A genetic determinant of VEGF-A levels is associated with telomere attrition.

Telomere length (TL) is a hallmark of cellular aging and is associated with chronic diseases development. The vascular endothelial growth factor A (VEGF-A), a potent angiogenesis factor, is implicated in the pathophysiology of many chronic diseases. The aim of the present study was to investigate the associations between VEGF-A and TL. TL in leukocytes (LTL) and skeletal muscle (MTL) were measured, 10 VEGF-related polymorphisms genotyped, and VEGF-A plasma concentrations determined in 402 individuals from the TELARTA cohort. LTL/MTL ratio was calculated as an estimate of lifelong TL attrition. Associations between VEGF-A variants and levels, and TL parameters were investigated. We identified one significant association between the minor allele (T) of rs6993770 variant and LTL/MTL ratio (P=0.001143, ß=0.0148, SE=0.004516). The rs6993770 is an intronic variant of the ZFPM2 gene, which is involved in haematopoiesis and the identified association with increased telomere attrition could be due to increased haematopoiesis. No significant epistatic interaction was identified, and no association was found between levels of VEGF-A and any of assessed phenotypes. We identified a potential common genetic regulation between VEGF-A and telomere length attrition that could be explained by mechanisms of increased hematopoiesis and production of platelets. VEGF-A and TL could play an important role in personalized medicine of chronic diseases and identification of molecular links between them can promote the understanding of their complex implications.

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

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 (ß = 2.32, SE = 0.41, Padj = 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 (Padj > 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.

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

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 (p = 0.027 and p = 0.025, respectively). These SNPs, both located on the TERC gene, were associated with the LTL/MTL ratio (p = 0.007 and p = 0.037, respectively), but not with MTL (p = 0.78 and p = 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.

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

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 × 10-7 to P = 5.64 × 10-15. 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.

Telomere length determinants in childhood.

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.

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

[This corrects the article DOI: 10.1371/journal.pone.0220902.].

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

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-1ß, 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 (ß = 0.028, P = 0.013), MCP-1 (ß = 0.015, P<0.0001) and EGF (ß = 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.

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

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 (PRKAG2; p = 1.39 × 10-8; KREMEN2; p = 5.75 × 10-9) were significantly associated with lipidomic profiles. Replication was sought in adipose tissue where one probe, cg08897188, was found to be nominally significant (KREMEN2; p = 0.0196). These results could provide new insight in the mechanisms underlying cardiovascular diseases and contribute to new therapeutic interventions.

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

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.

Personalised Medicine: The Odyssey from Hope to Practice.

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.

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

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.

The future of telomere length in personalized medicine.

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.