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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.

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.

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.

International audience; 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.Copyright © 2018 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Interleukin 6 receptor (IL-6R), mediating IL-6's biological functions, plays an important role in different diseases such as diabetes, obesity and cardio-vascular diseases. In this study, we investigated the effects of two single nucleotide polymorphisms (SNPs), within the IL-6R loci, previously associated with C-reactive protein (CRP) and coronary heart diseases risk, and with controversial effects on lipids traits: SNP rs4845625 and SNP rs4537545. The results showed that both investigated SNPs were antagonistically related with CRP levels; the minor rs4845625*T allele was associated with increased CRP levels (P-value = 0.011), while the minor rs4537545* T allele was associated with decreased CRP levels (P-value = 0.009). Interestingly, the minor rs4845625* T allele was significantly associated with higher low-density lipoprotein cholesterol (LDL-C) and ApoB levels (P = 0.007 and P = 0.009 respectively). Haplotype analysis showed that the TC haplotype, having the minor rs4845625* T allele, was related simultaneously with increased levels of CRP, LDL-C and ApoB levels, thus could be considered as a risk factor. Our investigation detects for the first time an independent effect of rs4845625 on LDL-C and ApoB traits, explaining an important range of those traits variability (3.49 and 5.57% respectively). Our findings might be of high clinical significance in pharmacogenomics studies of tocilizumab for which IL-6R is target.

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.

International audience

Background:TheABOgene has been widely studied and associated with many different diseases such as myocardial infarction and diabetes. Pleiotropic effects of theABOlocus 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 theABOgene with different phenotypes related with diseases where theABOgene has been involved.Methods:We analyzed the SNP rs644234 located in theABOgene, 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 thatABOis 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 ABOgene 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.

The aim of this study was to investigate the difference in the prevalence of metabolic syndrome and its components between an Iranian and a French population.The prevalence of metabolic syndrome, defined according to the Adult Treatment Panel III (ATP III), and of related abnormalities, was estimated in 1,386 French and 1,194 Iranian adults.The prevalence of metabolic syndrome was significantly higher in Iranian women (55.0%), followed by Iranian men (30.1%), than in French men (13.7%) and French women (6.6%). Iranian women were characterized by high rates of abdominal obesity (65.0%), hypertension (52.1%), hypertriglyceridemia (43.1%), and low high-density lipoprotein cholesterol (HDL-C; 92.7%). Iranian men were characterized by high rates of hypertension (48.9%), hypertriglyceridemia (42.8%), and low HDL-C (81.8%). French men had high rates of hypertension (44.7%) and mild rates of hypertriglyceridemia (28.6%) and hyperglycemia (23.9%). There was a relationship between waist circumference and the lipid components of metabolic syndrome in both countries.The main finding of this study is the high prevalence of low HDL-C concentrations in the Iranian population, especially in Iranian women, compared with French women. Explanation of this observation could help in establishing prevention strategies.

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 β-cell function, as indicated by homeostasis model assessment of β-cell function. Analysis using a weighted risk score showed an increase [β (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.

Familial history of cardiovascular disease is acknowledged as a risk indicator in offspring. The aim of this study was to assess whether the cardiovascular risk factors in parents predicted the risk of their children developing cardiovascular disease in a French population: the STANISLAS Cohort, in which Caucasian biparental families with at least two siblings were followed for 5 years. Silent risk factors (blood pressure, lipid traits, glycemia, BMI and waist circumference) of children were compared according to their parents’ risk status in a subsample of 693 families. All of these traits, with the exception of glucose, were significantly higher in children who had parents at a high risk than in children with parents at a low risk at the first health examination, and these results were confirmed again 5 years later at the second health examination. Thus, silent cardio–metabolic risk factors can be screened in children according to the risk status of their parents for early prevention. The influence of parents’ variants on their offspring underlined the need to initiate familial prevention strategies, with a particular follow-up of young individuals between childhood and adolescence.

International audience; ascular 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 (β = −0.08 mmol/l, Poverall = 1.2 × 10−7) and LDL-C (β = 0.13 mmol/l, Poverall = 1.5 × 10−4). We also identified a significant association between the interaction rs4416670×hypertension and apoE variation (Poverall = 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.

Cardiovascular diseases (CVDs) are a major public health concern ranked by WHO as the number one cause of death globally. Adverse cardiovascular events will largely contribute to the death of almost 23.6 million people a year by 2030 [101]. CVDs are multifactorial pathologies with a significant genetic component. Tremendous breakthroughs in the identification of the genetic variants involved have been made during the last few decades, notably thanks to the technological development of high-throughput genotyping technologies, especially genome-wide association studies (GWAS) [1], as well as the candidategene studies, which have also offered interesting results. However, for most of the variants revealed, the transition from a statistical association to a causal mechanism has proved far from straightforward. Transcriptional analyses meet difficulties in defining the transcripts likely to mediate the associations, thus blocking the translation of genetic discoveries into an improved understanding of disease biology. Moreover, the clinical usefulness of GWAS-identified CVD loci is almost negligible at this stage.

Genome-wide linkage analysis studies reported the importance of the long arm of chromosome 13 in systolic blood pressure regulation. Therefore, isolating a genetic variant related to this chromosomal region could be challenging. Klotho KL-VS allele is located on this chromosomal region and its relationships with cardio-vascular risk factors need extensive investigations. The aim of the present study is to examine whether the klotho KL-VS genotype is associated with cardio-vascular risk factors, more particularly hypertension, in two independent cohorts. A secondary objective was to investigate relationships with antihypertensive treatment, arterial stiffness and carotid artery parameters.A total of 1023 French individuals were genotyped for klotho KL-VS. Participants were part of the French ERA and STANISLAS cohorts. In both cohorts, klotho KL-VS/KL-VS genotype was significantly associated with lower systolic blood pressure and pulse pressure when compared to homozygous and heterozygous more frequent (WT) allele carriers (p=0.003 and p0.001 respectively). Antihypertensive treatment stratification confirmed the previous significant associations, while a significant interaction between klotho KL-VS genotype and antihypertensive treatment was also interestingly found (0.019 for p interaction).Klotho KL-VS/KL-VS genotype may be associated with decreased cardio-vascular risk and may interact with antihypertensive treatment in order to reduce blood pressure. This finding could lead to identify subgroups of hypertensive adults who might benefit antihypertensive drug therapies.

International audience; 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 = 3.7610 25). Furthermore, the same allele was associated with higher glycated hemoglobin levels (b = 0.02%; P = 9.2610 23). 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.

BackgroundAlthough numerous genetic studies have been performed, only 0.9% of blood pressure phenotypic variance has been elucidated. This phenomenon could be partially due to epistatic interactions. Our aim was to identify epistatic interaction(s) associated with blood pressure levels in a pre-planned two-phase approach.Methods and resultsIn a discovery cohort composed of 3,600 French individuals, we found rs6046A allele in F7 associated with decreased blood pressure levels (P≤3.7×10(-3)) and rs5355T allele in SELE associated with decreased diastolic blood pressure levels (P = 5×10(-3)). Both variants interacted in order to influence blood pressure levels (P≤0.048). This interaction was replicated with systolic blood pressure in 4,620 additional European individuals (P = 0.03). Similarly, in this replication cohort, rs6046A was associated with decreased blood pressure levels (P≤8.5×10(-4)). Furthermore, in peripheral blood mononuclear cells of a subsample of 90 supposed healthy individuals, we found rs6046A positively associated with NAMPT mRNA levels (P≤9.1×10(-5)), suggesting an eventual involvement of NAMPT expression in blood pressure regulation. Confirming this hypothesis, further transcriptomic analyses showed that increased NAMPT mRNA levels were positively correlated with ICAM1, SELL, FPR1, DEFA1-3, and LL-37 genes expression (P≤5×10(-3)). The last two mRNA levels were positively associated with systolic blood pressure levels (P≤0.01) and explained 4% of its phenotypic variation.ConclusionThese findings reveal the importance of epistatic interactions in blood pressure genetics and give new insights for the role of inflammation in its complex regulation.