Date of Degree
PhD (Doctor of Philosophy)
Richard J. Smith
Ménière's disease (MD) is a complex disorder of the inner ear characterized by the symptoms of hearing loss, tinnitus, and vertigo, with an incidence in Caucasians of one in 1000. The hallmark histopathologic feature of MD is endolymphatic hydrops. Symptoms of MD typically present in the fourth decade of life, and the vertigo attacks experienced by patients with MD can be debilitating. Treatments aimed at alleviating the symptoms of MD are ineffective in approximately 30% of patients. Several studies have attempted to identify genetic factors important in MD through the use of families segregating the disease, but causative genes have not been identified. Many of these studies have been unsuccessful due to the fact that families of sufficient size to generate meaningful linkage results are extremely rare. Attempts to identify a genetic component to MD through the use of candidate gene association studies have been underpowered or poorly designed and therefore also unsuccessful.
We hypothesize Ménière's disease is a complex disorder that is due to the interplay of genetic and environmental factors. We tested this hypothesis using linkage and association studies. Initially, we focused on candidate gene replication association studies (KCNE1, KCNE3, iNOS), as well as testing a novel candidate gene (AQP4). We were unable to replicate the previous associations and although we could not identify an association between MD and AQP4 we did discover rare variants of AQP4 in our MD patient population. These variants segregate with a `syndromic' MD phenotype. We also performed a genome-wide linkage study on a large Chilean family segregating MD over three generations and identified a novel MD locus on 1q32.1-1q32.3. Targeted exon capture and pyrosequencing of the region identified two potential disease-causing variants in two genes of unknown function. We next screened a cohort of singleton patients with MD for variants in these same genes. Surprisingly, in both genes, we identified common and rare variants supporting a possible role for either gene in the development of MD. The function of these two genes is unknown. Our results imply that additional studies must be undertaken to determine whether one or both genes has a role in the pathogenesis of MD. Identification of a causative gene will aid in the understanding of disease pathophysiology and lead to improved treatments.
Genetics, Hearing Loss, Meniere's disease
2, xiv, 163 pages
Includes bibliographical references (pages 150-163).
Copyright 2010 Colleen Ann Campbell