Background and AimThe marked inter-individual variability in warfarin dose requirement is mainly attributed to the variants of the main target genes across the warfarin pharmacological pathway, i.e. ...cytochrome P-450 (CYP) 2C9, CYP3A4, ABCB1, vitamin K epoxide reductase complex subunit 1 (VKORC1) and epoxide hydrolase 1 (EPHX1). The expression of these genes is primarily regulated by a complex network of nuclear receptors (NR) which are encoded, in turn, by polymorphic genes. Furthermore, microRNAs (miRNA) can reduce the expression of both warfarin target genes and the genes encoding NRs. We investigated whether the variants of genes encoding i) warfarin targets, ii) NRs involved in the regulation of the targets and iii) miRNA involved in the regulation of NRs and the targets, are associated with warfarin dose requirements.Methods and ResultsThe study was performed using the Quebec Warfarin Cohort consisting of 988 new warfarin users who were recruited over a period of 3 years and were followed-up for 12 months. The candidate genes were selected according to the literature and included 5 warfarin target genes, 9 NRs genes and 29 miRNA genes. SNPs with MAF>0.01 within these genes were selected for the present study from the NCBI database. Genotyping was previously performed using Omni 2.5 array (Illumina, CA) and iPLEX ADME CYP2C9/VKORC1 panel (Agena, CA) and missing SNPs were imputed. We tested the effect of SNPs on the log-transformed values of dose at 3-month post-initiation using multivariate linear regression analysis, and the adjusted significance threshold was set to 2.49 x 10-4. A total of 3970 SNPs, including 702 in target genes, 3162 in NRs and 106 in miRNA genes were studied. For the association with warfarin dose, 137 SNPs in CYP2C9 and VKORC1 were significant, as well as 3 SNPs in nuclear vitamin D receptor (VDR) geners4760658, β = -0,0852, P = 7,32x10-5; rs11168293, β = -0,0809, P = 1,78x10-4; rs4760655, β = -0,0799, P = 2,15x10-4. None of the variants in miRNA genes showed a significant association with warfarin dose.ConclusionsVariants in the gene encoding VDR, a nuclear receptor which has been previously shown to be involved in the regulation of CYP2C9, CYP3A4 and ABCB1, may contribute to the variability in response to warfarin.
RESULTS: The PAIR criteria include 50 DRPs grouped into 6 categories. A mean of 2.5 DRPs/ patient (95% CI: 2.0 to 3.1) were identified. Interraters reliability coefficients (kappa) by category varied ...from 0.8 to 1.0 with an intra-class correlation coefficient (ICC) of 0.93 (95% CI: 0.89 to 0.95) for the total DRPs/patient. Test-retest reliability coefficients by category varied from 0.74 to 1.00 with an ICC of 0.91 (95% CI: 0.82 to 0.96) for the total DRPs/ patient. A total of 3.5 DRPs/patient were identified by consensual evaluation based on implicit judgments.
Genetic studies, such as linkage and association studies, have contributed greatly to a better understanding of the etiology of several diseases. Nonetheless, despite the tens of thousands of genetic ...studies performed to date, a large part of the heritability of diseases and traits remains unexplained. The last decade experienced unprecedented progress in genomics. For example, the use of microarrays for high-density comparative genomic hybridization has demonstrated the existence of large-scale copy number variations and polymorphisms. These are now detectable using DNA microarray or high-throughput sequencing. In addition, high-throughput sequencing has shown that the majority of variations in the exome are rare or unique to the individual. This has led to the design of a new type of DNA microarray that is enriched for rare variants that can be quickly and inexpensively genotyped in high throughput capacity.In this context, the general objective of this thesis is the development of methodological approaches and bioinformatics tools for the detection at the highest quality standards of copy number polymorphisms and rare single nucleotide variations. It is expected that by doing so, more of the missing heritability of complex traits can then be accounted for, contributing to the advancement of knowledge of the etiology of diseases.We have developed an algorithm for the partition of copy number polymorphisms, making it feasible to use these structural changes in genetic linkage studies with family data. We have also conducted an extensive study in collaboration with the Wellcome Trust Centre for Human Genetics of the University of Oxford to characterize rare copy number definition metrics and their impact on study results with unrelated individuals. We have conducted a thorough comparison of the performance of genotyping algorithms when used with a new DNA microarray composed of a majority of very rare genetic variants. Finally, we have developed a bioinformatics tool for the fast and efficient processing of genetic data to increase quality, reproducibility of results and to reduce spurious associations.
Left ventricular outflow tract obstruction (LVOTO) is a wide spectrum of congenital heart defects ranging from bicuspid aortic valve to hypoplastic left heart syndrome. Increasing knowledge suggests ...a strong contribution of genetic factors in this disease spectrum.
We have recruited a large cohort of multiplex families with LVOTO. All individuals gave informed consent and underwent physical exam, ECG and echocardiography. We have chosen 45 highly informative families and 23 trios for analysis of linkage and structural genomic variation using high-density genotyping (total cohort n = 450, affected = 217). To confidently call copy number variants, a phenotyped control cohort with 1900 members was used.
In the 68 families analyzed to date, only one family with a clear Mendelian segregation pattern was identified. This family exhibits a novel X-linked syndrome with atrial septal defects, aortic valve disease, coarctation and atrial fibrillation. Significant linkage to Xq28 could be demonstrated, with a founder effect in a geographically confined area. In the cohort as a whole, significant linkage to chromosome 6q24 was found, defining an 8 Mb critical interval devoid of any obvious biological candidates and without any founder haplotypes. The analysis of copy number variants reveals 33 candidate loci in a highly complex pattern of inherited and de novo variants, 2/3 of which are gains.
We provide a comprehensive high-density scan of LVOTO and identify linkage to two novel candidate loci in the French-Canadian population. Detailed haplotype analyses show conservation in a subset of families. Several layers of genetic factors most likely co-exist within this cohort, with structural genomic variation explaining the majority of phenotypic variability. These results pave the way towards a better definition of the causal genes and gene-gene interactions in LVOTO.
Tableau d'honneur de la Faculté des études supérieures et postdoctorales, 2011-2012
Ce mémoire porte sur les groupes d'homotopie des sphères Sn. Plus précisément, on s'intéresse à la méthode des ...suites spectrales développée d'abord par Jean-Pierre Serre puis rafinée par la suite par d'autres mathématiciens tels que Frank Adams. On expose dans un premier temps les concepts inhérents aux suites spectrales et on introduit ensuite celles-ci pour enfin démontrer certains résultats classiques. Le premier théorème d'importance est que πk(Sn) est fini sauf si k = n ou si n paire et k = 2n — 1. Dans ce dernier cas, on a que π 4n-i(S2n) sont des groupes de type fini avec une seule composante Z. On obtient ensuite un contrôle modeste sur la p-torsion : le premier élément de p-torsion des groupes d'homotopie de Sn apparaissent en dimension n + 2p — 3 où la p-composante est Zp. On utilise enfin l'algèbre de Steenrod pour reproduire certains calculs explicites de groupes d'homotopie effectués par Jean-Pierre Serre : πn+1(Sn) = Z2, (n > 3), πn+2(Sn) = Z2 (n > 2), π6(S3) = Z12 et π7(S4) = Z 0 Z12.
Introduction: Lors de l'élaboration des modèles de dynamiques de transmission du virus du papillome humain (VPH), différentes hypothèses sont émises pour simplifier les aspects complexes et peu ...compris de la transmission. Dans cette thèse, on s'intéresse à deux limites de ces modèles: 1) la transmission du VPH entre différents sites n'est pas modélisée, 2) les changements dans l'activité sexuelle à travers le temps sont ignorés. Les changements dans l'activité sexuelle au cours du dernier siècle pourraient être l'une des causes de l'augmentation des cancers de l'oropharynx des quatre dernières décennies. Cependant, notre compréhension des tendances des cancers reliés au VPH est entravée par le manque de connaissance des patrons de contacts sexuels. Un tel type de patron, l'assortativité, pourrait produire de la confusion dans les études épidémiologiques portant sur les facteurs de risques du VPH. Les objectifs de cette thèse sont 1) d'évaluer l'impact d'inclure la transmission multi-site du VPH dans un modèle sur les prédictions d'efficacité populationnelle du vaccin VPH, 2) d'examiner comment les changements dans l'activité sexuelle ont pu influencer les tendances des cancers de l'oropharynx (CO) et du col de l'utérus (CU) depuis les années 1970, et de prédire les tendances futures de ces cancers, 3) déterminer les conditions sous lesquelles l'assortativité pourrait causer un biais dans les études évaluant la causalité des facteurs de risques des infections transmissibles sexuellement et quantifier la magnitude de ce biais. Méthodes : Pour le premier objectif, nous avons développé un modèle de transmission du VPH multi-site (sites génital et extra-génital) et uni-site (site génital). Avec ces modèles, nous avons estimé la réduction relative de la prévalence du VPH au site génital après la vaccination (RRindice prev). Nous avons considéré deux types d'immunité naturelle : site-spécifique et systémique. Pour le deuxième objectif, nous avons développé un modèle mathématique individus-centré simulant la transmission du VPH16, la progression du VPH16 vers le cancer (CO et CU) et les comportements sexuels des américains nés entre 1850 et 1999. Nous avons calibré ce modèle et réalisé des simulations de l'incidence de CO et CU entre 1915 et 2045. Pour le troisième objectif, nous avons développé un modèle de transmission du VPH avec stratification pour deux niveaux d'activité sexuelle (élevé et faible) et de tabagisme (fumeur et non-fumeur). On a supposé dans ce modèle que le tabagisme n'était pas une cause biologique d'infection au VPH, et que le choix du partenaire sexuel est assortatif au statut fumeur. Nous avons simulé une étude fictive dans laquelle nous avons estimé le rapport de cotes (RC) de la prévalence d'infection VPH entre fumeurs et non-fumeurs. La magnitude du biais se mesurait par l'écart entre le RC et la valeur nulle (1,00). Résultats : Pour l'objectif 1, le modèle multi-site prédisait un RRindice prev supérieur à celui estimé par le modèle uni-site quand l'immunité était site-spécifique, et inférieur quand l'immunité était systémique. La magnitude de la transmission entre les sites génital et extra-génital était un facteur expliquant la variance du RRindice prev. Pour l'objectif 2, notre modèle a prédit, en absence de dépistage du CU, une augmentation importante de l'incidence de CU d'au moins 120% entre 1975 et 2015. Pour le cancer de l'oropharynx relié au VPH16, le modèle a prédit une augmentation d'au moins 310% entre 1985 et 2015, et d'environ 50% entre 2015 et 2045. Pour l'objectif 3, nous avons obtenu un RC de 1,51 après ajustement parfait du niveau d'activité sexuel des sujets de l'étude. Une plus grande assortativité dans le choix du partenaire sexuel causait une augmentation de la magnitude du biais. Conclusion : Étant donné les connaissances actuelles dans le domaine du VPH, il semble peu probable que les prédictions d'efficacité populationnelle de la vaccination contre le VPH faites avec un modèle uni-site soient significativement biaisées. Cependant, l'utilisation d'un modèle multi-site nous a permis de reproduire les changements de comportements sexuels, d'expliquer les tendances de CO observées depuis les années 1980 et de prédire une augmentation future dans l'incidence de CO. Toutefois, cette augmentation future ne pourra pas être prévenue par la vaccination car elle touche surtout des hommes nés avant 1990, qui n'ont pas été vaccinés. Finalement, le rôle du tabagisme dans l'acquisition du VPH demeure incertain dû au biais d'assortativité que nous avons identifié.
Introduction: Dynamic models of HPV transmission have been the main tool to estimate the effectiveness and cost-effectiveness of different vaccination strategies. We focus on two limitations of these models: transmission of HPV across different sites (e.g., oral and anal) and changes in sexual behavior across birth cohorts are not modelled. Firstly, including multi-site transmission of HPV could affect estimates of effectiveness against genital diseases. Secondly, changes in sexual behavior throughout the last century could be causally related to the increase in oropharyngeal and anal cancers in the past four decades. Understanding these trends is hindered by our poor knowledge of sexual mixing patterns. One such pattern, assortative mixing, could cause confounding in epidemiological studies of HPV risk factors. The objectives of this thesis are to 1) Assess the impact of including multi-site transmission to current uni-site HPV models on predictions of the population-level effectiveness of HPV vaccination. 2) Examine how changes in specific aspects of sexual behavior such as mixing, rates of new partner acquisition, sexual practices, age of sexual debut, may have impacted trends in HPV-related oropharyngeal and cervical cancer incidence since the 1970s, and predict future trends in these cancers. 3) Determine conditions under which assortative mixing could cause bias in studies examining the causal role of risk factors of STIs and quantify the magnitude of this potential bias. Methods: For the first objective, we developed a multi-site (genital and extragenital sites) and a uni-site (genital site) model of HPV transmission. We estimated the reduction in genital HPV prevalence at equilibrium post-vaccination and compared the estimates of the two models. We considered two types of natural immunity: local (i.e., protects against subsequent infection at the same site) and systemic. For the second objective, we developed an individual-based model of HPV transmission at the genital and oral sites. We reproduced in this model the changes in sexual behavior from 1900 to 2015 in the US population, and simulated the incidence of HPV16-related oropharyngeal and cervical cancers between 1915 and 2045. We performed these simulations according to different scenarios regarding the practice of oral sex, the inclusion of oral infections, and the reporting bias in the number of sexual partners in surveys. Results of the simulations were compared with empirical data on HPV-related cancers. For the third objective, we developed a model of HPV transmission with stratifications for two levels of sexual activity and of smoking habits (smokers and non-smokers). In our simulation, smoking was not a biological cause of HPV infection. We then estimated the odds ratio of prevalent HPV infection between smokers and non-smokers. Deviation from the null value could only be due to a bias we termed assortativity bias. Results: For objective 1, multi-site model predicted higher vaccination effectiveness when natural immunity was local, and lower or equal effectiveness when natural immunity was systemic. Three important factors were identified to increase effectiveness predicted with the multi-site model: 1) higher proportion of genital infections caused by an extragenital infection, 2) lower proportion of extragenital infections caused by a genital infection, 3) higher proportion of susceptibles to extragenital infection. For objective 2, we predicted a sharp increase (IRR=220%-380%) between 1975 and 2015 in the simulations of cervical cancer incidence without cervical screening. The increase was lowest when assuming women under-report their number of sexual partners in surveys. In simulations of oropharyngeal cancer incidence, including past changes in the practice of oral sex produced a sharp increase between 1985 and 2015 similar to the observed US trends. Future incidence of oropharyngeal cancer was predicted to increase by 50% between 2015 and 2045. For objective 3, we obtained an OR of 1.51 after perfect adjustment for subjects' level of sexual activity. The non-biased OR for this simulation was 1.00. The magnitude of the bias, as measured by the deviation from the null value, increased with stronger association between sexual activity and smoking habits and with greater degree of assortativity with respect to smoking habits. Conclusion: The assumptions of natural immunity being local and of extragenital infections being an important reservoir for genital infections are not currently supported by evidences. Hence, a significant bias in estimates of vaccination effectiveness against genital infections and diseases from the use of uni-site models appears unlikely. However, using a multi-site model and including the practice of oral sex is necessary to reproduce trends in oropharyngeal cancer since the 1980s. Furthermore, the increase in oropharyngeal cancer is predicted to continue over the next three decades, affecting mainly unvaccinated men born before 1990. In addition, we predict that cervical screening prevented a sharp increase in cervical cancer in the past decades. Finally, the role of smoking in the acquisition and duration of HPV infection remains uncertain due to biases such as the assortativity bias.
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