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Discovering the associations between genetic variables and disease status can help reduce the burden of disease on society. This thesis focuses on the methods required to detect maternal genetic effects (an effect where the genes of the mother affect the disease risk of the child) and interaction effects between these maternal genes and environmental variables in trio data consisting of parents and an affected child. A simulation study was conducted to determine the extent to which testing for these effects is affected by violations to the mating symmetry assumption required for two current methods when control parents are not available.. This study showed that methods for maternal effect estimation are not robust to these violations; however, the interaction test is robust to the violation. Finally, a candidate gene study on orofacial clefts was conducted to evaluate maternal gene-environment interactions in international consortium data. Significant effects were found but the large magnitude of the effect estimates raises concerns about the validity of the results. This thesis tries also discusses the lack of methods and software available to estimate maternal gene environment interactions.

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No description available.

Circulating concentrations of vitamin D metabolites are associated with risk for a variety of diseases, including colorectal cancer. It is not known what level of circulating 25(OH)D is optimal for health; however, over-the-counter (OTC) vitamin D supplements are commonly used to improve status, though their effectiveness is unknown. It is also not known if polymorphic variation in genes associated with the vitamin D endocrine system is associated with differences in vitamin D metabolite levels or colorectal neoplasia.METHODS: A double-blind, randomized, placebo-controlled trial examined the effect of 400 IU OTC cholecalciferol on circulating concentrations of 25(OH)D. Associations between polymorphic variation in VDR, RXRA, GC, and CASR and circulating vitamin D metabolites or colorectal neoplasia were examined through analysis of the Ursodeoxycholic Acid (UDCA) and Wheat Bran Fiber (WBF) clinical trial data. A single nucleotide polymorphism (SNP) tagging approach was employed and a total of 42 VDR, 32 RXRA, 35 CASR and 25 GC tagSNPs were analyzed.RESULTS: The net change in serum 25(OH)D in the supplement versus placebo group was 2.3 ng/ml (8.5% change, P = 0.06). Principal components analyses revealed gene-level associations between RXRA and serum 1,25(OH)2D concentrations (p = 0.01) as well as GC and 25(OH)D concentrations (p < 0.01). Seven individual GC polymorphisms were significantly associated with circulating measures of 25(OH)D in addition to CASR polymorphism rs1042636 and proximal colorectal neoplasia (p-value =0.02), following a multiple comparisons adjustment. The CART analysis identified rs17467825 as predictive of continuous measures of 25(OH)D. GC polymorphisms rs1555563, rs7041, and rs222029 were identified as significantly predictive of the 25 ng/ml threshold for insufficiency.CONCLUSION: The results demonstrate that daily 400 IU OTC cholecalciferol is sufficient to maintain baseline concentrations of 25(OH)D in healthy adults, but not to significantly increase levels in all individuals. The results also identified polymorphisms in RXRA, GC, and CASR associated with or that predict vitamin D metabolite levels or colorectal neoplasia risk. The results justify further investigation on the optimal vitamin D supplementation dose for the general population and genetic variation that may be related to circulating concentrations of vitamin D metabolites or colorectal neoplasia.

Gene-environment interactions are an area of increasing interest in complex hu- man diseases. The first step in any study of the interactions between genes and the environment involves identifying genes which influence the trait of interest. In this dissertation, a new method for using the information in complex pedigrees to per- form a joint linkage disequilibrium and linkage mapping of quantitative trait loci is developed. Subsequently, methods are needed to determine the interaction, if any, between these genes and environmental risk factors. Many of these factors, such as weight or age, are continuous and little is known about their distributions. Thus, we introduce a new method for estimating the gene-environment interaction parameters in a logistic regression for the case-control study design. In doing so, we make the assumption that in the underlying population, the distributions of the genetic factors and the environmental covariates are independent. Additionally, we treat the envi- ronmental parameters nonparametricly, utilizing the profile likelihood. Furthermore, the methodology we develop is also general enough to be used on many different types of genetic information, including haplotypes, and can accommodate missing genotype data. The method is also extended to allow analysis in the presence of population stratification or genotype misclassification. We show that the standard errors of pa- rameter estimates using our method are smaller than those found using complete data only. These methods are illustrated using simulations and are applied to a real data set exploring the interaction between genotype and environment in disease risk.

Psoriatic Arthritis (PsA) is an inflammatory arthritis associated with psoriasis that leads to progressive joint damage. Genetic variants in the Major Histocompatibility Complex (MHC) region on human chromosome 6p, especially Human Leucocyte Antigen (HLA), are the most important genetic risk variants associated with susceptibility to PsA. I aimed to investigate the heritability of PsA and to determine the association between HLA polymorphisms with susceptibility and severity of PsA. I first validated the new CASPAR classification criteria for PsA in patients in with both early and established disease. Subsequently, I demonstrated that PsA as defined by the CASPAR criteria has a high recurrence risk ratio. In a large case-control and family-based association study, I demonstrated that the class I HLA alleles, HLA-C*12/B*38, -B*27 and -C*06/B*57 are associated with increased susceptibility to PsA. HLA class I molecules biologically interact with Killer-cell Immunoglobulin-like Receptors (KIR) on Natural Killer (NK) to influence immune response. I demonstrated that KIR2DS2 and HLA C group 2 and HLA-B Bw4 were associated with PsA susceptibility. Further analyses of PsA cases with Type II psoriasis and with dactylitis suggested that HLA-C*02, -B*27, -B*38 and KIR2DS2 may be markers of musculoskeletal manifestations of PsA. Furthermore, using longitudinal data, I demonstrated that HLA-B*39, -B*27, -A*02 and KIR3DS1 are associated with peripheral joint damage progression whereas the alleles –DQB1*0604, -C*04 and –B*60 are associated with less damage progression. HLA-C*02, -C*12, -DQB1*0609 and KIR2DS1 are associated with higher risk of sacroiliitis, and HLA-B*27 with syndesmophytes. HLA-A*29 was associated with reduced risk of development of both sacroiliitis and syndesmophytes. These studies indicate that HLA alleles and KIR genes are important in PsA susceptibility and severity and suggest that CD8+ T cells and NK cells that modulate the innate and adaptive immune response play an important role in the susceptibility and severity of PsA.

Psoriatic Arthritis (PsA) is an inflammatory arthritis associated with psoriasis that leads to progressive joint damage. Genetic variants in the Major Histocompatibility Complex (MHC) region on human chromosome 6p, especially Human Leucocyte Antigen (HLA), are the most important genetic risk variants associated with susceptibility to PsA. I aimed to investigate the heritability of PsA and to determine the association between HLA polymorphisms with susceptibility and severity of PsA. I first validated the new CASPAR classification criteria for PsA in patients in with both early and established disease. Subsequently, I demonstrated that PsA as defined by the CASPAR criteria has a high recurrence risk ratio. In a large case-control and family-based association study, I demonstrated that the class I HLA alleles, HLA-C*12/B*38, -B*27 and -C*06/B*57 are associated with increased susceptibility to PsA. HLA class I molecules biologically interact with Killer-cell Immunoglobulin-like Receptors (KIR) on Natural Killer (NK) to influence immune response. I demonstrated that KIR2DS2 and HLA C group 2 and HLA-B Bw4 were associated with PsA susceptibility. Further analyses of PsA cases with Type II psoriasis and with dactylitis suggested that HLA-C*02, -B*27, -B*38 and KIR2DS2 may be markers of musculoskeletal manifestations of PsA. Furthermore, using longitudinal data, I demonstrated that HLA-B*39, -B*27, -A*02 and KIR3DS1 are associated with peripheral joint damage progression whereas the alleles –DQB1*0604, -C*04 and –B*60 are associated with less damage progression. HLA-C*02, -C*12, -DQB1*0609 and KIR2DS1 are associated with higher risk of sacroiliitis, and HLA-B*27 with syndesmophytes. HLA-A*29 was associated with reduced risk of development of both sacroiliitis and syndesmophytes. These studies indicate that HLA alleles and KIR genes are important in PsA susceptibility and severity and suggest that CD8+ T cells and NK cells that modulate the innate and adaptive immune response play an important role in the susceptibility and severity of PsA.

This work describes the characterization of the CAN1 gene, thought to encode the arginine permease of yeast. I have identified the RNA transcript of this gene and obtained the DNA sequence, which specifies a highly hydrophobic protein with multiple potential membrane-spanning domains. I use a gene fusion approach to identify sequences within the CAN1 protein that can translocate adjacent sequences across the E.R. membrane in vitro and extend these observations by finding that the topology of E.R. insertion is conserved up to the plasma membrane in vivo. Using a series of CAN1 gene fusions to the secreted yeast killer toxin, I find that the pathway of membrane protein export to the cell surface need not be functionally distinct from that of secreted proteins. Finally, I describe a mutation in the CAN1 gene that leads to altered rates of lysine uptake and results in growth inhibition and rapid plasmid loss in the presence of lysine.

Mémoire (M.Sc.)-- Université du Québec à Chicoutimi, 1992. / Ce mémoire a été réalisé à l'UQAC dans le cadre du programme de maîtrise expérimentale (volet génétique), extensionné de l'Université Laval à l'UQAC. CaQCU Bibliogr.: f. 48-55. Document électronique également accessible en format PDF. CaQCU