**6. References**


Even though discrepancies between our data sets were observed, it is possible that the reduction in data between the gene and pathway level could have excluded some genes common to multiple diseases. With the increased density of GWAS and gene expression studies, the discrepancies and anomalies observed in this study might be better understood. We set out to support the idea that diseases potentially share phenotype similarity as a result of genetic factors, pathway associations, expression regulation, or some combination of these three ideas. Within the autoimmune disease group, we observed diseases that possessed some genetic similarity. We saw expected strong associations between T1D, MS, and RA, as well as less expected associations between AD and T2D. It would appear that systemic inflammation responses may be the key to shared susceptibility among many of the diseases and phenotypes for which we observed relatedness. Clinical studies suggested individuals with one immunemediated disease, such as T1D, may be more susceptible to pathogenesis of another (Dorman et al., 2003; Nielson et al., 2006; Toussirot et al., 2006; Doran, 2007). It has also been clinically suggested that inflammation plays a role in neurological diseases like AD (Akiyama et al., 2000; Perry, 2004) and PD (Perry, 2004). We also know that cardiovascular and metabolic diseases, such as atherosclerosis, T2D, and OBE have links to chronic inflammatory responses (Stienstra et al., 2006; Tontonoz&Spiegelman, 2008). In all of these cases, our results suggest the clinical manifestations may have genetic relevance and the unexpected cardiovascular/neurological links may be important. Given the broad scope of this study, the conclusions made here are suggestions for where genetic commonality could be found without specific identification of the related targets. A more detailed disease-by-disease analysis similar to the study conducted by Parikh et al. (Parikh et al., 2009) would need to be conducted to identify specific genes of interest shared by diseases. The methods used in the Parikh et al. study can be specifically applied to the study of T1D by performing a detailed step-by-step comparison between this disease and other possibly related diseases in order to elucidate genetic commonalities to T1D. The results from our study and from one tailored specifically for T1D could influence current treatment options and suggest new approaches for managing and treating the disease. We feel our study is a strong example of how GWAS and expression data can be used conjunctively to predict significant disease associations relevant to improving and unifying diagnoses and treatment options for multiple immune-mediated diseases.

The authors would like to acknowledge the faculty and students of the Spring 2010 Genetics, Bioinformatics, and Computational Biology Problem Solving course for feedback

Akiyama, H., S. Barger, et al. (2000). "Inflammation and Alzheimer's." Neurobiology of

Andersohn, F., M. Waring, et al. (2010). "Risk of ischemic stroke in patients with Crohn's

Barrett, T., D. Troup, et al. (2009). "NCBI GEO: archive for high-throughput functional

genomic data." Nucleic Acids Research 37: D885-D890.

disease: A population-based nested case-control study." Inflammatory Bowel

**5. Acknowledgements** 

**6. References** 

regarding the progress of this study.

Aging 21(3): 383-421.

Disease 16(8): 1387-1392.


**12** 

*Ireland* 

**Cytokine-Induced -Cell Stress and** 

Caitriona Holohan1, Timothy O'Brien2 and Afshin Samali1

**1.1 Pathophysiology of type I diabetes mellitus: Role of pro-inflammatory cytokines**  Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterised by the destruction of insulin-producing β-cells in the pancreatic islets of Langerhans (Fig.1), which is mediated by autoreactive T cells, macrophages and pro-inflammatory cytokines (Fig.2). This leads to an inability to produce sufficient insulin resulting in elevated blood glucose levels and

T1DM is believed to be initiated by physiological -cell death or islet injury triggering the homing of macrophages and dendritic cells that in turn launch an inflammatory reaction. The infiltrating macrophages secrete pro-inflammatory cytokines, namely interleukin-1β (IL-1 and tumour necrosis factor (TNF as well as various chemokines that attract immune cells such as dendritic cells, macrophages and T lymphocytes. T cells recognising cell-specific antigens become activated, infiltrate the inflamed islets and attack the -cells (Baekkeskov et al., 1990, Elias et al., 1995, Lieberman et al., 2003, Nakayama et al., 2005). In a normally functioning immune system, T cells with a high affinity for self-antigens are eliminated during their differentiation resulting in immune 'tolerance'. Autoreactive cells that have escaped these mechanisms are subject to 'peripheral immune regulation' that blocks their activation and clonal expansion, preventing development of an autoimmune disease (Mathis & Benoist, 2004). For reasons we do not fully understand, these immune regulatory mechanisms either fail to launch, or are ineffective in stopping the immune attack against the -cells in T1DM, and a positive feedback cycle is established (Mathis & Benoist, 2004). This forward-feeding process of T cell- and cytokine-mediated -cell killing can be ongoing for years progressively destroying the -cells. When over 80 % of the -cells are deleted by this continuous T lymphocyte and inflammatory cytokine-driven attack the insulin secretory capacity falls below a certain threshold and the disease manifests itself. Activated T cells induce death of a target cell by (1) secreting perforin and granzymes, (2) releasing pro-inflammatory cytokines including interferon-γ (IFNγ) and TNFα or (3) activation of Fas receptors on the surface of target cells. All these factors have also been described to contribute to β-cell killing in T1DM (Kägi et al., 1997, D. Liu et al., 2000, Petrovsky et al., 2002, Suk et al., 2001). In particular, recent evidence suggests that the

pathological effects (Eizirik & Mandrup-Poulsen, 2001).

**1. Introduction** 

**Death in Type 1 Diabetes Mellitus** 

Lisa Vincenz1, Eva Szegezdi1, Richard Jäger1,

*1Apoptosis Research Centre 2Regenerative Medicine Institute, National University of Ireland Galway* 

