Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor ... Show moreBackground Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. Conclusion This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction. Show less
Outline of the Thesis Part I Pneumocystis in kidney transplant recipients: transmission, risk factors , new diagnostic and chemo-prophylactic strategies. Chapter 2 describes the characteristics of... Show moreOutline of the Thesis Part I Pneumocystis in kidney transplant recipients: transmission, risk factors , new diagnostic and chemo-prophylactic strategies. Chapter 2 describes the characteristics of a large outbreak of Pneumocystis pneumonia among kidney transplant recipients. By performing a classical outbreak investigation and by application of new molecular genotyping techniques, the potential of the __interhuman transmission hypothesis__ is addressed and discussed. In Chapter 3 all currently available data on reported outbreaks of Pneumocystis pneumonia is systematically reviewed with the emphasis on mortality data, clinical risk factors and transmission analyses. In the case-control study described in Chapter 4, we performed a detailed risk factor analysis for development of PCP in kidney transplant recipients and used the multivariate output data to estimate the effects of several chemoprophylactic strategies by modeling the expected incidence and number-needed-to-treat to provide efficient PCP chemoprophylaxis over a 2-year period post transplantation. Chapter 5 reports the data of a prospective study on the serum markers S-adenosylmethionine and (1-->3)-_-D-glucan serum levels and correlation with clinical parameters in HIVnegative immunocompromised patients __ the majority kidney transplant recipients - with Pneumocystis pneumonia. Potential applicability for treatment monitoring and assessment of P. jirovecii pulmonary load is also discussed. Part II Genetic predisposition for development of invasive aspergillosis in stem cell transplant recipients Chapter 6 describes a multicenter study on the impact of the Y238X stop mutation in the human Dectin-1 receptor (which senses and attaches to glucan moieties of the fungal cell wall) on the risk of development of invasive aspergillosis in stem cell transplant recipients. In Chapter 7 a retrospective study of the influence of genetic variation in the macrophage activation route with respect to the relative additional risk for development of invasive aspergillosis is presented. Part III Experimental markers for detection of fungal infection: scintigraphic imaging. In Chapter 8 the clinical applicability of radiolabeled antimicrobial peptides and antifungal drugs for the diagnosis of invasive fungal infections is reviewed, together with a concise discussion about how promising agents should be further developed. The results of the thesis are summarized and discussed in Chapter 9. Show less
Complex Regional Pain Syndrome (CRPS) is a painful disorder affecting one or more extremities. CRPS is characterized by various combinations of sensory, autonomic and motor disturbances. Genetic... Show moreComplex Regional Pain Syndrome (CRPS) is a painful disorder affecting one or more extremities. CRPS is characterized by various combinations of sensory, autonomic and motor disturbances. Genetic factors are suggested to play a role in CRPS, but this has not been extensively studied. Therefore the aims of this thesis were to study the contribution and the size of the contribution of genetic factors in CRPS and to identify possible susceptibility and causative genes for CRPS. In our studies we have shown that CRPS may develop without a noxious event and it has been suggested that such patients have a larger genetic predisposition. Furthermore we have found that CRPS may occur in a familial form, but did not observe a clear inheritance pattern. We calculated a measure of familial aggregation. This study yielded no indications for a large overall increased risk of developing CRPS for siblings of CRPS patients. Significant associations were found with CRPS and dystonia and two HLA-B62 and HLA-DQ8. We also evaluated the presence of causative mutations in known primary dystonia genes and causative mutations in the SCN9A gene. No such mutations were identified, indicating that these genes do not seem to play a major role in CRPS. Show less
Glomerulosclerosis is a general term describing the process of scarring of the glomeruli, the functional units in the kidney that filter urine from the blood. This severe, irreversible complication... Show moreGlomerulosclerosis is a general term describing the process of scarring of the glomeruli, the functional units in the kidney that filter urine from the blood. This severe, irreversible complication can occur secondary to various already established systemic or local diseases. However, not all patients with renal diseases show progression to end stage renal disease (ESRD). Thus renal patients can be subdivided into progressors and non-progressors based on clinical parameters1. Why patients with renal diseases become progressors or non-progressors is unclear, and better insight into the pathogenesis of glomerulosclerosis may improve our understanding of the process towards progression. However, the pathogenesis of glomerulosclerosis is complex and still poorly understood, although genetic factors probably play a role, given the considerable variation among individuals in both the risk of developing glomerulosclerosis and the rate of progression. Therefore, the first aim of the work described in this thesis was to identify genes involved in the progression and repair of glomerulosclerosis, using an animal model that allows a clear distinction between progression and repair after renal injury. The second aim was to gain better insight into the pathogenesis of glomerulosclerosis by investigating the expression and activity of fibrosis-related molecules in an animal model and in patients with renal diseases. Show less
