Nitrogen (N), an essential plant macronutrient, is among the most limiting factors of crop yield. To sustain modern agriculture, N is often amended in soil in the form of chemical N fertilizer, a major anthropogenic contributor to nutrient pollution that affects climate, biodiversity and human health. To achieve agricultural sustainability, a comprehensive understanding of the regulation of N response in plants is required, in order to engineer crops with higher N use efficiency. Recently, epigenetic mechanisms, such as histone modifications, have gained increasing importance as a new layer of regulation of biological processes. However, our understanding of how epigenetic processes regulate N uptake and assimilation is still in its infancy. To fill this knowledge gap, we first performed a meta-analysis that combined functional genomics and network inference approaches to identify a set of N-responsive epigenetic regulators and predict their effects in regulating epigenome and transcriptome during plant N response. Our analysis suggested that histone modifications could serve as a regulatory mechanism underlying the global transcriptomic reprogramming during plant N response. To test this hypothesis, I applied chromatin immunoprecipitation-sequencing (ChIP-Seq) to monitor the genome-wide changes of four histone marks (H3K27ac, H3K4me3, H3K36me3 and H3K27me3) in response to N supply in tomato plants, followed by RNA-Seq to profile the transcriptomic changes. To investigate the organ specificity of histone modifications, I assayed shoots and roots separately. My results suggest that up to two-thirds of differentially expressed genes (DEGs) are modified in at least one of the four histone marks, supporting an integral role of histone modification in regulating N response. I observed a synergistic modification of active histone marks (H3K27ac, H3K4me3 and H3K36me3) at gene loci functionally relevant to N uptake and assimilation. Surprisingly, I uncovered a non-canonical role of H3K27me3, which is conventionally associated with repressed genes, in modulating active gene expression. Interestingly, such regulatory role of H3K27me3 is specifically associated with highly expressed genes or low expressed genes, depending on the organ context. Overall, I revealed the multi-faceted role of histone marks in mediating the plant N response, which will guide breeding and engineering of better crops with higher N use efficiency

La scoliose idiopathique est une déformation tridimensionnelle de la colonne vertébrale dont la pathogenèse reste obscure. Cette maladie affecte 2-4% des adolescents de 10-18 ans parmi les garçons et les filles. Il est à noter que les filles sont plus sévèrement affectées et ce en plus grand nombre que les garçons. Les études de jumeaux ont montré que les facteurs génétiques jouent un rôle important dans la scoliose idiopathique de l'adolescent (SIA). Depuis 2010, les études d'association pan génomiques ont été multipliées dans les recherches, visant à trouver des gènes candidats impliqués dans la SIA à travers des examens des polymorphismes nucléotidiques (SNPs). Un test génétique nommé "ScoliScore" a été publié pour essayer de prédire la progression de courbure dans la population caucasienne. Cependant, l'association n'a pas été reproduite dans une grande étude japonaise, soulignant l'importance d'une étude de réplication dans une population caucasienne indépendante. Dans ce contexte, mon projet de maîtrise a permis de génotyper plus de 1,4 millions de SNPs dans une cohorte canadienne-française dans le but: 1) de valider l'association de ScoliScoreTM; et 2) d’identifier les variants génomiques associées à la SIA dans la population québécoise. Notre étude a montré qu’aucun des variants constituant le test ScoliScoreTM n’était associé à la SIA. Ceci suggère que l'absence d'association dans une cohorte japonaise n'est pas due à l'appartenance ethnique. Aussi, nous avons identifié des variants génomiques associés significativement à l’initiation et/ou la progression de SIA dans la population québécoise, suggérant des gènes candidats impliqués dans la pathogenèse de SIA. / Idiopathic scoliosis is a common spinal deformation occurring without clear reason. This disease affects 2-4% adolescents aging from 10-18 years old in both genders. Of note, girls are more affected in number and severity than boys. Twin studies demonstrated that genetic factors play an important role in adolescent idiopathic scoliosis (AIS). Since 2010, Genome-wide association studies (GWAS) have been multiplied in AIS researches, aiming to find out candidate genes involved in the disease by an examination of single nucleotide polymorphisms (SNPs) throughout the entire genome. A genetic test named “ScoliScore” was released for the prediction of curvature progression in Caucasian AIS population using 53 SNPs. However, such association was not replicated in a larger Japanese-population study. Such a discrepancy could be explained by ethnicity, raising the importance of a replication study in an independent Caucasian population of European descent. In that context, we genotyped over 1.4 million SNPs in a French-Canadian cohort: 1) to validate the association in ScoliScoreTM test; and 2) to identify genomic variants associated with AIS in the population of Quebec. As a result, the association of ScoliScoreTM genomic markers could not be reproduced in French-Canadian AIS patients, suggesting that the lack of association of these SNPs in a Japanese cohort is not due to ethnicity. Meanwhile, we identified genome-wide significant variants associated with spinal curve initiation and/or progression in French-Canadian population, suggesting candidate genes involved in AIS pathogenesis.

No description available.

Die biotechnologischen Entwicklungen der letzten Jahre ermöglichen eine immer detailliertere Untersuchung von genetischen und molekularen Markern mit multiplen komplexen Traits. Allerdings liefern vorhandene statistische Methoden für diese komplexen Analysen oft keine valide Inferenz. Das erste Ziel der vorliegenden Arbeit ist, zwei neue statistische Methoden für Assoziationsstudien von genetischen Markern mit multiplen Phänotypen zu entwickeln, effizient und robust zu implementieren, und im Vergleich zu existierenden statistischen Methoden zu evaluieren. Der erste Ansatz, C-JAMP (Copula-based Joint Analysis of Multiple Phenotypes), ermöglicht die Assoziation von genetischen Varianten mit multiplen Traits in einem gemeinsamen Copula Modell zu untersuchen. Der zweite Ansatz, CIEE (Causal Inference using Estimating Equations), ermöglicht direkte genetische Effekte zu schätzen und testen. C-JAMP wird in dieser Arbeit für Assoziationsstudien von seltenen genetischen Varianten mit quantitativen Traits evaluiert, und CIEE für Assoziationsstudien von häufigen genetischen Varianten mit quantitativen Traits und Ereigniszeiten. Die Ergebnisse von umfangreichen Simulationsstudien zeigen, dass beide Methoden unverzerrte und effiziente Parameterschätzer liefern und die statistische Power von Assoziationstests im Vergleich zu existierenden Methoden erhöhen können - welche ihrerseits oft keine valide Inferenz liefern. Für das zweite Ziel dieser Arbeit, neue genetische und transkriptomische Marker für kardiometabolische Traits zu identifizieren, werden zwei Studien mit genom- und transkriptomweiten Daten mit C-JAMP und CIEE analysiert. In den Analysen werden mehrere neue Kandidatenmarker und -gene für Blutdruck und Adipositas identifiziert. Dies unterstreicht den Wert, neue statistische Methoden zu entwickeln, evaluieren, und implementieren. Für beide entwickelten Methoden sind R Pakete verfügbar, die ihre Anwendung in zukünftigen Studien ermöglichen. / In recent years, the biotechnological advancements have allowed to investigate associations of genetic and molecular markers with multiple complex phenotypes in much greater depth. However, for the analysis of such complex datasets, available statistical methods often don’t yield valid inference. The first aim of this thesis is to develop two novel statistical methods for association analyses of genetic markers with multiple phenotypes, to implement them in a computationally efficient and robust manner so that they can be used for large-scale analyses, and evaluate them in comparison to existing statistical approaches under realistic scenarios. The first approach, called the copula-based joint analysis of multiple phenotypes (C-JAMP) method, allows investigating genetic associations with multiple traits in a joint copula model and is evaluated for genetic association analyses of rare genetic variants with quantitative traits. The second approach, called the causal inference using estimating equations (CIEE) method, allows estimating and testing direct genetic effects in directed acyclic graphs, and is evaluated for association analyses of common genetic variants with quantitative and time-to-event traits. The results of extensive simulation studies show that both approaches yield unbiased and efficient parameter estimators and can improve the power of association tests in comparison to existing approaches, which yield invalid inference in many scenarios. For the second goal of this thesis, to identify novel genetic and transcriptomic markers associated with cardiometabolic traits, C-JAMP and CIEE are applied in two large-scale studies including genome- and transcriptome-wide data. In the analyses, several novel candidate markers and genes are identified, which highlights the merit of developing, evaluating, and implementing novel statistical approaches. R packages are available for both methods and enable their application in future studies.

L'ulcère de Buruli (UB), infection à Mycobacterium ulcerans, troisième mycobactériose mondiale, connait une émergence rapide depuis 1980, essentiellement dans les pays d'Afrique subsaharienne. Jusqu’ici, les connaissances épidémiologiques sur l’UB étaient fondées sur des séries de cas cliniques non confirmés par laboratoire. Nous avons constitué la plus grande cohorte de cas confirmés à ce jour rassemblant plus de 1200 patients traités au CDTUB de Pobè au Bénin entre 2005 et 2011, afin de décrire l'épidémiologie clinique de la maladie et d'explorer l’architecture génétique de la susceptibilité à cette maladie. Les patients atteints d’UB sont des enfants (âge médian au diagnostic de 12 ans), présentant une lésion unique (96%), large (plus de 15 cm, 36%), ulcérative (66%) du membre inférieur (60%). Nous rapportons une présentation clinique atypique de l’UB, dans laquelle les patients présentent exclusivement une ostéomyélite à M. ulcerans. Le sex-ratio varie avec l’âge : les garçons sont majoritaires parmi les enfants (57% de patients masculins chez les moins de 15 ans), et les femmes parmi les adultes (33% de patients masculins). La présentation clinique dépend de l’âge et du sexe. 9% des patients masculins ont présenté une ostéomyélite contre 4% des patients féminins. Un an après la fin du traitement, 22% des patients présentent des séquelles fonctionnelles fixées. Une présentation clinique comportant une lésion oedémateuse, osseuse, de grande taille ou plusieurs lésions est significativement associée avec le développement de séquelles fonctionnelles (OR 7.64, IC95% [5.29-11.31]). Les patients coinfectés par le VIH ont un risque significativement plus élevé de développer un UB sévère (OR 2.77, IC95% [1.32-6.33]). Nous avons exploré l’architecture génétique de la susceptibilité à l’UB dans une perspective mendélienne et une perspective complexe. Le cas le plus sévère de la maladie observé dans ce centre appartient à une famille consanguine dans laquelle la ségrégation du phénotype suggère un défaut génétique mendélien récessif. Une analyse de liaison génétique par cartographie d'homozygotie suggère l’implication du locus des béta-défensines sur le chromosome 8 dans la pathogénèse de l'UB, et mène à l’identification d’une délétion homozygote ségrégeant parfaitement avec la maladie. Dans une perspective complexe, une étude d’association pangénomique a été réalisée après génotypage d’une cohorte de 400 cas et 400 témoins exposés sur plus de 2 millions de SNPs par la puce Illumina Omni2.5 et a permis l’identification de nombreux signaux d’intérêt. L’étude de réplication est en cours. La compréhension de la physiopathologie de l'infection à M. ulcerans est cruciale pour générer de nouvelles pistes thérapeutiques et vaccinales. La dissection du contrôle génétique de l'infection par l'hôte est en ce sens indispensable. / Buruli ulcer (BU), caused by Mycobacterium ulcerans, is the third most frequent mycobacteriosis worldwide. It has been rapidly emerging in sub-Saharan African countries since 1980. Until now, knowledge of BU epidemiology relied on series of non laboratory-confirmed clinical cases. From 2005-2011, we recruited the current largest cohort of laboratory-confirmed cases (more than 1,200 patients) at the Pobe CDTUB, Benin, to describe the clinical epidemiology of the disease and to explore the genetic architecture of human susceptibility to BU. Typically, patients with BU were children (median age at diagnosis 12 years) presenting with a unique (96%) large (≥15 cm, 36%) ulcerative (66%) lesion of the lower limb (60%). Atypical clinical presentation of BU included osteomyelitis with no identifiable present or past BU skin lesions. The sex ratio of BU widely varied with age, with male patients accounting for 57% of patients aged 15 years and younger, but only 33% of those older than 15 years. Clinical presentation of BU was significantly dependent on age and sex. 9% male patients had BU osteomyelitis, whereas only 4% of female patients did. 1 year after treatment, 22% of patients with follow-up information presented with permanent functional sequelae. Presentation with oedema, osteomyelitis, or large (≥15 cm in diameter), or multifocal lesions was significantly associated with occurrence of permanent functional sequelae (OR 7•64, 95% CI 5•29–11•31) and operationally defines severe BU. When coinfected with HIV, patients had a significantly higher risk to develop severe BU (OR 2.77, IC95% [1.32-6.33]). We explored the genetic architecture of susceptibility to BU in both mendelian and complex genetic frameworks. The most severe case of the disease to have been treated at the Pobe CDTUB belonged to a consanguineous family in which the segregation of the phenotype was indicative of a recessive mendelian genetic defect. Genetic linkage analysis by homozygosity mapping suggested the implication of the beta-defensin locus on chromosome 8 in BU pathogenesis and lead to the identification of a homozygous deletion, which co-segregated perfectly with the disease in the family. In a complex genetics approach, we undertook a genome-wide association study, which involved the genotyping of more than 2 million SNPs (Illumina Omni2.5) in a cohort of 400 cases and 400 exposed controls. We identified many signals of interest. The replication study is ongoing. Understanding BU physiopathology is crucial to the development of efficient vaccines and drugs. Dissection of the genetic control of the infection by M. ulcerans by its human host therefore constitutes an indispensable step.

No description available.

Abstract Advances over the past few decades in ante- and neonatal care have led to the survival of a growing number of premature infants of extremely low gestational age. However, the occurrence of serious diseases, particularly those affecting the most immature infants, remains high. Bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants, is one such disease. Our current understanding of the molecular pathogenesis of BPD is incomplete; consequently, there are few preventive and therapeutic options for BPD. Moreover, it is challenging to predict the risk of BPD. Previous studies of BPD in twins revealed that the heritability of BPD is quite high. However, the individual genes that predispose premature infants to BPD are largely unknown. The aim of this study was to identify and study genes associated with BPD in order to investigate its pathogenesis. An additional aim was to add to knowledge of the risk of BPD in newborn premature infants, with an emphasis on twins. A candidate gene study found no consistent association between common polymorphisms of vascular endothelial growth factor receptor 2 and BPD. A second candidate gene study noted an association between the gene encoding Kit ligand and BPD. A genome-wide association study found a suggestive association between a locus close to the gene encoding C-reactive protein (CRP) and BPD, and in subsequent analyses, plasma levels of CRP during the first week of life predicted BPD. Finally, a nationwide register study found that the risk of BPD was lower in twins than in singletons. The results of this study add to what is known of the genetics and pathogenesis of BPD. They also provide new data on the risk of BPD, which may be used to improve early identification of infants for whom the risk of developing BPD is high. / Tiivistelmä Ennenaikaisen syntymän ja keskoslasten hoidon kehittymisen myötä yhä useammat huomattavan epäkypsinä syntyneet lapset jäävät henkiin. Samalla erityisesti juuri näitä lapsia uhkaavien sairauksien esiintyvyys on pysynyt korkeana. Bronkopulmonaalinen dysplasia (BPD, keskosen krooninen keuhkosairaus) on yksi näistä sairauksista. BPD:n molekyylitasoinen tautimekanismi on vielä osin tuntematon, eikä BPD:tä tehokkaasti estävää tai siitä parantavaa hoitoa ole. Myös BPD riskin arvioiminen vastasyntyneen keskoslapsen kohdalla on vaikeaa. BPD on huomattavan perinnöllinen tauti. BPD:lle altistavista geeneistä on kuitenkin vasta vähän tietoa. Tämän tutkimuksen tavoitteena oli lisätä tietoa BPD:n tautimekanismista tutkimalla BPD:lle altistavia geenejä. Lisäksi tutkimuksessa tarkasteltiin BPD:n esiintyvyyttä ja syntymää edeltäviä riskitekijöitä erityisesti kaksosten osalta. Ehdokasgeenitutkimuksessa verisuonten endoteelikasvutekijää koodaava geeni ei assosioitunut toistuvasti BPD:hen. Kit ligandia koodaava geeni sen sijaan assosioitui. Koko genomin assosiaatiotutkimuksessa C-reaktiivista proteiinia (CRP) koodaavan geenin lähistöltä löydettiin BPD:hen mahdollisesti assosioituva alue. Lisäksi ensimmäisen viikon CRP-arvojen osoitettiin ennakoivan myöhemmin kehittyvää BPD:tä. BPD-riskin todettiin olevan matalampi kaksi- kuin yksisikiöisistä raskauksista syntyneillä lapsilla. Tutkimuksen tulokset lisäävät tietoa BPD:n perinnöllisyydestä ja sitä kautta BPD:n tautimekanismista. Tutkimus toi myös uutta tietoa BPD:n riskitekijöistä parantaen vastasyntyneen keskoslapsen BPD-riskin arviota.

Les plantes sont des organismes immobiles qui doivent répondre et s’adapter à des contraintes abiotiques et biotiques. Parmi les stress biotiques, les maladies virales, établies ou émergentes, peuvent être responsables de pertes de rendement majeures aux conséquences économiques importantes. Face aux phytovirus la lutte génétique constitue le moyen de lutte le plus efficace, le plus respectueux de l’environnement et du consommateur. Comprendre l’interaction entre les plantes et les virus reste indispensable pour rechercher de nouvelles sources de résistances. Ce travail de thèse s’intéresse à l’étude du pathosystème naturel Arabidopis thaliana/Turnip mosaic virus (TuMV). Les essais ont été menés majoritairement en conditions extérieures permettant une analyse de l’interaction dans un environnement multistress. La réponse d’A. thaliana a été explorée par l’étude de traits liés à la maladie et par la variation en métabolites primaires et secondaires. Ce travail a permis i) de caractériser de façon fine la réponse d’A. thaliana au TuMV en conditionsmultistress en exploitant la diversité naturelle d’une population mondiale et française ii) de déterminer l’architecture génétique de cette interaction par des approches de génétique d’association et de QTL mapping. Plusieurs nouveaux loci potentiellement impliqués dans la réponse ont été identifiés iii) de montrer l’intérêt du phénotypage métabolique pour discriminer les accessions en fonction de leur sensibilité au TuMV. La multidisciplinarité des approches constitue la richesse de ce travail de thèse qui contribue à une meilleure caractérisation et compréhension de la réponse des plantes lors d’une infection virale. / Plants are immobile organisms which have to adapt to abiotic and biotic constraints. Among bioticstress, established or emerging viral diseases, may be responsible for major yield losses withsignificant consequences. Genetic control is the most effective, environmentally and consumerfriendlyway to control viral infections. Understanding plant/virus interactions remains essential tosearch for new sources of resistance. This work, focuses on the study of the natural pathosystemArabidopsis thaliana/Turnip mosaic virus (TuMV). Most of the trials were conducted in commongarden conditions allowing the analysis of the interaction in a multistress environment. A. thaliana’sresponse was explored through the study of disease-related traits and the variations in primary andsecondary metabolites. This work allows i) the fine characterization of A. thaliana’s response toTuMV in multistress conditions through the exploration of the natural diversity of a world and Frenchpopulation ii) to determine the genetic architecture of this interaction by genome wide associationsand QTL mapping. Several new loci potentially involved in the response have been identified iii) tohighlight the interest of metabolic phenotyping to discriminate accessions according to theirsusceptibility to TuMV. The multidisciplinary approaches contribute to a better characterization andunderstanding of plant-virus interaction.

Mapping of the human genome has been instrumental in understanding diseasescaused by changes in single genes. However, disease mechanisms involvingmultiple genes have proven to be much more elusive. Their complexityemerges from interactions of intracellular molecules and makes them immuneto the traditional reductionist approach. Only by modelling this complexinteraction pattern using networks is it possible to understand the emergentproperties that give rise to diseases.The overarching term used to describe both physical and indirect interactionsinvolved in the same functions is functional association. FunCoup is oneof the most comprehensive networks of functional association. It uses a naïveBayesian approach to integrate high-throughput experimental evidence of intracellularinteractions in humans and multiple model organisms. In the firstupdate, both the coverage and the quality of the interactions, were increasedand a feature for comparing interactions across species was added. The latestupdate involved a complete overhaul of all data sources, including a refinementof the training data and addition of new class and sources of interactionsas well as six new species.Disease-specific changes in genes can be identified using high-throughputgenome-wide studies of patients and healthy individuals. To understand theunderlying mechanisms that produce these changes, they can be mapped tocollections of genes with known functions, such as pathways. BinoX wasdeveloped to map altered genes to pathways using the topology of FunCoup.This approach combined with a new random model for comparison enables BinoXto outperform traditional gene-overlap-based methods and other networkbasedtechniques.Results from high-throughput experiments are challenged by noise and biases,resulting in many false positives. Statistical attempts to correct for thesechallenges have led to a reduction in coverage. Both limitations can be remediedusing prioritisation tools such as MaxLink, which ranks genes using guiltby association in the context of a functional association network. MaxLink’salgorithm was generalised to work with any disease phenotype and its statisticalfoundation was strengthened. MaxLink’s predictions were validatedexperimentally using FRET.The availability of prioritisation tools without an appropriate way to comparethem makes it difficult to select the correct tool for a problem domain.A benchmark to assess performance of prioritisation tools in terms of theirability to generalise to new data was developed. FunCoup was used for prioritisationwhile testing was done using cross-validation of terms derived fromGene Ontology. This resulted in a robust and unbiased benchmark for evaluationof current and future prioritisation tools. Surprisingly, previously superiortools based on global network structure were shown to be inferior to a localnetwork-based tool when performance was analysed on the most relevant partof the output, i.e. the top ranked genes.This thesis demonstrates how a network that models the intricate biologyof the cell can contribute with valuable insights for researchers that study diseaseswith complex genetic origins. The developed tools will help the researchcommunity to understand the underlying causes of such diseases and discovernew treatment targets. The robust way to benchmark such tools will help researchersto select the proper tool for their problem domain. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 5: Manuscript. Paper 6: Manuscript.</p>

Abstract Coronary heart disease (CHD), a manifestation of atherosclerosis, is the leading single cause of death in Finland. CHD is affected by numerous genetic and environmental factors, their combined effects and interactions between them. Low HDL-cholesterol (HDL-C) is an independent risk factor for atherosclerosis and the most common dyslipidemia associated with early onset CHD, but the mechanisms regulating HDL-C levels and protecting from atherosclerosis are still not completely understood. Adiponectin is a hormone that is secreted by adipose tissue and has several anti-atherosclerotic effects. There is multiple evidence suggesting that adiponectin could protect against CHD via positive effects on HDL metabolism. Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor that has a potentially conflicting role in atherosclerosis; it may have protecting or predisposing effects. The objective of this thesis was to study the genetic background of HDL-C regulation and atherosclerosis. Three studies were executed using extended families with CHD or case-control setting, with samples collected from Northern Finland. In the first study, seven chromosomal regions showing suggestive evidence of linkage were identified for HDL-C regulation, using genome-wide linkage approach. In the second study, we found a strong correlation between HDL-C and adiponectin, but failed to show evidence of a shared genetic background. However, a genetic correlation between adiponectin and low-density lipoprotein-cholesterol was revealed. We also studied the genetic regulation of adiponectin, and for the first time its most active form, high-molecular weight adiponectin, and found suggestive evidence of linkage to three chromosomal regions. In the third study, it was discovered that the studied VEGF gene polymorphisms did not have a major effect on atherosclerosis quantified as carotid intima-media thickness or the risk of acute myocardial infarction (AMI). This thesis presents potential regions for the genetic regulation of HDL-C and adiponectin and gives new information about their relationship and the effect of VEGF polymorphisms in atherosclerosis. The strong correlation between adiponectin and HDL-C was further strengthened, but we failed to show a shared genetic background between them. / Tiivistelmä Sepelvaltimotauti, eräs valtimonkovettumataudin ilmentymä, on yleisin yksittäinen kuolinsyy maassamme. Taudin syntyyn vaikuttavat lukuisat geneettiset ja ympäristötekijät sekä niiden väliset yhteis- ja vuorovaikutukset. Pieni HDL-kolesterolipitoisuus on valtimonkovettumataudin itsenäinen riskitekijä ja yleisin kolesterolipoikkeavuus, joka liittyy varhain ilmenevään sepelvaltimotautiin. HDL-kolesterolin vaihtelun syitä ja tämän "hyvän kolesterolin" sepelvaltimotaudilta suojaavia vaikutusmekanismeja ei kuitenkaan pystytä täysin selittämään. Adiponektiini on rasvakudoksen tuottama hormoni, jonka sepelvaltimotaudilta suojaavan ominaisuuden on ehdotettu johtuvan siitä, että se vaikuttaisi HDL-kolesterolin aineenvaihduntaan. VEGF (vascular endothelial growth factor) on verisuonten sisäseinämissä vaikuttava kasvutekijä, jolla saattaa olla joko sepelvaltimotaudilta suojaavia tai sille altistavia vaikutuksia. Väitöskirjatyön tavoitteena oli tutkia HDL-kolesterolin ja valtimonkovettumataudin geneettistä taustaa. Kolmessa osatyössä tutkittiin suuria pohjoissuomalaisia sepelvaltimotautisukuja; lisäksi käytettiin väestö- ja potilasaineistoja. Ensimmäisessä tutkimuksessa löydettiin koko genomin kytkentäkartoitusmenetelmällä seitsemän kromosomialuetta, jotka saattavat vaikuttaa HDL-kolesterolin säätelyyn. Toisessa tutkimuksessa selvitettiin adiponektiinin, ja ensimmäistä kertaa myös sen aktiivisimman muodon, HMW-adiponektiinin geneettistä taustaa. Kytkentäanalyysissä saatiin viitteitä kolmesta adiponektiineja mahdollisesti säätelevästä kromosomialueesta. Havaittiin myös, että HDL-kolesterolin ja adiponektiinin pitoisuudet korreloivat vahvasti keskenään, mutta yhteistä geneettistä säätelytekijää ei pystytty osoittamaan. LDL-kolesterolin ja adiponektiinin välillä kuitenkin havaittiin geneettinen korrelaatio. Kolmannessa tutkimuksessa todettiin, ettei tutkituilla VEGF-geenin nukleotidimuutoksilla todennäköisesti ole merkittävää syy-yhteyttä valtimonkovettumatautiin kaulavaltimoiden sisäseinämän paksuudella tai sydäninfarktiriskillä mitattuna. Tämä tutkimus tuo uutta tietoa HDL-kolesterolin ja adiponektiinin geneettisestä säätelystä ja niiden suhteesta sekä VEGF-geenin nukleotidimuutosten osuudesta valtimonkovettumataudissa. Tutkimus vahvistaa edelleen HDL-kolesterolin ja adiponektiinin yhteyden, muttei pysty osoittamaan niille yhteistä geneettistä tekijää.