AbstractsBiology & Animal Science

From epidemiology to function

by Tarik Bozoglu

Institution: Ludwig-Maximilians-Universität
Year: 2016
Posted: 02/05/2017
Record ID: 2133157
Full text PDF: https://edoc.ub.uni-muenchen.de/19153/


Arterial hypertension is the most prevalent risk factor for cardiovascular disorders. Most cases of hypertension are due to unknown etiology, with only 5-15 per cent being secondary effects. Primary aldosteronism (PA) is the single most prevalent form of secondary hypertension, and is defined by autonomous aldosterone secretion independent of the plasma renin activity. Routine usage of aldosterone to renin ratio (ARR) for screening PA has revealed greater prevalence of the disorder, especially in resistant or advanced forms of arterial hypertension. The two most common causes of PA are aldosterone producing adenomas (APA) and bilateral adrenal hyperplasia (BAH). Rare Mendelian forms of familial hyperaldosteronism are also described. Until recently, genetic background of only glucocorticoid-remediable familial PA was elucidated in detail. Utilization of the exome sequencing techniques since 2011 identified somatic mutations in the cation transporter genes KCNJ5, ATP1A1, ATP2B3 and CACNA1D as the causative factors for circa 50 % of APAs. The underlying genetic causes of BAH cases remain to be determined. Genome-wide association studies (GWAS) have been the predominant methodology in genetic epidemiological research in the past ten years, under the hypothesis of “common disease – common variant”. Its prevalent application identified many risk loci, containing targets for functional investigation. In this study ARR was used as a phenotypic parameter in a GWAS in the German KORA-F4 cohort of 1876 individuals, leading to genome-wide significance of a locus in chromosome 5q32. The four genes in this locus (SLC26A2, TIGD6, HMGXB3 and CSF1R) were evaluated by their known characteristics and functions, and functional studies investigating their relevance to aldosterone biosynthesis and function were carried out for SLC26A2 and CSF1R. SLC26A2, a ubiquitously expressed solute carrier with mainly sulfate, oxalate and chloride affinities, was found to be co-regulated with aldosterone production in vivo and in vitro. RNA interference in a model adrenocortical cell line resulted in significantly higher rate of aldosterone production and aldosterone synthase expression, as well as increased overall steroidogenic capacity. Subsequent studies identified calcium signaling dependent pathways as the mediator of this effect. A germline SLC26A2 knock-in mouse model also showed confirmatory endocrine and adrenal phenotype in a sex-specific manner, with elevated plasma aldosterone concentration and ARR in females. The evidence derived from these findings suggests a possible role of SLC26A2 function in the pathophysiology of PA, which requires further epidemiological and functional experiments to confirm and elucidate. Die arterielle Hypertonie gilt als wichtigster Risikofaktor für kardiovaskuläre Erkrankungen. Während in den meisten Fällen eine essentielle Hypertonie angenommen werden kann, liegt in 5-15 % der Patienten dem Bluthochdruck eine andere Erkrankung zugrunde. Mit dem Einsatz des Aldosteron-Renin-Quotienten (ARQ) konnte der… Advisors/Committee Members: Beuschlein, Felix (advisor).