The intentions of French health university students to recommend and to receive the HPV vaccine are mainly influenced by vaccine knowledge, confidence in vaccines and personal HPV vaccination.

INTRODUCTION: Despite documented effectiveness in preventing several cancers, genital warts and safety of Human Papillomavirus (HPV) vaccine, immunization coverage among French adolescents remains far from the 80 % target. University health students (HS) in France may promote HPV vaccine through a national service (Service Sanitaire des Etudiants en Santé). We aimed to evaluate intentions to recommend the HPV vaccine to friends and relatives, to receive HPV vaccine, and to identify factors associated with these attitudes. METHODS: We conducted a cross-sectional survey in five French Universities from October 2019 to February 2020, using a self-administered online questionnaire. We used bivariable and multivariable logistic regression models to identify determinants of behavior around HPV vaccine: (i) individual intention for vaccination, and (ii) vaccine recommendation to friends and relatives. RESULTS: Among the 732 respondents (180 men, 552 women), 305 (41.7%) reported previous HPV vaccination (54.5 % among women), 504 (68.9%) would recommend the HPV vaccine to friends and relatives, 532 (72.7%) respondents would be vaccinated today if it was recommended for them. Intentions to recommend or to receive the HPV vaccine were less frequent in nursing students compared to medical and pharmacy students. After adjustment for demographical factors, HPV vaccine knowledge was associated with intention [aOR 1.30 (95%-confidence interval, 1.15-1.47)] and recommendation [1.26 (1.10-1.45)], respectively. Additionally, adjusting for knowledge about HPV infections, and confidence in vaccines in general was associated with vaccine intention [1.55, (1.30-1.84)] and recommendation [1.52 (1.24-1.86)]. HPV-vaccinated HS were more prone to recommend the HPV vaccine to friends and relatives [10.9 (6.6-17.9)]. CONCLUSION: A majority of HS would accept and/or recommend HPV vaccines. HS with greater knowledge about the HPV vaccine were more prone to recommend it. Strengthening knowledge about HPV and its vaccination is probably necessary before their Involvement in a HPV immunization program.

Deep Dive Into MicroRNAs in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is thought to develop in genetically predisposed individuals as a consequence of complex interactions between dysregulated inflammatory stimuli, immunological responses, and environmental factors. The pathogenesis of IBD has yet to be fully understood. The global increase in the incidence of IBD suggests a gap in the current understanding of the disease. The development of a new diagnostic tool for inflammatory bowel disease that is both less invasive and more cost-effective would allow for better management of this condition. MicroRNAs (miRNAs) are a class of noncoding RNAs with important roles as posttranscriptional regulators of gene expression, which has led to new insights into understanding IBD. Using techniques such as microarrays and real-time polymerase chain reactions, researchers have investigated the patterns in which patients with Crohn's disease and ulcerative colitis show alterations in the expression of miRNA in tissue, blood, and feces. These miRNAs are found to be differentially expressed in IBD and implicated in its pathogenesis through alterations in autophagy, intestinal barrier, and immune homeostasis. In this review, we discuss the miRNA expression profiles associated with IBD in tissue, peripheral blood, and feces and provide an overview of the miRNA mechanisms involved in IBD.

We review the published studies on microRNA (miRNA) expression in inflammatory bowel disease, including miRNAs extracted from blood, tissue, and stool samples. We discuss the main mechanisms of miRNA involvement in inflammatory bowel disease and their potential use as biomarkers.

Impact of the Exposome on the Epigenome in Inflammatory Bowel Disease Patients and Animal Models.

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract that encompass two main phenotypes, namely Crohn's disease and ulcerative colitis. These conditions occur in genetically predisposed individuals in response to environmental factors. Epigenetics, acting by DNA methylation, post-translational histones modifications or by non-coding RNAs, could explain how the exposome (or all environmental influences over the life course, from conception to death) could influence the gene expression to contribute to intestinal inflammation. We performed a scoping search using Medline to identify all the elements of the exposome that may play a role in intestinal inflammation through epigenetic modifications, as well as the underlying mechanisms. The environmental factors epigenetically influencing the occurrence of intestinal inflammation are the maternal lifestyle (mainly diet, the occurrence of infection during pregnancy and smoking); breastfeeding; microbiota; diet (including a low-fiber diet, high-fat diet and deficiency in micronutrients); smoking habits, vitamin D and drugs (e.g., IBD treatments, antibiotics and probiotics). Influenced by both microbiota and diet, short-chain fatty acids are gut microbiota-derived metabolites resulting from the anaerobic fermentation of non-digestible dietary fibers, playing an epigenetically mediated role in the integrity of the epithelial barrier and in the defense against invading microorganisms. Although the impact of some environmental factors has been identified, the exposome-induced epimutations in IBD remain a largely underexplored field. How these environmental exposures induce epigenetic modifications (in terms of duration, frequency and the timing at which they occur) and how other environmental factors associated with IBD modulate epigenetics deserve to be further investigated.

Long-Term Overconsumption of Fat and Sugar Causes a Partially Reversible Pre-inflammatory Bowel Disease State.

Nutrition appears to be an important environmental factor involved in the onset of inflammatory bowel diseases (IBD) through yet poorly understood biological mechanisms. Most studies focused on fat content in high caloric diets, while refined sugars represent up to 40% of caloric intake within industrialized countries and contribute to the growing epidemics of inflammatory diseases. Herein we aim to better understand the impact of a high-fat-high-sucrose diet on intestinal homeostasis in healthy conditions and the subsequent colitis risk. We investigated the early events and the potential reversibility of high caloric diet-induced damage in mice before experimental colitis. C57BL/6 mice were fed with a high-fat or high-fat high-sucrose or control diet before experimental colitis. In healthy mice, a high-fat high-sucrose diet induces a pre-IBD state characterized by gut microbiota dysbiosis with a total depletion of bacteria belonging to Barnesiella that is associated with subclinical endoscopic lesions. An overall down-regulation of the colonic transcriptome converged with broadly decreased immune cell populations in the mesenteric lymph nodes leading to the inability to respond to tissue injury. Such in-vivo effects on microbiome and transcriptome were partially restored when returning to normal chow. Long-term consumption of diet enriched in sucrose and fat predisposes mice to colitis. This enhanced risk is preceded by gut microbiota dysbiosis and transcriptional reprogramming of colonic genes related to IBD. Importantly, diet-induced transcriptome and microbiome disturbances are partially reversible after switching back to normal chow with persistent sequelae that may contribute to IBD predisposition in the general population.

NOD2/CARD15 polymorphisms (P268S, IVS8+158, G908R, L1007fs, R702W) among Kuwaiti patients with Crohn's disease: A case-control study.

Background: Nucleotide-binding oligomerization domain-containing two (NOD2/CARD15) gene polymorphisms are implicated in the pathogenesis of Crohn's disease (CD). Aim: To describe the allelic frequency of NOD2/CARD15 gene variants among Kuwaiti patients with CD and investigate potential genotype/phenotype associations. Methods: Adult Kuwaiti citizens with an established diagnosis of CD and healthy controls were enrolled from October 2018 to May 2020. Three common NOD2/CARD15 polymorphisms (R702W, G908R, and L1007fs) and P268S and IVS8+158 polymorphisms were screened by polymerase chain reaction/restriction analysis length polymorphism (PCR/RFLP). Results: Ninety adult Kuwaiti patients with CD and 210 healthy subjects (as controls) were recruited. P268S, IVS8+158, G908R, and R702W minor alleles were identified in 38.9%, 21.1%, 12.2%, and 4.4% of CD patients, respectively. NOD2/CARD15 polymorphisms coexisted in 35 healthy controls (16.7%) and 21 CD patients (23.3%). Individuals with either a single or multiple polymorphism were approximately two times more likely to have CD than those with no polymorphism. Patients with multiple polymorphisms had significantly more stricturing and penetrating disease. Conclusion: NOD2/CARD15 gene polymorphisms were significantly associated with an increased risk of disease and aggressive phenotypes among the Kuwaiti CD population.

Telomeres: New players in immune-mediated inflammatory diseases?

Telomeres are repetitive DNA sequences located at the ends of linear chromosomes that preserve the integrity and stability of the genome. Telomere dysfunctions due to short telomeres or altered telomere structures can ultimately lead to replicative cellular senescence and chromosomal instability, both mechanisms being hallmarks of ageing. Chronic inflammation, oxidative stress and finally telomere length (TL) dynamics have been shown to be involved in various age-related non-communicable diseases (NCDs). Immune-mediated inflammatory diseases (IMIDs), including affections such as inflammatory bowel disease, psoriasis, rheumatoid arthritis, spondyloarthritis and uveitis belong to this group of age-related NCDs. Although in recent years, we have witnessed the emergence of studies in the literature linking these IMIDs to TL dynamics, the causality between these diseases and telomere attrition is still unclear and controversial. In this review, we provide an overview of available studies on telomere dynamics and discuss the utility of TL measurements in immune-mediated inflammatory diseases.

Investigating ADR mechanisms with Explainable AI: a feasibility study with knowledge graph mining.

BACKGROUND: Adverse drug reactions (ADRs) are statistically characterized within randomized clinical trials and postmarketing pharmacovigilance, but their molecular mechanism remains unknown in most cases. This is true even for hepatic or skin toxicities, which are classically monitored during drug design. Aside from clinical trials, many elements of knowledge about drug ingredients are available in open-access knowledge graphs, such as their properties, interactions, or involvements in pathways. In addition, drug classifications that label drugs as either causative or not for several ADRs, have been established. METHODS: We propose in this paper to mine knowledge graphs for identifying biomolecular features that may enable automatically reproducing expert classifications that distinguish drugs causative or not for a given type of ADR. In an Explainable AI perspective, we explore simple classification techniques such as Decision Trees and Classification Rules because they provide human-readable models, which explain the classification itself, but may also provide elements of explanation for molecular mechanisms behind ADRs. In summary, (1) we mine a knowledge graph for features; (2) we train classifiers at distinguishing, on the basis of extracted features, drugs associated or not with two commonly monitored ADRs: drug-induced liver injuries (DILI) and severe cutaneous adverse reactions (SCAR); (3) we isolate features that are both efficient in reproducing expert classifications and interpretable by experts (i.e., Gene Ontology terms, drug targets, or pathway names); and (4) we manually evaluate in a mini-study how they may be explanatory. RESULTS: Extracted features reproduce with a good fidelity classifications of drugs causative or not for DILI and SCAR (Accuracy = 0.74 and 0.81, respectively). Experts fully agreed that 73% and 38% of the most discriminative features are possibly explanatory for DILI and SCAR, respectively; and partially agreed (2/3) for 90% and 77% of them. CONCLUSION: Knowledge graphs provide sufficiently diverse features to enable simple and explainable models to distinguish between drugs that are causative or not for ADRs. In addition to explaining classifications, most discriminative features appear to be good candidates for investigating ADR mechanisms further.

Calorie Restriction as a New Treatment of Inflammatory Diseases.

Immoderate calorie intake coupled with a sedentary lifestyle are major determinants of health issues and inflammatory diseases in modern society. The balance between energy consumption and energy expenditure is critical for longevity. Excessive energy intake and adiposity cause systemic inflammation, whereas calorie restriction (CR) without malnutrition, exerts a potent anti-inflammatory effect. The objective of this review was to provide an overview of different strategies used to reduce calorie intake, discuss physiological mechanisms by which CR might lead to improved health outcomes, and summarize the present knowledge about inflammatory diseases. We discuss emerging data of observational studies and randomized clinical trials on CR that have been shown to reduce inflammation and improve human health.

Characteristics of Lymphoma in Patients with Inflammatory Bowel Disease: A Systematic Review.

BACKGROUND: Lymphoma is a dreaded complication of inflammatory bowel diseases [IBD]. Knowledge about lymphoma in patients with IBD is limited to epidemiological data and the description of risk factors. We performed a systematic review to describe the clinical characteristics and prognosis of lymphoma in patients with IBD. METHODS: Electronic databases were searched up to June 1, 2020. All published clinical characteristics of lymphoma occurring in patients with IBD were collected. RESULTS: Eleven studies were included. A total of 589 lymphomas were described in patients with IBD. As seen in de novo lymphoma, non-Hodgkin's lymphoma [NHL] was the most common histological subtype [83.9%]. Diffuse large B-cell lymphoma [DLBCL] and follicular lymphoma were the most well-represented NHL in patients with IBD [30% and 13% respectively]. Two main differences were observed in comparison with de novo lymphoma: primary intestinal lymphoma [PIL] represented a large proportion of lymphoma in patients with IBD [22-75%] whereas mucosa-associated lymphoid tissue [MALT] lymphoma was under-represented. Epstein-Barr virus [EBV]-positive status was observed in a large proportion of tumours [44-75%]. Survival data of lymphoma in patients with IBD were similar to those of de novo lymphoma. DISCUSSION: This systematic review first highlights that PIL [especially DLBCL subtype] is significantly more frequent in patients with IBD and represents the most common entity. Conversely, MALT lymphoma is extremely rare in the IBD population. However, the overall quality of the evidence is low. Further studies are required to better define lymphoma characteristics in patients with IBD.

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

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 ß 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 (ß = -0.012 ± 0.004, p = 0.006) but positively associated in obese children (ß = 2.178 ± 0.71, p = 0.002). A significant interaction between rs7556897T > C and the obesity status (obese or normal weight) was detected (ß = 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 (ß = 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.

Genomic and molecular alterations in human inflammatory bowel disease-associated colorectal cancer.

Patients with inflammatory bowel disease are at increased risk of colorectal cancer, which has worse prognosis than sporadic colorectal cancer. Until recently, understanding of pathogenesis in inflammatory bowel disease-associated colorectal cancer was restricted to the demonstration of chromosomic/microsatellite instabilities and aneuploidy. The advance of high-throughput sequencing technologies has highlighted the complexity of the pathobiology and revealed recurrently mutated genes involved in the RTK/RAS, PI3K, WNT, and TGFß pathways, leading to potentially new targetable mutations. Moreover, alterations of mitochondrial DNA and the dysregulation of non-coding sequences have also been described, as well as several epigenetic modifications. Although recent studies have brought new insights into pathobiology and raised the prospect of innovative therapeutic approaches, the understanding of colorectal carcinogenesis in inflammatory bowel disease and how it differs from sporadic colorectal cancer remains not fully elucidated. Further studies are required to better understand the pathogenesis and molecular alterations leading to human inflammatory bowel disease-associated colorectal cancer.

PGxCorpus, a manually annotated corpus for pharmacogenomics.

Pharmacogenomics (PGx) studies how individual gene variations impact drug response phenotypes, which makes PGx-related knowledge a key component towards precision medicine. A significant part of the state-of-the-art knowledge in PGx is accumulated in scientific publications, where it is hardly reusable by humans or software. Natural language processing techniques have been developed to guide experts who curate this amount of knowledge. But existing works are limited by the absence of a high quality annotated corpus focusing on PGx domain. In particular, this absence restricts the use of supervised machine learning. This article introduces PGxCorpus, a manually annotated corpus, designed to fill this gap and to enable the automatic extraction of PGx relationships from text. It comprises 945 sentences from 911 PubMed abstracts, annotated with PGx entities of interest (mainly gene variations, genes, drugs and phenotypes), and relationships between those. In this article, we present the corpus itself, its construction and a baseline experiment that illustrates how it may be leveraged to synthesize and summarize PGx knowledge.

Genetic determinants of circulating haptoglobin concentration.

Haptoglobin (Hp) is a major plasma acute-phase glycoprotein, which binds free haemoglobin to neutralize its toxicity. The HP gene exists as two copy number variants (CNV), Hp1 and HP2, which differ in two ways: serum Hp level and functional differences in Hp protein products. Both mechanisms may underlie the HP CNV's influence on susceptibility and/or outcome in several diseases. A single nucleotide polymorphism rs2000999 has also been associated with serum Hp level. In a meta-analysis of three studies from England, France and Japan, with a combined sample size of 1210 participants, we show that rs2000999's effect on circulating Hp level is independent from that of the HP CNV. The combined use of rs2000999 and the HP CNV can be an important genetic epidemiological tool to discriminate between the two potential mechanisms underlying differences between HP1 and HP2 alleles.

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

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.

Pleiotropy of ABO gene: correlation of rs644234 with E-selectin and lipid levels.

BACKGROUND: The ABO gene has been widely studied and associated with many different diseases such as myocardial infarction and diabetes. Pleiotropic effects of the ABO locus have been demonstrated. Indeed it affects different phenotypes such as E- and P-selectins, triglycerides and total cholesterol. The goal of this work was to study the SNP rs644234 located in the ABO gene with different phenotypes related with diseases where the ABO gene has been involved. METHODS: We analyzed the SNP rs644234 located in the ABO gene, by performing association studies with different lipid phenotypes as well as with the soluble E-selectin levels in 348 adults from the STANISLAS Family Study. RESULTS: The major rs644234*T allele was associated with increased levels of soluble E-selectin (p=8.7×10-12). According to the lipid phenotypes, the major rs644234*T allele was associated with decreased levels of apolipoproteins E (ApoE) (p=0.001) and low-density lipoprotein cholesterol (LDL-C) (p=0.032) but was associated with increased levels of high-density lipoprotein cholesterol (HDL-C) (p=0.013). The association of the HDL-C was especially significant in the male individuals (p=0.001). CONCLUSIONS: We confirmed that ABO is a major locus for serum soluble E-selectin levels variability, and we also correlated this gene with different lipid phenotypes. Furthermore, we demonstrated that this pleiotropic effect is independent. This is the first time that a correlation has been made between the ABO gene and the ApoE levels. According to these results, the major allele of this polymorphism may have a protective effect when it comes to cardiovascular related diseases, and more specifically when it comes to the lipid phenotypes.

TREM-1 Inhibition Restores Impaired Autophagy Activity and Reduces Colitis in Mice.

BACKGROUND AND AIMS: Triggering receptor expressed on myeloid cells-1 [TREM-1] is known to amplify inflammation in several diseases. Autophagy and endoplasmic reticulum [ER] stress, which activate the unfolded protein response [UPR], are closely linked and defects in these pathways contribute to the pathogenesis of inflammatory bowel disease [IBD]. Both autophagy and UPR are deeply involved in host-microbiota interactions for the clearance of intracellular pathogens, thus contributing to dysbiosis. We investigated whether inhibition of TREM-1 would prevent aberrant inflammation by modulating autophagy and ER stress and preventing dysbiosis. METHODS: An experimental mouse model of colitis was established by dextran sulphate sodium treatment. TREM-1 was inhibited, either pharmacologically by LR12 peptide or genetically with Trem-1 knock-out [KO] mice. Colon tissues and faecal pellets of control and colitic mice were used. Levels of macroautophagy, chaperone-mediated autophagy [CMA], and UPR proteins were evaluated by western blotting. The composition of the intestinal microbiota was assessed by MiSeq sequencing in both LR12-treated and KO animals. RESULTS: We confirmed that inhibition of TREM-1 attenuates the severity of colitis clinically, endoscopically and histologically. We observed an increase in macroautophagy [ATG1/ULK-1, ATG13, ATG5, ATG16L1, and MAP1LC3-I/II] and in CMA [HSPA8 and HSP90AA1], whereas there was a decrease in the UPR [PERK, IRE-1α, and ATF-6α] protein expression levels in TREM-1 inhibited colitic mice. TREM-1 inhibition prevented dysbiosis. CONCLUSIONS: TREM-1 may represent a novel drug target for the treatment of IBD, by modulating autophagy activity and ER stress.

Learning from biomedical linked data to suggest valid pharmacogenes.

BACKGROUND: A standard task in pharmacogenomics research is identifying genes that may be involved in drug response variability, i.e., pharmacogenes. Because genomic experiments tended to generate many false positives, computational approaches based on the use of background knowledge have been proposed. Until now, only molecular networks or the biomedical literature were used, whereas many other resources are available. METHOD: We propose here to consume a diverse and larger set of resources using linked data related either to genes, drugs or diseases. One of the advantages of linked data is that they are built on a standard framework that facilitates the joint use of various sources, and thus facilitates considering features of various origins. We propose a selection and linkage of data sources relevant to pharmacogenomics, including for example DisGeNET and Clinvar. We use machine learning to identify and prioritize pharmacogenes that are the most probably valid, considering the selected linked data. This identification relies on the classification of gene-drug pairs as either pharmacogenomically associated or not and was experimented with two machine learning methods -random forest and graph kernel-, which results are compared in this article. RESULTS: We assembled a set of linked data relative to pharmacogenomics, of 2,610,793 triples, coming from six distinct resources. Learning from these data, random forest enables identifying valid pharmacogenes with a F-measure of 0.73, on a 10 folds cross-validation, whereas graph kernel achieves a F-measure of 0.81. A list of top candidates proposed by both approaches is provided and their obtention is discussed.

Cardiovascular diseases-related GNB3 C825T polymorphism has a significant sex-specific effect on serum soluble E-selectin levels.

BACKGROUND: The C825T polymorphism (rs5443) of the Guanine Nucleotide-Binding protein subunit ß3 (GNB3) gene has been associated with obesity, essential hypertension, atherosclerosis, coronary diseases, and cerebrovascular events, but with some sex-specific effects. Its association with inflammatory mediators such as cell adhesion molecules has not been studied, although they are heavily involved in cardiovascular diseases' (CVDs) processes. The aim of our study was then to investigate a possible sex-specific effect of the GNB3 C825T polymorphism on serum soluble cell adhesion molecules such as E, P and L-selectins (sE, sP and sL-selectins). RESULTS: Participants were from the STANISLAS Family Study and were free of chronic disease as CVDs or cancer. We included in total 771 subjects aged 6 to 58 years (391 males (50.71%) and 380 females (49.29%)). No significant association of rs5443 was observed in the whole population with serum sE, sP and sL-selectins after adjusting for age, sex, body mass index, systolic blood pressure, anti-inflammatory drugs and hormonal drugs consumption. A significant interaction of rs5443 was observed with sex for sE-selectin (p < 0.001), but not for sP and sL-selectins. After adjusting for covariables, the T allele was significantly associated with an additive increase effect on serum sE-selectin levels in males (ß = 5.03 ± 2.18; p = 0.020), while a significant additive decrease effect was observed in females (ß =-4.46 ± 2.06; p = 0.030). These associations stayed significant after correction for multiple tests (p = 0.045 in males and in females). The additive phenotypic variance was 21.54% in males versus 1.91% in females. CONCLUSIONS: In our Caucasian population, the GNB3 C825T polymorphism showed a significant sex-specific effect on serum sE-selectin levels, with a disadvantage for males, as increased sE-selectin levels has been associated with CVDs outcomes. The T allele has been previously associated with the same CVDs as increased sE-selectin, but more often in males. The link we observed between this polymorphism and E-selectin is then consistent with previous findings, and helps to better understand the deleterious effect of the GNB3 825 T allele on CVDs outcomes in males. We revealed in this study an important pathway through which the GNB3 gene induces CVDs' outcomes.

Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies.

Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79 x 10(-13)), rs74506613 (JMJD1C, P = 1.17 x 10(-19)), rs4782371 (ZFPM1, P = 1.59 x 10(-9)) and rs2639990 (ZADH2, P = 1.72 x 10(-8)), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52 x 10(-18); rs7043199, VLDLR-AS1, P = 5.12 x 10(-14)) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39 x 10(-1467); rs1740073, C6orf223, P = 2.34 x 10(-17); rs6993770, ZFPM2, P = 2.44 x 10(-60); rs2375981, KCNV2, P = 1.48 x 10(-100)). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and functionality, suggesting the importance of this process in regulation of VEGF levels. This work also provided new insights into the involvement of genes implicated in various angiogenesis related pathologies in determining circulating VEGF levels. The understanding of the molecular mechanisms by which the identified genes affect circulating VEGF levels could be important in the development of novel VEGF-related therapies for such diseases.