published_or_final_version / abstract / Medicine / Doctoral / Doctor of Philosophy

Systemic lupus erythematosus (SLE) is characterized as an autoimmune disorder with unclear etiology. To identify the genetic effect of SLE, a genome wide association study (GWAS) and its further replication were conducted on SLE patients in Asian populations and ethnically matched controls. Before this study, most of the confirmed association loci were identified by GWAS studies in European populations. Apart from the established associations, we identified a SLE susceptible single nucleotide polymorphisms (SNP) located in ETS1 (rs1128334, P=2.3E-11, OR=1.29) in four different cohorts. This locus is probably an Asian-specific susceptibility locus since no Caucasian study has reported further validation in the last years. A new susceptibility variant in UHRF1BP1 (rs13205210, P=4.4E-09, OR=1.49) independent from the previously confirmed SNPs in Caucasian study was also confirmed to be associated with SLE in the Hong Kong Chinese population. Meta-analysis was performed by introducing another Chinese Han GWAS data set from Anhui province, China. Three loci, TET3-DGUOK, CD80, DRAM1, were confirmed to be associated with SLE. Two loci with suggestive signals in Hong Kong GWAS and further replication were also confirmed by the meta-analysis: PTTG1-MiRNA146a, YDJC. In order to identify the genetic effect for females who have predominant chance to suffer from SLE, X chromosome specific meta-analysis based on the Hong Kong and Anhui GWAS data and further replication study were performed by considering the difference between females and males. A signal in PRPS2, and three independent signals in the Xq28 were confirmed with the replication in three different cohorts by considering both females and males. Gene-gene interactions were also investigated genome-widely in a hypothesis free manner based on the meta-analysis results. The further validation processes were preceeded based on each independent GWAS data set. Four pairswise interacting loci were found and cross validated by three methods including logistic regression and Multifactor Dimensionality Reduction (MDR) and information gain theory based on the Anhui GWAS data set. Further studies are still needed to better explain the real features of genetic epistasis and the potential biological roles. By incorporating two GWAS from the same population, the population difference is efficiently avoided. Together with the putative gene-gene interactions, this study presents a comprehensive analysis based on the GWAS data conducted on SLE. It may shed new light on the disease mechanisms of SLE. / published_or_final_version / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

abstract / Medicine / Doctoral / Doctor of Philosophy

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In order to safely move through the environment, visually-guided animals use several types of visual cues for orientation. Optic flow provides faithful information about ego-motion and can thus be used to maintain a straight course. Additionally, local motion cues or landmarks indicate potentially interesting targets or signal danger, triggering approach or avoidance, respectively. The visual system must reliably and quickly evaluate these cues and integrate this information in order to orchestrate behavior. The underlying neuronal computations for this remain largely inaccessible in higher organisms, such as in humans, but can be studied experimentally in more simple model species. The fly Drosophila, for example, heavily relies on such visual cues during its impressive flight maneuvers. Additionally, it is genetically and physiologically accessible. Hence, it can be regarded as an ideal model organism for exploring neuronal computations during visual processing. In my PhD studies, I have designed and built several autonomous virtual reality setups to precisely measure visual behavior of walking flies. The setups run in open-loop and in closed-loop configuration. In an open-loop experiment, the visual stimulus is clearly defined and does not depend on the behavioral response. Hence, it allows mapping of how specific features of simple visual stimuli are translated into behavioral output, which can guide the creation of computational models of visual processing. In closedloop experiments, the behavioral response is fed back onto the visual stimulus, which permits characterization of the behavior under more realistic conditions and, thus, allows for testing of the predictive power of the computational models. In addition, Drosophila’s genetic toolbox provides various strategies for targeting and silencing specific neuron types, which helps identify which cells are needed for a specific behavior. We have focused on visual interneuron types T4 and T5 and assessed their role in visual orientation behavior. These neurons build up a retinotopic array and cover the whole visual field of the fly. They constitute major output elements from the medulla and have long been speculated to be involved in motion processing. This cumulative thesis consists of three published studies: In the first study, we silenced both T4 and T5 neurons together and found that such flies were completely blind to any kind of motion. In particular, these flies could not perform an optomotor response anymore, which means that they lost their normally innate following responses to motion of large-field moving patterns. This was an important finding as it ruled out the contribution of another system for motion vision-based behaviors. However, these flies were still able to fixate a black bar. We could show that this behavior is mediated by a T4/T5-independent flicker detection circuitry which exists in parallel to the motion system. In the second study, T4 and T5 neurons were characterized via twophoton imaging, revealing that these cells are directionally selective and have very similar temporal and orientation tuning properties to directionselective neurons in the lobula plate. T4 and T5 cells responded in a contrast polarity-specific manner: T4 neurons responded selectively to ON edge motion while T5 neurons responded only to OFF edge motion. When we blocked T4 neurons, behavioral responses to moving ON edges were more impaired than those to moving OFF edges and the opposite was true for the T5 block. Hence, these findings confirmed that the contrast polarityspecific visual motion pathways, which start at the level of L1 (ON) and L2 (OFF), are maintained within the medulla and that motion information is computed twice independently within each of these pathways. Finally, in the third study, we used the virtual reality setups to probe the performance of an artificial microcircuit. The system was equipped with a camera and spherical fisheye lens. Images were processed by an array of Reichardt detectors whose outputs were integrated in a similar way to what is found in the lobula plate of flies. We provided the system with several rotating natural environments and found that the fly-inspired artificial system could accurately predict the axes of rotation.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfilment of the requirements for the degree of Master of Medicine in the branch of Internal Medicine. Johannesburg, 2014 / BACKGROUND: Interstitial lung disease (ILD) is one of the leading causes of death in systemic sclerosis (SSc). PATIENTS AND METHODS: A retrospective review of case records, over 20 years, of SSc patients attending a tertiary Connective Tissue Diseases Clinic. Comparisons between ILD and non-ILD groups at presentation were performed in order to identify baseline associations and predictors of ILD. RESULTS: Of the 151 participants that met inclusion criteria, 60 (40%) had ILD. On multivariate analysis the only three variables to remain significant were median duration of disease (OR 1.2 (1.1-1.3); p<0.001), speckled anti-nuclear antibody (ANA) pattern (OR 2.95 (1.22-7.15); p=0.017) and bibasal crackles (OR 5.4 (2.1- 13.5); p<0.0001). Univariate analysis of baseline variables associated with interstitial lung disease in systemic sclerosis. Baseline Variable ILD (n=60) Non-ILD (n=91) OR (CI 95%) p Bibasal crackles (%) 28 (46.7) 10 (11.0) 7.1 (3.1-16.3) <0.0001 Diffuse disease subtype (%) 49 (81.7) 45 (48.9) 4.6 (2.1-9.9) <0.001 Limited disease subtype (%) 8 (13.3) 38 (41.3) 0.2 (0.1-0.5) <0.001 Anti-centromere antibodies (%) 0 (0.0) 10 (13.0) - 0.006 Cough (%) 21 (35.0) 15 (16.5) 2.7 (1.3-5.9) 0.007 Median duration in years (IQR) 6.1 (8.3) 4.0 (5.0) 2.2 (1.8-2.4) 0.009 Speckled ANA pattern (%) 29 (50.9) 25 (32.5) 2.5(1.2-4.9) 0.010 Dyspnoea (%) 27 (45.0) 24 (26.4) 2.3 (1.1-4.6) 0.014 Gold mining history (%) 5 (8.3) 1 (1.1) 8.2 (0.9-71.9) 0.037 ANA=antinuclear antibody; ILD=interstitial lung disease; IQR= interquartile range; OR=odds ratio Additionally, dyspnoea was associated with ILD severity (p=0.008). Bibasal crackles (p=0.014), increased plasma urea (p=0.041), and reduced serum albumin (p=0.007) were associated with mortality in the ILD group. CONCLUSION: Interstitial lung disease in South African SSc patients is common. The diffuse cutaneous disease subtype appears to drive the disease process. There should be a high index of suspicion for ILD in SSc patients presenting with a gold mining history, dyspnoea, cough and bibasal crackles.