Abstract
Research into the polygenic underpinnings of Type I Diabetes has been a developing area of clinical practice in recent years. Current literature shows there are over 50 regions of the genome associated with onset of disease, however individual and combined contributions to diabetes risk are still being explored. Understanding genetics as the backbone for disease pathophysiology can provide a powerful tool to describing multiple diseases, but also plays an important role in risk prediction and informing person-centred care. Within this integrative review, major alleles (DNA variants) influencing genetic susceptibility to Type I Diabetes will be explored to provide a better understanding of the pathophysiology of diabetes. This study is aimed at gathering the currently available knowledge surrounding the function of these genes and their role in pathogenicity. Ultimately, this project will enable informed and up-to-date information for clinicians including nurses working in the field of diabetes care.
Aim and Review Question: The aim of this research is to gain an understanding of the current pathophysiological mechanisms affected by significant genetic variants contributing to the onset of Type I Diabetes
Research design and methods: Research was conducted as an integrative review. The constant comparison model was used to analyse data. The search strategy was carried out using PECO and structured using the PRISMA framework. A total of 97 full-text articles were screened, with 17 meeting quality appraisal criteria for final analysis and inclusion of the data investigated.
Results: The following genes had polymorphisms with known function explaining T1D pathogenesis: HLA DR3/DR4 and HLA DR4/DQ8, PTPN22, CTLA-4, IL2RA, CVB P2C // GAD65.
Conclusions: HLA genes were found to permit presentation of self-antigens in the thymus during negative selection. Failure of tolerance was found to be further perpetuated due to downregulation of T-cell receptor signalling mediated by PTPN22 polymorphisms. CTLA-4 and IL2RA polymorphisms affect T-regulatory cell function, leading to proliferation of autoreactive T-effector cells that mediate destruction of pancreatic tissues and insulin. Lastly, molecular mimicry of the Coxsackievirus B4 protein 2C with the GAD65 amino acid sequence generates autoreactive immunoglobulins as part of the B-cell pathway to autoimmune disease.