Globally Monotonic Tracking Control of Multivariable Systems

© 1963-2012 IEEE. In this technical note we present a method for designing a linear time invariant (LTI) state-feedback controller to monotonically track a step reference at any desired rate of convergence for any initial condition. This method is developed for multi-input multi-output (MIMO) systems, and can be applied to strictly/nonstrictly proper systems, and also minimum/nonminimum-phase systems. This framework shows that for MIMO systems the objectives of achieving a rapid settling time, while at the same time avoiding overshoot/undershoot, are not always competing objectives

Stratégies de recherches de phénomènes d'interactions dans les maladies multifactorielles

Les études d'associations en génome entier ("GWAS") ont récemment permis la découverte de nombreux polymorphismes génétiques impliqués dans la susceptibilité aux maladies multifactorielles. Cependant, ces polymorphismes n'expliquent qu'une faible part de l'héritabilité génétique de ces maladies, nous poussant ainsi à explorer de nouvelles pistes de recherche. Une des hypothèses envisagées serait qu'une partie de cette héritabilité manquante fasse intervenir des phénomènes d'interactions entre polymorphismes génétiques. L'objectif de cette thèse est d'explorer cette hypothèse en adoptant une stratégie de recherche d'interactions basée sur des critères statistiques et biologiques à partir de données issues de différentes études "GWAS". Ainsi, en utilisant différentes méthodes statistiques, nous avons commencé par rechercher des interactions entre polymorphismes qui pourraient influencer le risque de thrombose veineuse. Cette recherche n'a malheureusement pas abouti à l'identification de résultats robustes vis à vis du problème des tests multiples. Dans un deuxième temps, à partir d'hypothèses "plus biologiques", nous avons tenté de mettre en évidence des interactions entre polymorphismes impliqués dans les mécanismes de régulation de l'expression génique associés aux microARNs. Nous avons pu ainsi montrer de manière robuste dans deux populations indépendantes qu'un polymorphisme au sein de la séquence du microARN hsa-mir-219-1 interagissait avec un polymorphisme du gène HLA-DPB1 pour en moduler l'expression monocytaire. Nous avons également montré que l'expression monocytaire du gène H1F0 était influencée par un phénomène d'interaction impliquant un polymorphisme du microARN hsa-mir-659. En apportant sa propre contribution à l'engouement récent que suscite la recherche d'interactions entre polymorphismes dans les maladies dites complexes, ce travail de thèse illustre clairement la difficulté d'une telle tâche et l'importance de réfléchir à de nouvelles stratégies de recherches.Recently, Genome-Wide Association Studies (GWAS) have led to the discovery of numerous genetic polymorphisms involved in complex human diseases. However, these polymorphisms contribute only a little to the overall genetic variability of these diseases, suggesting the need for new kind of investigations in order to disentangle the so-called "missing heritability". The purpose of my PhD project was to investigate how different research strategies relying on statistical and biological considerations could help in determining whether part of this missing heritability could reside in interaction phenomena between genetic polymorphisms. Firstly, we applied different statistical methodologies and looked for interactions between polymorphisms that could influence the risk of venous thrombosis (VT). Even though this study was based on two large GWAS datasets, we were not able to identify pairwise interactions that survive multiple testing. This work suggests that strong interactive phenomena between common SNPs are unlikely to contribute much to the risk of VT. Second, by adopting a hypothesis-driven approach relying on biological arguments, we sought for interactions between microRNA related polymorphisms that could alter genetic expression. Using two large GWAS datasets in which genome-wide monocyte expression was also available, we were able to demonstrate the existence of two pairwise interaction phenomena on monocyte expression involving miRNAs polymorphisms: 1/ the expression of HLA-DPB1 was modulated by a polymorphism in its 3'UTR region with a polymorphism in the hsa-mir-219-1 microRNA sequence; 2/ similarly, the expression of H1F0 was influenced by a polymorphism in its 3'UTR region interacting with a polymorphism in the microRNA hsa-mir-659. Altogether, this project supports for the role of gene x gene interactions in the interindividual variability of biological processes but their identifications remain a tedious task requiring large samples and the development of new research strategies and methodologies.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

A study of the relationships between KLF2 polymorphisms and body weight control in a French population

BACKGROUND: Factors governing adipose tissue differentiation play a major role in obesity development in humans. The Krüppel-like zinc finger transcription factor KLF2/Lung KLF (LKLF) is a negative regulator of adipocyte differentiation. In this study, we sequenced the human KLF2 gene and several common polymorphisms were found, among them the Pro104Leu and 3'UTR 1239C>A polymorphisms. METHODS: To evaluate the impact of these polymorphisms on anthropometric variables in humans, we genotyped a general population composed of 1155 French individuals (including 232 obese subjects) for these polymorphisms and looked for potential statistical associations with obesity-related variables. RESULTS: The frequency of the Leu104 and 1239A alleles were 0.22 and 0.18 respectively. Genotype and allele frequencies of the two polymorphisms were comparable in obese, overweight and normal weight subjects. No association between the rare alleles of the polymorphisms and anthropometric variables (BMI, weight, waist and hip circumferences, waist-to-hip ratio and plasma leptin levels) could be detected. Haplotype analyses did not reveal further significant associations. CONCLUSION: These data indicate that the Pro104Leu and 3'UTR 1239C>A polymorphisms in KLF2 are not associated with obesity and obesity-related traits in humans

A polymorphism in ACE2 is associated with a lower risk for fatal cardiovascular events in females: the MORGAM project

Angiotensin II, a vasoconstrictor and the main effector molecule of the renin-angiotensin system, is known to influence inflammation, thrombosis, low-density lipoprotein oxidation and growth factors, all of which contribute to cardiovascular disease. The associations of polymorphisms in the angiotensin-converting enzyme 2 (ACE2) gene with cardiovascular risk have not been fully determined. Single nucleotide polymorphisms (SNPs) in ACE2 were genotyped in participants of the prospective MORGAM study (n = 5092) from five cohorts: ATBC, FINRISK, Northern Sweden, PRIME/Belfast and PRIME/France. Using a case-cohort design, associations were sought between SNPs and haplotypes with cardiovascular events during follow-up (Cox proportional hazards model). The comparison group were a subset of all MORGAM participants who were selected to ensure similar age and sex distributions among the cases and controls. The A allele of the rs2285666 SNP (HR = 0.3, p = 0.04) was significantly associated with the risk of cardiovascular death in female subjects. These findings complement those found in other studies of SNPs in the ACE2 gene in relation to cardiovascular disease risk. As females carry two copies of the ACE2 gene, and given its plausible biological role in cardiovascular disease risk, further studies of ACE2 should be prioritized

Cardiovasc Res

The hemostatic system is pivotal to maintaining vascular integrity. Multiple components involved in blood coagulation have central functions in inflammation and immunity. A derailed hemostasis is common in prevalent pathologies such as sepsis, cardiovascular disorders and, lately, COVID-19. Physiological mechanisms limit the deleterious consequences of a hyperactivated hemostatic system through adaptive changes in gene expression. While this is mainly regulated at the level of transcription, co- and posttranscriptional mechanisms are increasingly perceived as central hubs governing multiple facets of the hemostatic system. This layer of regulation modulates the biogenesis of hemostatic components, for example in situations of increased turnover and demand. However, they can also be 'hijacked' in disease processes, thereby perpetuating and even causally entertaining associated pathologies. This review summarizes examples and emerging concepts that illustrate the importance of posttranscriptional mechanisms in hemostatic control and crosstalk with the immune system. It also discusses how such regulatory principles can be used to usher in new therapeutic concepts to combat global medical threats such as sepsis or cardiovascular disorders

Identification de facteurs génétiques modulant deux phénotypes intermédiaires de la maladie thrombo-embolique veineuse (les taux de facteurs VIII et von Willebrand)

La Maladie Thrombo-Embolique Veineuse (MTEV) est une maladie dont les facteurs de risque sont à la fois environnementaux et génétiques. Les facteurs de risque génétiques bien établis sont les déficits en anti-thrombine, en protéine S, en protéine C, la mutation du Facteur V de Leiden (FVL), la mutation du Facteur (F) II G20210A, ainsi que le gène ABO dont les allèles A1 et B augmentent le risque de MTEV par rapport aux allèles A2 et O. Alors qu une part importante de l héritabilité de la MTEV reste inexpliquée, les études contemporaines se heurtent à un manque de puissance pour découvrir de nouveaux facteurs génétiques dont les effets sont de plus en plus faibles. En vue d augmenter la puissance de détection de nouveaux gènes de susceptibilité à la MTEV, j ai recherché les déterminismes génétiques de deux de ses phénotypes intermédiaires : les taux d activité plasmatique du FVIII et les taux d antigénémie de sa protéine de transport, le Facteur de von Willebrand (vWF). Dans un premier temps, j ai réalisé une analyse de liaison des taux de FVIII et de vWF à partir d un échantillon de cinq grandes familles franco-canadiennes (totalisant 255 personnes) recrutées via un cas de MTEV avec mutation FVL. Quatre régions liées aux taux de FVIII et/ou vWF ont été identifiées. L une de ces régions correspondait au locus du gène ABO déjà connu pour influencer les taux de FVIII et vWF. La recherche de gènes candidats au sein des autres signaux de liaison s est effectuée par l étude in silico d une analyse d association pangénomique de la MTEV incluant 419 cas et 1228 témoins. Deux gènes candidats ont été identifiés : STAB2 et BAI3. J ai ensuite réalisé des études d associations de cinq polymorphismes de BAI3. L un d entre eux était d une part associé à une élévation des taux de vWF (résultat obtenu dans un échantillon de 108 familles nucléaires en bonne santé et reproduit dans un échantillon de 916 patients non apparentés atteints de MTEV), et d autre part associé au risque de survenue de MTEV parmi les sujets non porteurs de mutations FVL et FII de deux échantillons cas-témoins (respectivement 916 cas et 801 témoins, et 250 cas et 607 témoins). Quant à STAB2, durant le courant de ma thèse, deux de ces polymorphismes ont été décrits comme associés aux taux de FVIII et vWF au cours d une vaste étude d association pangénomique (GWAS) menée par le consortium CHARGE rassemblant 23 600 personnes. Dans un second temps, j ai réalisé une méta-analyse de trois GWAS des taux de FVIII et vWF. Ces analyses avaient été conduites avec l échantillon des cinq grandes familles franco-canadiennes et deux échantillons de 972 et 570 patients atteints de MTEV. Elles étaient ajustées sur les polymorphismes du gène ABO permettant de distinguer les allèles A1, A2, B et O, dans l optique d augmenter la puissance des analyses en diminuant la variance résiduelle des phénotypes. Aucun polymorphisme n était associé ni aux taux de vWF ni à ceux de FVIII après prise en compte de la correction de Bonferroni pour tests multiples (p<10-7). Cependant, parmi les onze gènes qui présentaient des polymorphismes associés aux taux de vWF ou de FVIII avec une significativité p<10-5, de manière intéressante se trouvait STAB2. Cette étude a de plus permis de confirmer les associations nouvellement découvertes de polymorphismes situés dans les gènes VWF, STXBP5 et STX2.The Venous Thromboembolism (VTE) risk factors are environmental and genetic. The well established risk factors are anti-thrombin, protein C, protein S deficiency, Factor V Leiden and factor II mutation and ABO gene, with A1 and B allele increasing the risk of VTE. While an important part of VTE heritability remains unexplained, contemporary studies fail to discover new susceptibility genes with weaker effects. In order to increase the discovery power, I searched for genetic geterminism of two intermediary phenotypes of VTE : Factor VIII plasmatic activity (FVIII) and von Willebrand factor antigenemia (vWF)First, I performed a linkage study of FVIII and vWF from a sample of 5 large pedigrees (N=255). Four loci have been identified. One included ABO gene. I searched for candidate genes located in the others loci by studying in silico results from o Genome Wide Association Study (GWAS) of the VTE including 419 cases and and 1228 controls. témoins. Two candidate genes were identified : STAB2 et BAI3. Then I performed association studies of five SNPs in BAI3 with FVIII and vWF. One of them was associated to vWF (in a sample of 108 nuclear families and 916 VTE patients), and associated to VTE in two case-controls samples (respectively 916 cases and 801 controls, and 250 cases et 607 controls).Second, I performed a meta-analysis of three GWAS of FVIII and vWF from the same 5 pedigrees and two samples of VTE (N=972 and 570) adjusted on ABO blood group. No polymorphisms were significant after Bonferoni correction (p<10-7). Nevertheless, among 11 genes carrying polymorphisms with a p<10-5, interestingly was STAB2. Futhermore, this study allowed to confirm newly discoverd association with VWF, STXBP5 et STX2.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

MFGE8 does not influence chorio-retinal homeostasis or choroidal neovascularization in vivo

Purpose: Milk fat globule-epidermal growth factor-factor VIII (MFGE8) is necessary for diurnal outer segment phagocytosis and promotes VEGF-dependent neovascularization. The prevalence of two single nucleotide polymorphisms (SNP) in MFGE8 was studied in two exsudative or “wet” Age-related Macular Degeneration (AMD) groups and two corresponding control groups. We studied the effect of MFGE8 deficiency on retinal homeostasis with age and on choroidal neovascularization (CNV) in mice. Methods: The distribution of the SNP (rs4945 and rs1878326) of MFGE8 was analyzed in two groups of patients with “wet” AMD and their age-matched controls from Germany and France. MFGE8-expressing cells were identified in Mfge8+/− mice expressing ß-galactosidase. Aged Mfge8+/− and Mfge8−/− mice were studied by funduscopy, histology, electron microscopy, scanning electron microscopy of vascular corrosion casts of the choroid, and after laser-induced CNV. Results: rs1878326 was associated with AMD in the French and German group. The Mfge8 promoter is highly active in photoreceptors but not in retinal pigment epithelium cells. Mfge8−/− mice did not differ from controls in terms of fundus appearance, photoreceptor cell layers, choroidal architecture or laser-induced CNV. In contrast, the Bruch's membrane (BM) was slightly but significantly thicker in Mfge8−/− mice as compared to controls. Conclusions: Despite a reproducible minor increase of rs1878326 in AMD patients and a very modest increase in BM in Mfge8−/− mice, our data suggests that MFGE8 dysfunction does not play a critical role in the pathogenesis of AMD

Blood pressure and risk of venous thromboembolism: a cohort analysis of 5.5 million UK adults and Mendelian randomization studies

\ua9 The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. Aims Evidence for the effect of elevated blood pressure (BP) on the risk of venous thromboembolism (VTE) has been conflicting. We sought to assess the association between systolic BP and the risk of VTE. Methods and results Three complementary studies comprising an observational cohort analysis, a one-sample and two-sample Mendelian randomization were conducted using data from 5 588 280 patients registered in the Clinical Practice Research Datalink (CPRD) dataset and 432 173 UK Biobank participants with valid genetic data. Summary statistics of International Network on Venous Thrombosis genome-wide association meta-analysis was used for two-sample Mendelian randomization. The primary outcome was the first occurrence of VTE event, identified from hospital discharge reports, death registers, and/or primary care records. In the CPRD cohort, 104 017(1.9%) patients had a first diagnosis of VTE during the 9.6-year follow-up. Each 20 mmHg increase in systolic BP was associated with a 7% lower risk of VTE [hazard ratio: 0.93, 95% confidence interval (CI): (0.92–0.94)]. Statistically significant interactions were found for sex and body mass index, but not for age and subtype of VTE (pulmonary embolism and deep venous thrombosis). Mendelian randomization studies provided strong evidence for the association between systolic BP and VTE, both in the one-sample [odds ratio (OR): 0.69, (95% CI: 0.57–0.83)] and two-sample analyses [OR: 0.80, 95% CI: (0.70–0.92)]. Conclusion We found an increased risk of VTE with lower BP, and this association was independently confirmed in two Mendelian randomization analyses. The benefits of BP reduction are likely to outweigh the harms in most patient groups, but in people with predisposing factors for VTE, further BP reduction should be made cautiously