An epidemiologic and genetic exploration of the etiology of Type 2 diabetes in the Atherosclerosis Risk in Communities (ARIC) and Epidemiology of Hearing Loss (EHLS)/Beaver Dam Offspring (BOSS) Studies.
2011-10
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An epidemiologic and genetic exploration of the etiology of Type 2 diabetes in the Atherosclerosis Risk in Communities (ARIC) and Epidemiology of Hearing Loss (EHLS)/Beaver Dam Offspring (BOSS) Studies.
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2011-10
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Type 2 diabetes is a major contributor to mortality and morbidity in the United States. The etiology of this disease is complex and our knowledge of it is incomplete. These analyses sought to increase our understanding of the etiology of type 2 diabetes and to distinguish newly identified risk factors that could someday be useful in clinical risk prediction models.
The first paper examined the contributions of novel risk factors to the prediction of type 2 diabetes in the Atherosclerosis Risk in Communities (ARIC) study. There was only modest reclassification of risk with the addition of forced expiratory volume in 1 second (FEV1) to the risk model and a small improvement in the integrated discrimination index (IDI) with the addition of white blood cell count, activated partial thromboplastin time (aPTT), albumin, factor VIII, magnesium, hip circumference, heart rate, and a genetic risk score in the total cohort. In the case-cohort analysis there was no significant reclassification of risk, but the addition of adiponectin, leptin, gamma-glutamyl transpeptidase (GGT), ferritin, inter-cellular adhesion molecule 1 (ICAM-1), and complement C3 to models modestly improved the IDI. A second paper examined the association between sets of genome-wide association (GWA) derived type 2 diabetes score alleles with both incident type 2 diabetes and prostate cancer in the ARIC cohort. We found that these score sets derived from men were not significantly associated with type 2 diabetes in an independent target dataset of women, nor were they associated with prostate cancer in men. Secondarily, we conducted a pathway analysis of our GWA analyses of type 2 diabetes and prostate cancer. We failed to identify pathways significantly associated with both diseases; however, we did identify a pathway statistically significantly associated with type 2 diabetes, the growth hormone signaling pathway. A third paper looked for associations between genetic variants in the Wnt pathway and hemoglobin A1C (HbA1c) levels in the Epidemiology of Hearing Loss (EHLS) and Beaver Dam Offspring Study (BOSS) studies. No Wnt variants were significantly associated with HbA1c. Nor were we able to replicate the associations between three SNPS and HbA1c recently identified in a meta-analysis. This dissertation contributes to our understanding of type 2 diabetes risk prediction by showing that few novel risk factors contribute meaningfully to existing risk prediction and expands our understanding of the etiology of type 2 diabetes by identifying a genetic pathway significantly associated with this disease and its related quantitative traits.
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University of Minnesota Ph.D. dissertation. October 2011. Major: Epidemiology. Advisor:James S. Pankow. 1 computer file (PDF); ix, 184 pages, appendix I.
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Raynor, Laura A.. (2011). An epidemiologic and genetic exploration of the etiology of Type 2 diabetes in the Atherosclerosis Risk in Communities (ARIC) and Epidemiology of Hearing Loss (EHLS)/Beaver Dam Offspring (BOSS) Studies.. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/117909.
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