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  • The present study is a genetic association study using the

    2020-03-13

    The present study is a genetic association study using the classic candidate gene approach. This method has been repeatedly criticized in the past to produce highly unreliably findings (e.g. Flint & Munafò, 2013). The alternative would be the conduction of a Irsogladine wide association study (GWAS). GWAS is a completely a-theoretical and therefore explorative method, correlating millions of polymorphisms simultaneously with the phenotype under investigation. GWAS although being a great technical achievement also bears its disadvantages. The immense number of investigated polymorphisms demands extremely large samples, potential findings have again to be replicated in independent studies, and statistical findings have to be controlled for an alpha error inflation. Ironically most GWAS findings could not be replicated and sometimes the functionality of polymorphisms of replicated findings is unknown or does not make sense (for an overview see Reuter, Felten, & Montag, 2016). Therefore, the candidate gene approach and GWAS both have their legitimation. Luckily the present candidate gene approach study provides replication data and the sample size is rather large for studies in the field of genetic personality research. This will be even of advantage in the future: The larger the sample the more representative it is and this is a positive effect for future meta-analyses. Meta-analyses relying on data from numerous but underpowered samples could provide unreliable findings.
    Introduction Essential hypertension is a heterogeneous disorder, genetic and environmental factors are associated with its pathogenesis, and it is a risk factor for cardiovascular disease and mortality. Carotid bodies (CB) are peripheral chemoreceptors that are responsible for monitoring changes in PO2, PCO2, and pH in arterial blood and play an important role in triggering respiratory and cardiovascular responses (Gonzalez et al., 1994, Nurse, 2005). Previous studies reported that CB was morphometrically enlarged in essential hypertensives (Smith et al., 1982, Habeck, 1986). Furthermore, hyperventilation was observed in essential hypertensive patients under resting conditions (Trzebski et al., 1982). Spontaneously hypertensive rat (SHR) strains are often used as an animal model for human essential hypertension in studies on the pathogenesis of essential hypertension. Similar to essential hypertensives, the enlargement of CB was reported in SHR (Heath et al., 1985, Habeck et al., 1987). SHR also showed hyperventilation under resting conditions (Habeck, 1991). Moreover, a stronger discharge in the afferent nerves (the carotid sinus nerve) of CB by hypoxic exposure was detected in anesthetized SHR (Fukuda et al., 1987). A recent study demonstrated that the development of hypertension in SHR was inhibited by denervation of the carotid sinus nerve at prehypertensive 4weeks of age (Abdala et al., 2012). These findings suggest that functional alterations in CB are associated with the development of hypertension. Glomus cells are regarded as chemoreceptor cells within CB, and many neurotransmitters including acetylcholine, ATP, and catecholamines have been detected in these cells (Gonzalez et al., 1994, Nurse, 2005). Regarding the expression of catecholamines in the CB of SHR, we previously investigated immunoreactivity for catecholamine-synthesizing enzymes in the glomus cells of established Irsogladine hypertensive 16-week-old SHR/Izm, which is one SHR strain, and age-matched Wistar Kyoto rats (WKY/Izm) (Kato et al., 2012). We reported that immunoreactivity for tyrosine hydroxylase (TH; EC1.14.16.2), the rate-limiting enzyme of catecholamine biosynthesis, was similar between the two rat strains, whereas that for dopamine β-hydroxylase (DBH; EC1.14.17.1), the enzyme catalyzing the synthesis of noradrenaline (NA) from dopamine, was stronger in the glomus cells of SHR/Izm than in those of WKY/Izm. Although our previous findings suggest that the expression of DBH is enhanced in glomus cells under hypertensive conditions, the comparison of immunoreactivity for DBH in glomus cells was only conducted on 16-week-old animals, and the relationship between increases in DBH in glomus cells and blood pressure changes during postnatal development currently remains unknown. Regarding age-related blood pressure changes in SHR, systolic blood pressure was found to gradually increase from 4 to 6weeks, and reached a plateau 10weeks or more after birth (Beierwaltes et al., 1982). Therefore, we hypothesized that increases in DBH in glomus cells are associated with the development of hypertension. In order to verify this hypothesis, changes in DBH immunoreactivity in glomus cells need to be examined using SHR/Izm at the prehypertensive stage and developmental hypertensive stage.