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.

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.

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.

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.

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.

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.

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.

Angiogenesis related genes NOS3, CD14, MMP3 and IL4R are associated to VEGF gene expression and circulating levels in healthy adults.

BACKGROUND: Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis. The aim was to assess the genetic connections between the angiogenesis-related NOS3, CD14, MMP3, IL4R, IL4 genes and VEGF expression and plasma levels. METHODS: The associations between VEGF plasma levels with the polymorphisms of NOS3, CD14, MMP3, IL4R, and IL4 were assessed in 403 healthy unrelated adults. The epistatic and environmental interactions were explored, including four VEGF-related polymorphisms previously identified. The VEGF expression in peripheral blood mononuclear cells was quantified (n = 65) for the VEGF121, VEGF145, VEGF165, and VEGF189 isoforms. RESULTS: The polymorphism rs1799983 of NOS3 was associated with the sum of all VEGF isoforms mRNA levels (P = 0.032) and VEGF145 (P = 0.033). Rs1800779 of NOS3 interacted with rs3918226 of the same gene and with the rs2569190 of CD14 (P = 0.022, P = 0.042, respectively) for VEGF plasma levels. Other epistatic interactions included the rs1801275 of IL4R with the rs6921438 (VEGF-related variant) and rs3025058 of MMP3 (P = 0.042, P = 0.010 respectively) and the rs2569190 of CD14 with the rs3025058 of MMP3 (P = 0.0119). We also identified an interaction of rs1800779 with obesity, high-density lipoprotein cholesterol and triglycerides (P = 0.018, P = 0.005, P = 0.043, respectively) as well as the interaction of rs6921438 with hypertension (P = 0.028). CONCLUSIONS: Our findings indicated that genetic variants of NOS3, CD14, MMP3 and IL4R are implicated in the determination of VEGF expression and plasma levels. Thus, they support the hypothesis that in physiological conditions there are complex biological relationships between pathways (such as angiogenesis and inflammation), which are involved in the development of chronic diseases.

Conference Scene: Systems biology and personalized health science and translation.

After a 1-day advanced course on systems biology, the main themes of this 3-day colloquium were developed: from systems biology to systems medicine with special applications to cancer; pharmacogenomics in drug discovery and clinical application; and epigenomics and genome-wide association studies in cardiovascular diseases. In two roundtable discussions on pharmacogenomics and genome-wide association studies, the progress and the difficulties in the implementation of omics technologies in clinical practice were discussed. Three workshops were also organized on technical tools linked to the meeting themes.

What is the contribution of two genetic variants regulating VEGF levels to type 2 diabetes risk and to microvascular complications?

Vascular endothelial growth factor (VEGF) is a key chemokine involved in tissue growth and organ repair processes, particularly angiogenesis. Elevated circulating VEGF levels are believed to play a role in type 2 diabetes (T2D) microvascular complications, especially diabetic retinopathy. Recently, a genome-wide association study identified two common single nucleotide polymorphisms (SNPs; rs6921438 and rs10738760) explaining nearly half of the variance in circulating VEGF levels. Considering the putative contribution of VEGF to T2D and its complications, we aimed to assess the effect of these VEGF-related SNPs on the risk of T2D, nephropathy and retinopathy, as well as on variation in related traits.SNPs were genotyped in several case-control studies: French and Danish T2D studies (N(cases) = 6,920-N(controls) = 3,875 and N(cases) = 3,561-N(controls) = 2,623; respectively), two French studies one for diabetic nephropathy (N(cases) = 1,242-N(controls) = 860) and the other for diabetic retinopathy (N(cases) = 1,336-N(controls) = 1,231). The effects of each SNP on quantitative traits were analyzed in a French general population-based cohort (N = 4,760) and two French T2D studies (N = 3,480). SNP associations were assessed using logistic or linear regressions.In the French population, we found an association between the G-allele of rs6921438, shown to increase circulating VEGF levels, and increased T2D risk (OR = 1.15; P = 3.7×10(-5)). Furthermore, the same allele was associated with higher glycated hemoglobin levels (ß = 0.02%; P = 9.2×10(-3)). However, these findings were not confirmed in the Danes. Conversely, the SNP rs10738760 was not associated with T2D in the French or Danish populations. Despite having adequate statistical power, we did not find any significant effects of rs6921438 or rs10738760 on diabetic microvascular complications or the variation in related traits in T2D patients.In spite of their impact on the variance in circulating VEGF, we did not find any association between SNPs rs6921438 and rs10738760, and the risk of T2D, diabetic nephropathy or retinopathy. The link between VEGF and T2D and its complications might be indirect and more complex than expected.

A common variant highly associated with plasma VEGFA levels also contributes to the variation of both LDL-C and HDL-C.

Vascular endothelial growth factor A (VEGFA) is among the most-significant stimulators of angiogenesis. Its effect on cardiovascular diseases and on the variation of related risk factors such as lipid parameters is considered important, although as yet unclear. Recently, we identified four common variants (rs6921438, rs4416670, rs6993770, and rs10738760) that explain up to 50% of the heritability of plasma VEGFA levels. In the present study, we aimed at assessing the contribution of these variants to the variation of blood lipid levels (including apoE, triglycerides, total cholesterol, low- and high-density lipoprotein cholesterol levels (LDL-C and HDL-C)] in healthy subjects. The effect of these single-nucleotide polymorphisms (SNPs) on lipid levels was assessed using linear regression in discovery and replication samples (n = 1,006 and n = 1,145; respectively), followed by a meta-analysis. Their gene×gene and gene×environment interactions were also assessed. SNP rs6921438 was associated with HDL-C (ß = -0.08 mmol/l, P(overall) = 1.2 × 10(-7)) and LDL-C (ß = 0.13 mmol/l, P(overall) = 1.5 × 10(-4)). We also identified a significant association between the interaction rs4416670×hypertension and apoE variation (P(overall) = 1.7 × 10(-5)). Therefore, our present study shows a common genetic regulation between VEGFA and cholesterol homeostasis molecules. The SNP rs6921438 is in linkage disequilibrium with variants located in an enhancer- and promoter-associated histone mark region and could have a regulatory effect in the expression of surrounding genes, including VEGFA.

Associations of vascular endothelial growth factor (VEGF) with adhesion and inflammation molecules in a healthy population.

Vascular endothelial growth factor (VEGF) is implicated in numerous pathologies through complex relationships with cellular adhesion molecules (CAMs) and inflammation markers. These have not been assessed in non-pathological conditions. Our aim was the evaluation of associations between VEGF and CAM/inflammation molecules in a healthy population, and of possible genomic interplays in order to better apprehend the underlying mechanisms leading to the pathology. We examined the associations between VEGF and ICAM-1, VCAM-1, E-, L-, P-selectins, TNF-α, CRP and IL-6 plasma levels in 403 healthy individuals. Gene expression of CAM/inflammation molecules and VEGF isoforms (121, 145, 165, and 189) were quantified in peripheral blood mononuclear cells (PBMCs). The effect of four genetic variants (explaining ≈ 50% of the heritability of circulating VEGF levels) and of their interactions on plasma and mRNA levels of CAM/inflammation molecules was examined. VEGF was associated with ICAM-1 and E-selectin in plasma. In PBMCs, VEGF(145) mRNA was associated with ICAM-1, L-selectin and TNF-α expression. Interactions of the genetic variants were shown to affect ICAM-1, E-selectin, IL-6 and TNF-α plasma levels, while rs4416670 was associated with L-selectin expression. These findings propose a biological connection between VEGF and CAM/inflammation markers. Common genetic and transcriptional mechanisms may link these molecules and control their effect in healthy conditions.

Clinical necessity of partitioning of human plasma haptoglobin reference intervals by recently-discovered rs2000999.

BACKGROUND: Very recently, we identified a novel polymorphism, rs2000999, located in haptoglobin gene (HP) as a strong genetic determinant of the haptoglobin levels (Hp). We aim to determine the reference values of Hp on the basis of its main sources of biological variation including the rs2000999 in a large French origin population, the STANISLAS Family Study (SFS). METHODS: Through a stepwise regression analysis, the main biological variables of Hp levels were identified in 3129 "apparently" disease-free individuals of the SFS. Hp reference ranges were subsequently established in a subgroup of 2923 selected healthy subjects, as the reference population. RESULTS: The plasma reference values of Hp ranged 0.08-1.97 g/L in males and 0.08-2.19 g/L in females. Gender, age, smoking, plasma levels of hemoglobin and the newly-discovered HP polymorphism, rs2000999, were found to be the strongest biological predictors of the Hp concentrations in human plasma. Hp levels, in both genders and in all age groups, were negatively associated with the presence and number of rs2000999 minor allele. CONCLUSION: To be reliably interpretable in daily medical practice, the HP polymorphism, rs2000999, should be considered for partitioning its reference values. This polymorphism may also help for setting decision limits for medical interpretation of Hp concentrations.

Identification of cis- and trans-acting genetic variants explaining up to half the variation in circulating vascular endothelial growth factor levels.

RATIONALE: Vascular endothelial growth factor (VEGF) affects angiogenesis, atherosclerosis, and cancer. Although the heritability of circulating VEGF levels is high, little is known about its genetic underpinnings. OBJECTIVE: Our aim was to identify genetic variants associated with circulating VEGF levels, using an unbiased genome-wide approach, and to explore their functional significance with gene expression and pathway analysis. METHODS AND RESULTS: We undertook a genome-wide association study of serum VEGF levels in 3527 participants of the Framingham Heart Study, with preplanned replication in 1727 participants from 2 independent samples, the STANISLAS Family Study and the Prospective Investigation of the Vasculature in Uppsala Seniors study. One hundred forty single nucleotide polymorphism (SNPs) reached genome-wide significance (P<5×10(-8)). We found evidence of replication for the most significant associations in both replication datasets. In a conditional genome-wide association study, 4 SNPs mapping to 3 chromosomal regions were independently associated with circulating VEGF levels: rs6921438 and rs4416670 (6p21.1, P=6.11×10(-506) and P=1.47×10(-12)), rs6993770 (8q23.1, P=2.50×10(-16)), and rs10738760 (9p24.2, P=1.96×10(-34)). A genetic score including these 4 SNPs explained 48% of the heritability of serum VEGF levels. Six of the SNPs that reached genome-wide significance in the genome-wide association study were significantly associated with VEGF messenger RNA levels in peripheral blood mononuclear cells. Ingenuity pathway analyses showed found plausible biological links between VEGF and 2 novel genes in these loci (ZFPM2 and VLDLR). CONCLUSIONS: Genetic variants explaining up to half the heritability of serum VEGF levels were identified. These new insights provide important clues to the pathways regulating circulating VEGF levels.

Association of genetic Loci with glucose levels in childhood and adolescence: a meta-analysis of over 6,000 children.

OBJECTIVE: To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents. RESEARCH DESIGN AND METHODS: A total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9-16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose. RESULTS: Nine loci were associated with glucose levels in healthy children and adolescents, with four of these associations reported in previous studies and five reported here for the first time (GLIS3, PROX1, SLC2A2, ADCY5, and CRY2). Effect sizes were similar to those in adults, suggesting age-independent effects of these fasting glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced ß-cell function, as indicated by homeostasis model assessment of ß-cell function. Analysis using a weighted risk score showed an increase [ß (95% CI)] in fasting glucose level of 0.026 mmol/L (0.021-0.031) for each unit increase in the score. CONCLUSIONS: Novel fasting glucose loci identified in genome-wide association studies of adults are associated with altered fasting glucose levels in healthy children and adolescents with effect sizes comparable to adults. In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interindividual differences in glucose levels from childhood onwards.

Functional genomics towards personalized healthcare and systems medicine.

The 5th Biologie Prospective Santorini Conference explored the themes of systems biology, nutrigenomics and pharmacogenomics, all of which are related to personalized health, personalized therapy and personalized medicine. The conference started with a satellite meeting on genome-wide scan studies where the need for simplified models, the quality of the phenotypes and the input of epigenetics were dominant remarks. All of the omics approaches were then applied during the 3 days' sessions to multifactorial diseases (e.g., diabetes, atherosclerosis, cancer and inflammation) and often focused on gene-gene and gene-environment interactions. Afterwards, a fundamental session on drug metabolism, theranostics and pharmacogenetics and their practical aspects showed that the translation to clinical practice is finally happening although much slower than expected.