Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Made available in DSpace on 2011-05-04T12:36:29Z (GMT). No. of bitstreams: 0 Previous issue date: 2009 / O aumento das taxas de incidência e mortalidade dos tumores do sistema nervoso central no Brasil e no mundo tem impulsionado a investigação de seus fatores etiológicos. As exposições ambientais, principalmente as ocupacionais, têm sido foco crescente destes trabalhos. Este estudo caso-controle de base hospitalar realizado na região metropolitana do Rio de Janeiro, entre 1999-2002, teve como objetivo identificar as associações entre ramos de atividade econômica e ocupações referidas com as neoplasias intracranianas em adultos, segundo subtipos histológicos gliomas emeningiomas. Foi analisada a história ocupacional de 239 casos e 267 controles, pareados por freqüência de sexo e idade, utilizando as classificações por ramos de atividades econômicas e por grupos ocupacionais. Os riscos foram estimados por regressão logística. Na análise por ramo de atividade, a Agricultura apresentou OR: 2,52(IC 95 por cento: 1,15 5,53) para o conjunto das neoplasias cerebrais. Além disso, Saúde e Social, Administração Pública e Educação apresentaram associação positiva sem significância estatística. Quanto aos meningiomas, observou-se risco em trabalhadores das áreas de Transporte (OR: 3,14, IC 95 por cento: 1,08 9,19) e Bens Imóveis (OR: 2,45, IC 95 por cento: 1,17 5,15). Em relação aos grupos ocupacionais, os agricultores apresentaram risco significativo: OR: 2,44 (IC 95 por cento: 1,14 5,18). Associação direta foi evidenciada nos grupos de Transporte / Produção de Equipamentos e Forças Armadas enquanto que Profissionais Técnicos e Trabalhadores com Vendas apresentaram associação inversa. A análise para gliomas mostrou risco para Empregados de Escritório: OR: 2,33 (IC 95 por cento: 1,02 5,29). Os achados sugerem que trabalhadores da agricultura, militares e profissionais de saúde apresentam risco para neoplasias intracranianas, demandando novas pesquisas para identificação de exposições específicas. / The increase of incidence and mortality taxes of brain tumors in Brazil and the world has stimulated the inquiry of its etiological factors. Environmental exposure, mainly the occupational ones, have been extensively focused in the studies. This case-control study of hospital base carried through in the metropolitan region of Rio de Janeiro, between 1999-2002, had as objective to identify associations between branches of economic activity and occupations related with brain tumors in adults, according to histological subtypes gliomas and meningiomas. It was analyzed the occupational history of 239 cases and 267 controls, matched by frequency of sex and age, using the classifications for branches of economic activities and occupational groups. The risks had been esteem by logistic regression. In the analysis for activity branch, Agriculture presented OR: 2,52 (CI 95%: 1,15 - 5,53) for brain tumors with no histological stratification. Moreover, Social and Health, Public Administration and Education had presented positive association without significance statistics. To meningiomas, it´s observed elevated risk in workers of the areas of Transport (OR: 3,14 CI 95%: 1,08 - 9,19) and Real Estate Activities (OR: 2,45, CI 95%: 1,17 - 5,15). In relation to the occupational groups, the agriculturists had presented significant risk: OR: 2,44 (CI 95%: 1,14 - 5,18). Direct association was evidenced in the groups of Transport/Production of Equipaments and Professional Armed Forces, whereas Technical Workers and Sell Workers had presented inverse association. The analysis for gliomas showed risk for Office Employees: OR: 2,33 (IC 95%: 1,02 - 5,29). The findings suggest that agriculture workers, military and health professionals present risk for brain tumors, demanding new researches for identification of specific expositions.

Methicillin-resistant Staphylococcus aureus (MRSA) is an antibiotic-resistant bacterium of epidemiologic importance in Canadian healthcare facilities. The contact between MRSA colonized or infected patients with other patients, healthcare workers (HCWs) and/or the healthcare environment can result in MRSA transmission and healthcare-associated MRSA (HA-MRSA) infections in hospitals. These HA-MRSA infections are linked with increased length of hospital stay, economic burden, morbidity and mortality. Although infection prevention and control programs initiated in 2009 in Canada and other developed countries (e.g., UK, France, Belgium, Denmark, etc.) have been relatively successful in reducing the rate of HA-MRSA infections, they continue to pose a threat to patients, especially to the more vulnerable in long term care and geriatric institutions. Historically, MRSA was a problem mainly in hospital settings but after mid-1990s new strains of MRSA have been identified among people without healthcare-related risks and have been classified as community-associated MRSA (CA-MRSA). Furthermore, the distinction between HA-MRSA and CA-MRSA strains is gradually waning due to both the introduction of HA-MRSA in communities, and the emergence of CA-MRSA strains in hospitals. The purpose of this thesis was to explore the feasibility of constructing healthcare networks to evaluate the role of healthcare providers (e.g., physicians) and places (e.g., patient rooms) in the transmission of MRSA in a large tertiary care facility. Method of investigation: a secondary data case-control study, using individual characteristics and network structure measures, conducted at The Ottawa Hospital (TOH) between April 1st, 2013 and March 31th, 2014. Results: It was feasible to build social networks in a large tertiary care facility based on electronic medical records data. The networks' size (represented by the number of vertices and lines) increased during the outbreak period (period 1) compared to the pre-outbreak period (period 0) for both groups and at all three TOH campuses. The calculated median degree centrality showed significant increase in value for both study groups during period 1 compared to period 0 for two of the TOH campuses (Civic and General). There was no significant difference between the median degree centrality calculated for each study group at the Heart Institute when compared for the two reference periods. The median degree centrality of the MRSA case group for period 0 showed no significant difference when compared to the same measure determined for the control group for all three TOH campuses. However, the median degree centrality calculated for period 1 was significantly increased for the control group compared to the MRSA case group for two TOH campuses (Civic and General) but showed no significant difference between the two groups from the Heart Institute. In addition, there was a correlation between the two network measures (degree centrality and eigenvector centrality) calculated to determine the most influential person or place in the MRSA case group networks. However, there was no correlation between the two network’s measures calculated for physicians included in MRSA case group networks. Conclusions: It is feasible to use social network analysis as an epidemiologic analysis tool to characterize the MRSA transmission in a hospital setting. The network's visible changes between the groups and reference periods were reflected by the network measures and supported also by known hospital patient movements after the outbreak onset. Furthermore, we were able to identify potential source cases and places just prior of the outbreak start. Unfortunately, we were not able to show the role of healthcare workers in MRSA transmission in a hospital setting due to limitations in data collection and network measure chosen (eigenvector centrality). Further research is required to confirm these study findings.

Les pneumonies chez l’enfant de moins de 5 ans restent à l’heure actuelle un enjeu majeur de santé publique. Afin d’étudier les agents étiologiques des pneumonies chez les enfants de moins de 5 ans dans les pays à revenu faible ou intermédiaire, une étude cas-témoins a été réalisée entre 2010 et 2014 dans cette population par le réseau Global Approach for Biological Research on Infectious Epidemics in Low Income Countries (GABRIEL). Notre travail s’est attaché à décrire la distribution des sérotypes de Streptococcus pneumoniae retrouvés dans la population de l’étude, d’évaluer la prévalence du virus infuenza et d’évaluer l’effet du virus sur la gravité de la pneumonie, et enfin d’étudier la fréquence des co-détections bactériennes et virales au niveau nasopharyngé ainsi que leur effet sur le risque de pneumonie. Les résultats montraient que la majorité des sérotypes pneumococciques retrouvés étaient inclus dans le vaccin pneumococcique conjugué 13-valent (PCV13) et suggèraient que les souches de S. pneumoniae retrouvées au niveau nasopharyngé et au niveau sanguin étaient identiques chez un même individu atteint de pneumonie. L’importance du virus influenza, et particulièrement d’influenza A H1N1 a été soulignée. Enfin, de nombreuses co-détections nasopharyngées de microorganismes étaient observées chez les cas mais aussi chez les témoins. Leur pathogénicité semblait différer selon les espèces et pourrait dépendre des interactions avec le microbiome du tractus respiratoire. Les résultats suggèraient que la mise en œuvre de campagnes de vaccination par PCV13 pourrait être efficace dans les pays étudiés. Néanmoins, de nouvelles études précisant le rôle des co-détections entre bactéries et virus dans la physiopathologie de la pneumonie sont nécessaires pour guider les décisions de santé publique de façon optimale / Pneumonia remains a public health issue in children under 5 years old. In order to study the etiological agents of pneumonia in this population, a case-control study was carried out between 2010 and 2014 by the Global Approach for Biological Research on Infectious Epidemics in Low Income Countries (GABRIEL) Network in 9 study sites located in 8 low or middle-income countries. The objectives of the present work were to describe the distribution of Streptococcus pneumoniae serotypes, to assess the burden of influenza virus and its effect on the severity of pneumonia, and to study bacterial/viral co-detection in nasopharyngeal samples and their effect on the risk of pneumonia. Results showed that most of S. pneumoniae serotypes detected were included in the pneumococcal 13-Valent conjugate vaccine (PCV13) and confirmed the assumption that the isolate carrying or causing disease in an individual were of the same serotype. The importance of the burden of influenza virus in pneumonia cases, and particularly A H1N1 influenza, was highlighted. Finally, numerous nasopharyngeal co-detections were found both in pneumonia cases and in control subjects. Pathogenicity of microorganisms differs between species and might depend of the interactions with the microbiome of the respiratory tract. Results suggested that the implementation of PCV13 vaccination policies might be effective in the study population. Nevertheless, further studies focused on the most important co-detections of micro-organisms are needed to improve the understanding of their role in the pathogenesis of pneumonia and to guide appropriate public health interventions

Introduction : Le cancer de l’ovaire est le cancer gynécologique le plus fatal dans le monde et est associé à un fardeau économique considérable pour les systèmes de santé publique, les patients et leurs familles. Actuellement, la prévention de ce cancer passe par l’identification des facteurs de risque, dont l’inflammation. Le double rôle de l’inflammation dans la carcinogenèse (transformation néoplasique et stimulation de la croissance pour l’inflammation chronique, mais également l’inhibition de la croissance pour inflammation aiguë) a déjà été observé au 19ième siècle, par Rudolf Virchow et par l’allemand Bruns, respectivement. Plusieurs preuves suggèrent aussi que le cancer de l’ovaire pourrait être lié à l’inflammation chronique de l’épithélium ovarien d’où l’hypothèse selon laquelle les analgésiques ayant une action anti-inflammatoire comme les anti-inflammatoires non stéroïdiens (AINS) et l’acétaminophène pourraient prévenir le cancer de l’ovaire. Contrairement à l’inflammation chronique, un autre facteur intéressant qui pourrait jouer un rôle sur le cancer de l’ovaire par le biais d’une inflammation aiguë est la mastite puerpérale qui est la forme la plus courante de mastite. Cependant, la littérature existante, examinant l’usage des analgésiques (aspirine, AINS non aspirine et acétaminophène) et le risque de cancer ovarien, est incohérente avec des différences populationnelles (cohortes de naissance différentes) et méthodologiques : variations des définitions de l’utilisation régulière, des variables d’ajustement, mais aussi dans la prise en compte d’une possible causalité inverse. De plus, aucune étude n’a tenté d’évaluer l’association dépendante du temps entre l’utilisation régulière de ces médicaments et le risque de cancer ovarien. Pour la mastite puerpérale pendant l’allaitement, deux articles avaient évalué son association avec le risque de cancer épithélial de l’ovaire (CEO), mais avec des limites méthodologiques : violation de la positivité avec l’inclusion des femmes qui n’ont jamais eu de grossesse et sur-ajustement avec la durée d’allaitement qui est dans le chemin causal. Objectif : Cette thèse visait à atteindre deux objectifs généraux qui sont de fournir de nouvelles preuves concernant les associations entre : 1) l’utilisation régulière d’analgésiques et le risque de CEO ; 2) la mastite puerpérale et le risque de CEO. Méthode : Nous avons utilisé les données d’une étude cas-témoin populationnelle visant à documenter les facteurs pour la prévention du cancer de l’ovaire au Québec (Étude PROVAQ). Cette étude a été menée dans la grande région de Montréal, Canada, de mars 2011 à septembre 2016 avec 498 cas et 908 témoins. Notre approche méthodologique a été effectuée en trois étapes. Premièrement, nous avons utilisé l’ensemble des données de PROVAQ pour l’évaluation des associations entre l’utilisation régulière de types de médicaments analgésiques, et aussi selon l’indication et le risque de CEO. Deuxièmement, à partir des données de PROVAQ, nous avons évalué l’association dépendante du temps entre l’utilisation régulière d’un type de médicaments et le risque de CEO à l'aide d'un indice cumulatif pondéré flexible d'exposition dans des modèles de régression logistique conditionnelle. Enfin, nous avons évalué l’association entre la mastite puerpérale et le risque de CEO chez les femmes allaitantes (174 cas et 431 témoins). La régression logistique a été utilisée pour estimer ces associations. Résultats : Nos résultats suggèrent que l'utilisation régulière d’aspirine et d'AINS non aspirine était inversement associée au CEO avec des rapports de cotes (RC) ajustés de 0,81 (IC à 95 % : 0,57–1,12) et 0,74 (IC à 95 % : 0,54–1,00), respectivement. Pour l'utilisation régulière d'AINS non aspirine, les RCs ajustés des COX-2 non sélective et sélective étaient de 0,73 (IC à 95 % : 0,50–1,00) et de 0,83 (IC à 95 % : 0,48–1,40), respectivement. Des associations similaires ont été observées selon le niveau de durée cumulative à vie ou de quantité cumulative à vie de prises d’aspirine et d’AINS non aspirine. Cependant, les associations entre les types de médicaments analgésiques et le CEO peuvent différer selon leurs indications. Aucune association n’a été trouvée entre le moment de l'utilisation régulière d’un type de médicaments analgésiques au cours des 40 années précédant la date index et le CEO. Aucune association significative n’a été aussi trouvée entre la mastite puerpérale pendant l'allaitement et le CEO (RC = 1,15 ; IC à 95 % : 0,71–1,84). Conclusions : Cette thèse fournit des preuves qui appuient l'hypothèse selon laquelle l'utilisation régulière d'aspirine et d'AINS non aspirine sont inversement associées au CEO. Nos résultats suggèrent également l'importance de considérer les indications d'utilisation lors de l'examen des relations entre les types de médicaments analgésiques et le CEO. Elle n’a pas trouvé d'association entre le moment de l'utilisation régulière d’analgésiques et le CEO mais aussi entre la mastite puerpérale pendant l’allaitement et le CEO. Cependant, notre étude a manqué de puissance. / Introduction: Ovarian cancer is the most fatal gynecological cancer in the world and is associated with a considerable economic burden for public health systems, patients and their families. Currently, the prevention of this cancer requires the identification of risk factors including inflammation. The dual role of inflammation in carcinogenesis (neoplastic transformation and stimulation of cancer growth for chronic inflammation, but also inhibition of cancer growth for acute inflammation) has already been observed in the 19th century, by Rudolf Virchow and by the German Bruns, respectively. Several pieces of evidence also suggest that ovarian cancer could be linked to chronic inflammation of the ovarian epithelium, hence the hypothesis that analgesics with an anti-inflammatory action such as nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen could prevent ovarian cancer. Unlike chronic inflammation, another interesting factor that could play a role in ovarian cancer through acute inflammation is puerperal mastitis which is the most common form of mastitis. However, the existing literature examining the use of analgesics (aspirin, non-aspirin NSAIDs and acetaminophen) and the risk of ovarian cancer is inconsistent with population (different birth cohorts) and methodological differences: variations in definitions of regular use, adjustment variables but also in taking into account a possible reverse causality. In addition, no studies have attempted to assess the time-dependent association between regular use of these drugs and the risk of ovarian cancer. For puerperal mastitis during breastfeeding, two articles had assessed its association with the risk of epithelial ovarian cancer (EOC) but with methodological limitations: violation of positivity with the inclusion of women who never had of pregnancy and over-adjustment with the duration of breastfeeding which is in the causal path. Objective: This thesis aimed to achieve two general objectives which are to provide new evidence regarding the associations between: 1) the regular use of analgesics and the risk of EOC; 2) puerperal mastitis and the risk of EOC. Method: We used data from a population-based case-control study aimed at documenting factors for the prevention of ovarian cancer in Quebec (PROVAQ study). This study was conducted in the greater Montreal area, Canada, from March 2011 to September 2016 with 498 cases and 908 controls. Our methodological approach was carried out in three stages. First, we used the PROVAQ dataset to assess associations between regular use of analgesic drugs types, and also by indication and EOC risk. Second, from PROVAQ data, we evaluated the time-dependent association between regular use of a type of medication and the risk of EOC using a flexible weighted cumulative index of exposure in conditional logistic regression models. Finally, we evaluated the association between puerperal mastitis and the risk of EOC in lactating women (174 cases and 431 controls). Unconditional logistic regression was used to estimate associations between regular use of analgesic drugs types, puerperal mastitis during breastfeeding and EOC risk. Results: Our results suggest that regular use of aspirin and non-aspirin NSAIDs were inversely associated with EOC with adjusted ORs of 0.81 (95% CI: 0.57–1.12) and 0.74 (95% CI: 0.54–1.00), respectively. For regular non-aspirin NSAID use, the adjusted ORs for non-selective and selective COX-2 were 0.73 (95% CI: 0.50–1.00) and 0.83 (95% CI: 0.48–1.40), respectively. Similar associations were observed according to the level of lifetime cumulative duration or lifetime cumulative quantity of aspirin and non-aspirin NSAID. However, the associations between analgesic drug types and EOC may differ according to their indications. No association was found between the time of regular use of any type of analgesic medication in the 40 years prior to the index date and EOC. No significant association was also found between puerperal mastitis during breastfeeding and EOC (OR = 1.15; 95% CI: 0.71–1.84). Conclusions: This thesis provides evidence that supports the hypothesis that regular use of aspirin and non-aspirin NSAIDs are inversely associated with EOC. Our results also suggest the importance of considering indications for use when examining relationships between analgesic drug types and EOC. We found no association between the timing of regular analgesic use and EOC but also between puerperal mastitis during breastfeeding and EOC. However, our study was underpowered.

Abstract Oral lichen planus (OLP) is a chronic immune-mediated mucosal disease with unknown etiology. According to the current view, the pathogenesis of OLP involves activation of T-cell mediated immunity against the epithelial keratinocytes. A proportion of OLP patients are affected by painful symptoms, and the risk of oral cancer is increased in OLP. There is no curative treatment for OLP. Topical corticosteroids are used most commonly in the management of OLP. However, the evidence base for the effectiveness of any therapy is weak. The objective of this thesis was to study novel aspects of OLP etiopathogenesis and management. An epidemiologic, retrospective case-control study was conducted to determine whether systemic diseases, in particular thyroid diseases, are associated with OLP. In addition, a randomized controlled trial comparing the effectiveness of topical tacrolimus, triamcinolone acetonide and placebo in symptomatic OLP was carried out. Furthermore, immunohistochemical expression of toll-like receptors 4 and 9, hyaluronan and its principal receptor CD44 antigen, hyaluronan synthases 1-3, hyaluronidases 1-2 and cathepsin K was studied in OLP tissue samples and in healthy oral mucosa. The effect of topical tacrolimus on the expression of these molecules in OLP was also studied. The results of the present study showed that a history of hypothyroidism was associated with an approximately twofold risk of having OLP. Furthermore, both tacrolimus and triamcinolone acetonide were more efficient than placebo in reducing the signs and symptoms of OLP. No statistically significant differences were noted in the efficacy between tacrolimus and triamcinolone acetonide. In addition, the expression of the studied molecules was altered in the epithelium or stroma in OLP compared to healthy oral mucosa. Tacrolimus treatment decreased the expression of CD44 antigen in the stroma and the expression of cathepsin K in the epithelium in OLP. In conclusion, the present study extends our knowledge about systemic associated factors and management of OLP. In addition, the results improve our understanding of molecular level changes that occur in OLP. / Tiivistelmä Suun punajäkälä on krooninen immuunivälitteinen limakalvotauti, jonka etiologia on tuntematon. Taudin syntymekanismiin liittyy tämän hetkisen näkemyksen mukaan T-soluvälitteisen immuniteetin aktivoituminen epiteelin keratinosyyttejä vastaan. Suun punajäkälä aiheuttaa osalle potilaista kivuliaita oireita ja lisää suusyövän riskiä. Parantavaa hoitoa tautiin ei ole. Yleisimmin suun punajäkälän oireiden hoidossa käytetään paikallisia kortikosteroidivalmisteita. Kuitenkin eri hoitomuotojen tehosta on vain heikkoa näyttöä. Tämän väitöskirjatyön tarkoituksena oli tutkia uusia näkökohtia liittyen suun punajäkälän etiopatogeneesiin ja hoitoon. Epidemiologisessa tapaus-verrokkitutkimuksessa selvitettiin, liittyvätkö yleissairaudet, erityisesti kilpirauhassairaudet, suun punajäkälään. Lisäksi satunnaistetussa kontrolloidussa tutkimuksessa verrattiin paikallisen takrolimuusin, triamsinoloniasetonidin ja lumelääkkeen tehoa oireisesta suun punajäkälästä kärsivillä potilailla. Tutkimuksessa selvitettiin myös tollin kaltaisten reseptorien 4 ja 9, hyaluronaanin ja sen pääasiallisen reseptorin CD44-antigeenin, hyaluronaanisyntaasien 1–3, hyaluronidaasien 1–2 sekä katepsiini K:n immunohistokemiallista ilmentymistä suun punajäkälänäytteissä ja terveessä suun limakalvossa. Lisäksi tutkittiin takrolimuusihoidon vaikutusta näiden molekyylien ilmentymiseen suun punajäkälässä. Tämän tutkimuksen tulokset osoittivat, että kilpirauhasen vajaatoimintaan liittyi noin kaksinkertainen riski sairastaa suun punajäkälää. Lisäksi havaittiin, että suun punajäkälässä sekä takrolimuusi että triamsinoloniasetonidi ovat tehokkaampia kuin lumelääke oireiden ja kliinisen taudinkuvan lievittämisessä. Takrolimuusin ja triamsinoloniasetonidin tehossa ei todettu tilastollisesti merkitseviä eroja. Lisäksi suun punajäkälänäytteissä tutkittujen molekyylien ilmentyminen oli muuttunut joko epiteelissä tai stroomassa verrattuna terveeseen limakalvoon. Takrolimuusihoito vähensi CD44-antigeenin ilmentymistä stroomassa ja katepsiini K:n ilmentymistä epiteelissä suun punajäkälässä. Yhteenvetona voidaan todeta, että tämä tutkimus lisää tietoa suun punajäkälään liittyvistä systeemisistä tekijöistä ja suun punajäkälän hoidosta. Lisäksi löydökset lisäävät ymmärtämystä suun punajäkälässä tapahtuvista molekyylitason muutoksista.

Ankylosing spondylitis (AS) is a common inflammatory arthritis of the spine and other affected joints, which is highly heritable, being strongly influenced by the HLA-B27 status, as well as hundreds of mostly unknown genetic variants of smaller effect. The aim of my research was to confirm some of the previously observed genetic associations and to identify new associations, many of which are in biological pathways relevant to AS pathogenesis, most notably the IL-23/T_H17 axis (IL23R) and antigen presentation (ERAP1 and ERAP2). Studies presented in this thesis include replication and refinement of several potential associations initially identified by earlier GWAS (WTCCC-TASC, 2007 and TASC, 2010). I conducted an extended study of IL23R association with AS and undertook a meta-analysis, confirming the association between AS and IL23R (non-synonymous SNP rs11209026, p=1.5 x 10-9, OR=0.61). An extensive re-sequencing and fine mapping project, including a meta-analysis, to replicate and refine the association of TNFRSF1A with AS was also undertaken; a novel variant in intron 6 was identified and a weak association with a low frequency variant, rs4149584 (p=0.01, OR=1.58), was detected. Somewhat stronger associations were seen with rs4149577 (p=0.002, OR=0.91) and rs4149578 (p=0.015, OR=1.14) in the meta-analysis. Associations at several additional loci had been identified by a more recent GWAS (WTCCC2-TASC, 2011). I used in silico techniques, including imputation using a denser panel of variants from the 1000 Genomes Project, conditional analysis and rare/low frequency variant analysis, to refine these associations. Imputation analysis (1782 cases/5167 controls) revealed novel associations with ERAP2 (rs4869313, p=7.3 x 10-8, OR=0.79) and several additional candidate loci including IL6R, UBE2L3 and 2p16.3. Ten SNPs were then directly typed in an independent sample (1804 cases/1848 controls) to replicate selected associations and to determine the imputation accuracy. I established that imputation using the 1000 Genomes Project pilot data was largely reliable, specifically for common variants (genotype concordence~97%). However, more accurate imputation of low frequency variants may require larger reference populations, like the most recent 1000 Genomes reference panels. The results of my research provide a better understanding of the complex genetics of AS, and help identify future targets for genetic and functional studies.