 was associated with IL-4 and IL-6 (P = 0.019 and P = 0.034, respectively).

Conclusions: To our knowledge, the present study represents the first investigation that successfully demonstrates links between VEGF protein levels and inflammatory molecules levels derived from PBMCs extracts and identifies associations between specific VEGF mRNA isoforms and inflammatory molecules.

Impact: These findings provide novel insights that may assist in the development of new tissue and mRNA isoform specific measurements of VEGF levels, which may positively contribute to predicting the risk of common complex diseases and response of currently used anti-VEGF agents, and developing of novel targeted therapies for VEGF-related pathophysiology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220902PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697334PMC
March 2020

Epigenome-Wide Association Study (EWAS) of Blood Lipids in Healthy Population from STANISLAS Family Study (SFS).

Int J Mol Sci 2019 Feb 26;20(5). Epub 2019 Feb 26.

Université de Lorraine, Inserm, IGE-PCV, 54000 Nancy, France.

Epigenome-Wide Association Studies (EWAS) are furthering our knowledge of epigenetic modifications involved in the regulation of lipids' metabolism. Furthermore, epigenetic patterns associated with lipid levels may play an important role in predicting the occurrence of cardiovascular events. To further investigate the relationship between methylation status and lipids, we performed an EWAS in 211 individuals from the STANISLAS Family study (SFS). Methylation at two CpG sites (; = 1.39 × 10; ; = 5.75 × 10) were significantly associated with lipidomic profiles. Replication was sought in adipose tissue where one probe, cg08897188, was found to be nominally significant (; = 0.0196). These results could provide new insight in the mechanisms underlying cardiovascular diseases and contribute to new therapeutic interventions.
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http://dx.doi.org/10.3390/ijms20051014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429274PMC
February 2019

Association of TLR4 Polymorphisms, Expression, and Vitamin D with Helicobacter pylori Infection.

J Pers Med 2019 01 11;9(1). Epub 2019 Jan 11.

Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Beirut 1107 2809, Lebanon.

Helicobacter pylori () infection is the strongest recognized risk factor for gastric adenocarcinoma. Since previous observations have shown that polymorphisms in innate immune system genes, as well as vitamin D (VitD) levels, could modify the risk of infection with (), we analyzed the relation between single nucleotide polymorphisms (SNPs) in (, , ) , and VitD levels with infection. A case-control study on four hundred sixty Lebanese individuals was conducted. Eleven SNPs in total were genotyped and gene expression analysis using real-time PCR was performed in white blood cells of a subsample of eight individuals. A total of 49% of the participants were affected. Although no direct association was found between the SNPs and infection, rs4986790G>A and rs4986791T>C in were negatively associated with VitD levels (β = -0.371, = 5 × 10 and β = -0.4, = 2 × 10, respectively), which was negatively associated with infection (OR = 0.01, < 1 × 10). expression was 3× lower in individuals with compared with non-infected ( = 0.01). polymorphisms, expression, and VitD could be implicated in infection and further development of gastric adenocarcinoma.
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http://dx.doi.org/10.3390/jpm9010002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463146PMC
January 2019

The 9th Santorini Conference: Systems Medicine, Personalised Health and Therapy. "The Odyssey from Hope to Practice", Santorini, Greece, 30 September⁻3 October 2018.

J Pers Med 2018 12 12;8(4). Epub 2018 Dec 12.

PRAHealthSciences, Salt Lake City, UT 84124, USA.

The 9th traditional biannual conference on Systems Medicine, Personalised Health & Therapy-"The Odyssey from Hope to Practice", inspired by the Greek mythology, was a call to search for practical solutions in cardio-metabolic diseases and cancer, to resolve and overcome the obstacles in modern medicine by creating more interactions among disciplines, as well as between academic and industrial research, directed towards an effective 'roadmap' for personalised health and therapy. The 9th Santorini Conference, under the Presidency of Sofia Siest, the director of the INSERM U1122; IGE-PCV (www.u1122.inserm.fr), University of Lorraine, France, offered a rich and innovative scientific program. It gathered 34 worldwide distinguished speakers, who shared their passion for personalised medicine with 160 attendees in nine specific sessions on the following topics: First day: The Odyssey from hope to practice: Personalised medicine-landmarks and challenges Second day: Diseases to therapeutics-genotype to phenotype an "-OMICS" approach: focus on personalised therapy and precision medicine Third day: Gene-environment interactions and pharmacovigilance: a pharmacogenetics approach for deciphering disease "bench to clinic to reality" Fourth day: Pharmacogenomics to drug discovery: a big data approach and focus on clinical data and clinical practice. In this article we present the topics shared among the participants of the conference and we highlight the key messages.
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http://dx.doi.org/10.3390/jpm8040043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313418PMC
December 2018

Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.

Am J Hum Genet 2018 11;103(5):691-706

Department of Epidemiology and Prevention, Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
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http://dx.doi.org/10.1016/j.ajhg.2018.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218410PMC
November 2018

Personalised Medicine: The Odyssey from Hope to Practice.

J Pers Med 2018 Sep 21;8(4). Epub 2018 Sep 21.

Inserm, IGE-PCV, Université de Lorraine, 54000 Nancy, France.

In this endeavour, inspired by the Odyssey, we aim to embark with the reader on a journey on a ship from Troy to Ithaca, coursing through the history of the momentous events and achievements that paved the way for personalised medicine. We will set sail amidst important genetic discoveries, beginning with the discovery of the first human genome, and voyage through the projects that contributed to the progress of pharmacogenomic studies. Concurrently, we will propose methods to overcome the obstacles that are slowing the potential full implementation of accumulated knowledge into everyday practice. This journey aims to reflect on the frontiers of current genetic knowledge and the practical use of this knowledge in preventive, diagnostic and pharmacogenomic approaches to directly impact the socio-economic aspects of public health.
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http://dx.doi.org/10.3390/jpm8040031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313378PMC
September 2018

The Relationship Between Vascular Endothelial Growth Factor Cis- and Trans-Acting Genetic Variants and Metabolic Syndrome.

Am J Med Sci 2018 06 8;355(6):559-565. Epub 2018 Mar 8.

Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Biochemistry of Nutrition Research Center, School of Medicine. Electronic address:

Background: We have investigated the association between 4 cis- and trans-genetic variants (rs6921438, rs4416670, rs6993770 and rs10738760) of the vascular endothelial growth factor (VEGF) gene and metabolic syndrome (MetS) and its individual components in an Iranian population.

Material & Method: Three hundred and thirty-six subjects were enrolled and MetS was defined according to the International-Diabetes-Federation (IDF) criteria. Genotyping was carried out in all the individuals for 4 VEGF genetic variants using an assay based on a combination of multiplex polymerase chain reaction and biochip array hybridization.

Results: As may be expected, patients with MetS had significantly higher levels of serum high-sensitivity C-reactive protein, waist circumference, hip circumference, body mass index, fat percentage, systolic blood pressure, diastolic blood pressure and triglyceride, whereas the high-density lipoprotein cholesterol levels were significantly lower, compared to the control group (P < 0.05). We also found that 1 of the VEGF- level associated genetic variants, rs6993770, was associated with the presence of MetS; the less common T allele at this locus was associated with an increased risk for MetS. This association remained significant after adjustment for confounding factors (P = 0.007). Individuals with MetS carrying the AT + TT genotypes had markedly higher levels of fasting blood glucose, triglyceride and systolic blood pressure (P < 0.05).

Conclusions: We have found an association between the rs6993770 polymorphism and MetS. This gene variant was also associated with serum VEGF concentrations. There was also an association between this variant and the individual components of the MetS, including triglyceride, fasting blood glucose and systolic blood pressure.
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http://dx.doi.org/10.1016/j.amjms.2018.03.009DOI Listing
June 2018

Epistatic interaction of apolipoprotein E and lipolysis-stimulated lipoprotein receptor genetic variants is associated with Alzheimer's disease.

Neurobiol Aging 2018 09 3;69:292.e1-292.e5. Epub 2018 May 3.

UMR INSERM U1122; Université de Lorraine, Inserm, IGE-PCV, Nancy, France; Department of Internal Medicine and Geriatrics, CHU Nancy-Brabois, Nancy, France. Electronic address:

The ε4 allele of the apolipoprotein E (APOE) gene common polymorphism is the strongest genetic risk factor for Alzheimer's disease (AD). Human APOE gene is located on chromosome 19q13.1, a region linked to AD that also includes the LSR gene, which encodes the lipolysis-stimulated lipoprotein receptor (LSR). As an APOE receptor, LSR is involved in the regulation of lipid homeostasis in both periphery and brain. This study aimed to determine the potential interactions between 2 LSR genetic variants, rs34259399 and rs916147, and the APOE common polymorphism in 142 AD subjects (mean age: 73.16 ± 8.50 years) and 63 controls (mean age: 70.41 ± 8.49 years). A significant epistatic interaction was observed between APOE and both LSR variants, rs34259399 (beta = -0.95; p = 2 × 10) and rs916147 (beta = -0.83; p = 6.8 × 10). Interestingly, the interaction of LSR polymorphisms with APOE non-ε4 alleles increased AD risk. This indicates the existence of complex molecular interactions between these 2 neighboring genes involved in the pathogenesis of AD, which merits further investigation.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.04.013DOI Listing
September 2018

The polymorphism rs6918289 located in the downstream region of the TREM2 gene is associated with TNF-α levels and IMT-F.

Sci Rep 2018 05 8;8(1):7160. Epub 2018 May 8.

Université de Lorraine, Inserm, IGE-PCV, F-54000, Nancy, France.

Triggering receptor expressed on myeloid cells 2 (TREM2) is known for its anti-inflammatory properties during the immune response, and influences negatively on TNF-α expression levels. Genetic epidemiology studies have identified polymorphisms located in the TREM2 gene associated with neurodegenerative and chronic inflammatory diseases. TREM2 levels have been observed to affect plasma levels of TNF-α and plaque stability in symptomatic and asymptomatic patients with carotid stenosis. In this study, we investigated polymorphisms located in the TREM2 gene region and association with TNF-α levels and the intima media thickness of the femoral artery. The discovery population from the STANISLAS Family Study comprised of 809 individuals, whereas the replication population utilized an independent cohort of French origin (n = 916). Our results suggest that the minor allele (T) of SNP rs6918289 is positively associated with elevated plasma levels of TNF-α in discovery and replication populations (P = 0.0026, SE = 0.04 and P = 0.023, SE = 0.09, respectively), including femoral artery thickness in the discovery cohort (P = 0.026, SE = 0.009). Results indicate that rs6918289 may be considered as a risk factor for inflammatory diseases and could be used in stratified medicine with patients diagnosed with chronic inflammatory-related conditions, such as atherosclerosis.
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http://dx.doi.org/10.1038/s41598-018-25553-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940861PMC
May 2018

The future of telomere length in personalized medicine.

Front Biosci (Landmark Ed) 2018 03 1;23:1628-1654. Epub 2018 Mar 1.

INSERM UMR U1122, IGE-PCV, Gene-Environment Interactions in Cardio-Vascular Physiopathology, Faculty of Pharmacy - University of Lorraine, Nancy, 54000, France,

Telomere length has been subject of studies for many decades, aiming to elucidate its role in physiological processes, in process of aging and in diverse pathologies. Yet today, there is still no "big title" discovery that would lead to a practical use of telomeres as a reliable biomarker or target for a new drug. However, therapies for chronic disease patients are being tested and companies are already offering commercial tests for telomere length measurement. The strong genetic heritability of telomeres is opening the place for pharmacogenomics researches that could promote the personalized treatment of diverse diseases. In this article, we present the recent knowledge of telomeres genetic determination obtained by genome-wide association studies (GWAS), important biomarkers related to telomere length and review the possibilities of telomere's practical implementation in the medical treatment of diverse diseases and as a potential biomarker in personalized medicine. Furthermore, we summarise commercial offers of telomere length measurements available and we discuss the actions that should be taken to make steps forward into final application of the accumulated knowledge into practical use.
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http://dx.doi.org/10.2741/4664DOI Listing
March 2018

Pharmacogenomic Challenges in Cardiovascular Diseases: Examples of Drugs and Considerations for Future Integration in Clinical Practice.

Curr Pharm Biotechnol 2017 ;18(3):231-241

UMR INSERM U1122 - Interactions Gene-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Universite de Lorraine, Rue Lionnois, 54000 Nancy. France.

Introduction: Even if cardiovascular disease (CVD) drugs are supported by high level proofs, the results of CVD treatment present great disparities: there are still patients dying with supposed optimal treatment, patients facing adverse events and CVD remains the primary cause of death in the world. Pharmacogenomics is the basis of personalisation of the treatment able to allow higher medication success rates. In this review, we will present detailed examples of CVD drugs to highlight the complexity of this challenging field and we will discuss novel concepts that should be considered for a fastest integration of pharmacogenomics in clinical practice of CVD. Areas Covered: The complexity of pharmacogenetics and pharmacogenomics of CVD drugs are presented though examples of medications such as statins, with a focus on their effectiveness and adverse effects. Expert Opinion: The application of personalised medicine in the CVD medical practice requires the study of human genome with regard to drugs pharmacokinetics, pharmacodynamics, interactions and tolerance profile. The existing state -of-the-art of CVD drugs gives hopes for a future revolution in the drug development that will maximise cardiovascular patients benefit while decreasing their risks for adverse effects. Article Highlights Box: • Coronary heart disease (CHD) remains the first cause of death worldwide. • Cardiovascular treatment has a significant percentage of insufficient efficacy, poor tolerance and compliance. • Predicting the response to therapy while diminishing the side effects is the basis of personalised medicine; pharmacogenomics is leading towards this direction. • The response to CVD therapy and side effects are in the heart of CVD pharmacogenomics and significant progress has been noted. • The application of pharmacogenomics in the CVD medical practice is facing many methodological, technical, ethical, behavioral and financial issues, while cost-effectiveness is the main prerequisite. • The consideration of gene × gene × environment interactions and the inclusion of "omics" data in pharmacogenomic studies of CVD drugs will facilitate the generation of reliable results and will promote tailored treatments and new strategies of drug research and development.
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http://dx.doi.org/10.2174/1389201018666170123153626DOI Listing
December 2017

VEGF, the underlying factor for metabolic syndrome; fact or fiction?

Diabetes Metab Syndr 2017 Nov 9;11 Suppl 1:S61-S64. Epub 2016 Dec 9.

UMR INSERM U 1122, IGE-PCV "Interactions Gène-Environnement en Physiopathologie CardioVasculaire ", Université de Lorraine, Nancy, France.

Metabolic syndrome (MetS) is currently diagnosed by the co-presence of at least three of the five following abnormalities: abdominal obesity, dysglycaemia, elevated serum triglycerides, low high-density cholesterol (HDL) and finally elevated blood pressure. Metabolic syndrome increases the risk of developing cardiovascular disease and diabetes. This review is on the associations between MetS and vascular endothelial growth factor (VEGF). VEGF induces migration and proliferation of endothelial cells (ECs), increases vascular permeability and has a role in tumor growth, adipose tissue expansion, age-related macular degeneration and diabetic retinopathy. Circulating levels of VEGFs are elevated in obese individuals and it has also been suggested that VEGF is secreted from adipose tissues, especially from intra-abdominal adipose tissue. There is abundant evidence to support that poor glycemic control in diabetic patients is associated with increased plasma VEGF, which in turn may cause hypertension and several vascular complications in diabetic patients. Circulating VEGF levels are increased in children and young adults with type 1 diabetes mellitus and middle-aged diabetic patients with proliferative retinopathy. It has been revealed that plasma VEGF increases in patients with hyperlipidemia and may trigger the development of atherosclerosis. It can be concluded that there is a positive association between VEGF and components of MetS. Because of the importance of this relationship, more investigations are needed in this field.
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http://dx.doi.org/10.1016/j.dsx.2016.12.004DOI Listing
November 2017

Pro- and anti-angiogenic VEGF mRNAs in autoimmune thyroid diseases.

Autoimmunity 2016 09 5;49(6):366-372. Epub 2016 Aug 5.

a UMR INSERM U1122, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Université de Lorraine , Nancy , France.

The aim of this study was to assess the relationships between five different splice isoforms of VEGF mRNA and its plasma levels in individuals treated for autoimmune thyroid diseases (AITD); mainly Graves' disease (GD) and Hashimoto's thyroiditis (HT). In a population from Tunisia, levels of thyroid hormones and antibodies were quantified simultaneously with plasma VEGF and VEGF mRNA isoforms after a period of 6 months of patients' treatment. Plasma VEGF was measured in 110 AITD patients (21 GD and 89 HT patients). VEGF isoforms (VEGF121, VEGF165, VEGF145 and VEGF189 pro-angiogenic isoforms and VEGF165b anti-angiogenic isoform) in peripheral blood mononuclear cells were quantified in 71 patients (20 GD and 51 HT patients) and 86 healthy controls. Decreased levels of VEGF189 mRNA were observed in AITD compared to controls. VEGF165 was increased in GD patients compared to controls and the VEGF165b was increased in HT patients compared to GD. We observed increased levels of VEGF165b in hypothyroid AITD patients after treatment. We have also shown that the VEGF145 isoform levels were determined by FT4 in all patients and by the thyroid status after 6 months of treatment only in HT patients. An association was observed for VEGF165 mRNA levels with anti-TPO antibodies in all patients. Finally, FT4 was associated with VEGF plasma levels but only in healthy controls. In conclusion, this descriptive study highlights the specificity of VEGF mRNA isoforms in AITD, a fact underlining the need for novel clinical trials and the development of personalised theranostic approaches.
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http://dx.doi.org/10.1080/08916934.2016.1199019DOI Listing
September 2016

Plasma VEGF-related polymorphisms are implied in autoimmune thyroid diseases.

Autoimmunity 2016 06 8;49(4):229-35. Epub 2016 Mar 8.

a UMR INSERM U1122; Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Université de Lorraine , Nancy , France .

Autoimmune thyroid diseases (AITD), including Graves' disease (GD) and Hashimoto thyroiditis (HT), are complex multifactorial diseases. Vascular endothelial growth factor (VEGF) is implicated in various inflammatory diseases, especially autoimmune diseases. Our aim was to elucidate the relationships between plasma VEGF levels and four genome-wide association study-identified single nucleotide polymorphisms (SNPs) related to VEGF with AITD in Tunisian patients. A total of 364 healthy controls and 389 patients with AITD were genotyped for the SNPs rs6921438, rs4416670, rs6993770 and rs10738760. Levels of thyroid hormones and antibodies were quantified simultaneously with plasma VEGF after a period of six months of treatment. We found that the minor alleles of rs10738760 and rs6921438 are associated with the presence of GD. A allele of rs10738760 polymorphism is associated with increased plasma levels of free tri-iodothyronin (FT3) while no relationship was found with circulating VEGF plasma levels after six months of treatment. We also showed that the T allele of rs4416670 polymorphism was associated with increased risk of hyperthyroidism in patients treated for six months, independently of their initial diagnosis. There was no significant association between the SNPs and the risk for HT compared with controls. This study shows that AITD are influenced by 3 SNPs linked to VEGF circulating levels. Whereas rs10738760 appeared specific to GD and FT3 production after six months of treatment, rs6921438 and rs4416670 were implicated in the risk for GD. This study opens new ways to test pharmacogenomics concepts in the future especially in GD in which recurrence prognosis is still challenging.
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http://dx.doi.org/10.3109/08916934.2016.1151005DOI Listing
June 2016
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