Genetic factors in primary hypertension- with emphasis on renal sodium reabsorption

Detta är en avhandling från Dept of Endocrinology, Wallenberg lab, floor 3, Ent 46, UMAS, S-205 02 Malmö, Sweden

Sammanfattning: Genetic factors are of importance for the development of primary hypertension (HT). Intrauterine growth retardation, salt sensitivity and insulin resistance are all characteristic features of individuals prone to develop HT. Monogenic forms of hypertension such as Liddle´s syndrome (LS) and Apparent Mineralocorticoid Excess (AME), and hypotension such as Gitelman´s syndrome (GIT) have recently been explained at the molecular level. The present study was undertaken to investigate: if heredity for HT influences intrauterine growth (study I), if salt intake influences insulin sensitivity and if salt sensitivity and insulin sensitivity are related (study II), and if the genes involved in LS (the epithelial sodium channel, ENaC), AME (11-beta hydroxysteroid dehydrogenase type 2, 11BHSD2), GIT (the thiazide sensitive NaCl-cotransporter, TSC) and a gene which has been implicated in rat hypertension and human HT (alpha-adducin), affect susceptibility to HT (studies III-VI). We observed that men with heredity for HT had a reduced intrauterine growth compared with men without heredity for HT. Thinness at birth was related to higher adult systolic blood pressure only in men with heredity for HT (study I). In men with heredity for HT, high- as compared to low salt intake induced a change in insulin sensitivity which was closely related to the degree of salt sensitivity. This was not seen in women. Salt sensitivity was not related to insulin sensitivity (study II). We identified a mutation in the ENaC gene, causing LS in a Swedish family. Although several other genetic variants of the ENaC were found, none of them was more common in HT patients than in control subjects (study III). In contrast to an earlier study reporting an increased risk for HT in carriers of the Trp460 allele of the alpha-adducin gene, we found that the Gly460 allele was associated with HT, suggesting that the association with HT is due to another mutation in linkage disequilibrium with the Gly460Trp variant (study IV). In the 11BHSD2 gene a G534A variant was found and the G534G genotype was significantly associated with HT (study V). Mutations were identified in the TSC gene in 4 patients with GIT. The Gln904Gln genotype of the Arg904Gln variant in the TSC gene was significantly overrepresented in HT patients (study VI). Our data suggest that: (1) genetic factors contributing to HT may also influence intrauterine growth; (2) high as compared to low salt intake may increase insulin sensitivity in salt sensitive men; (3) variants in the TSC-, alpha-adducin- and 11BHSD2 genes may affect susceptibility to HT.

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