Association of (pro)renin receptor gene polymorphisms with lacunar infarction and left ventricular hypertrophy in Japanese women: the Ohasama study

Abstract

Recent studies have revealed that (pro)renin receptor ((P)RR), a newly identified member of the renin-angiotensin system, is associated with organ damage that occurs with cardiovascular disease. We investigated the association of genetic polymorphisms in the (P)RR gene with lacunar infarction, white matter hyperintensity and left ventricular hypertrophy (LVH) in a Japanese general population recruited from the Ohasama study, a Japanese cohort study. A total of 779 subjects (men¼250 and women¼529) were recruited. For the association study, we selected three polymorphisms: À782A4G (rs2968915), intervening sequence (IVS)5+169C4T (rs5918007) and +1513A4G (rs6609080). In women, the prevalence of lacunar infarction and LVH was significantly higher in subjects with the +1513GG genotype than in those with the AA or AG genotypes (lacunar infarction: P¼0.01, LVH: P¼0.003). Plasma renin activity (PRA) levels in women with the GG genotype were significantly lower than in women with the AA or AG genotypes (P¼0.01). Multiple logistic regression analysis adjusted for confounding factors demonstrated that +1513A4G polymorphism was significantly and independently associated with the risk of lacunar infarction (trend P¼0.03) and LVH (trend P¼0.003). In men, there were no significant differences in lacunar infarction, LVH or PRA levels among the three genotypes. The polymorphism of the (P)RR gene +1513A4G is associated with lacunar infarction and LVH in Japanese women. These results suggest that (P)RR has a role in organ damage in humans.

(Pro)renin receptor and V-ATPase: from Drosophila to humans

“…Firstly, the 5+169C>T polymorphism was significantly associated to blood pressure in Japanese men [46] and more recently also in Caucasian men [47]. Secondly, the +1513A>G polymorphism was significantly associated with the risk of lacunar infarction and left ventricular hypertrophy in Japanese women [48]. Finally, two additional polymorphisms were significantly associated with hypertension in additional populations with vascular diseases [49].…”

Ontogeny of the (pro)renin receptor

“…Transgenic overexpression of the (P)RR in rats causes elevated blood pressure (29). Of note, polymorphism in the (P)RR gene is associated with a high blood pressure in men (IVS5+169C>T) and left-ventricular hypertrophy in women (+1513A>G) (30,31). High (P)RR mRNA and protein levels observed in the fetal heart suggest a role for (P)RR in heart development.…”

Biochemical, Structural and Pathophysiological Aspects of Prorenin and (Pro)renin Receptor

“…Also, another major finding ) stated that (P)RR play essential role in neuronal cell differentiation. Other than the embryonic development, (P)RR gene polymorphism has been found to be associated with high blood pressure in Caucasian and Japanese male subjects (Hirose et al, 2011;Ott et al, 2011). Elevated blood pressure and increased heart rate in transgenic rats over expressing (P)RR in smooth muscles have been reported in their models .…”

“…These data demonstrated the possible involvement of (P)RR in the pathogenesis of heart failure and kidney tissue damage. Association of (P)RR gene polymorphism with high blood pressure and left ventricular hypertrophy substantiate the important role of (P)RR in the pathogenesis of hypertension in humans (Hirose et al, 2011;Ott et al, 2011) In vitro and animal studies have shown that increased receptor expression could be linked to high blood pressure and to cardiac and glomerular fibrosis by activating mitogen-activated protein kinases and by upregulating gene expression of profibrotic molecules. Also, animal studies with angiotensin-II type 1a receptor deficiency showed that the (P)RR is involved in the development and progression of diabetic nephropathy through angiotensin-II independent pathway via activation of intracellular pathways (Ichihara et al, 2006c).…”