Single Nucleotide Polymorphisms in G Protein Signaling Pathway Genes in Preeclampsia

Abstract

Preeclampsia is a pregnancy specific disorder and a risk factor for later cardiovascular disease. The cause and detailed pathophysiology remains unknown. G protein signaling is involved in a variety of physiological processes, including blood pressure regulation. We assessed whether distributions of 3 single nucleotide polymorphisms in genes coding for components of G protein signaling pathways that have been associated with hypertension differ between women with preeclampsia and normotensive pregnant women; the G protein β3 subunit gene ( GNB3 ) C825T polymorphism (rs5443), the angiotensin II type 1 receptor gene ( AGTR1 ) 3′UTR A1166C polymorphism (rs5186), and the regulator of G protein signaling 2 gene ( RGS2 ) 3′UTR C1114G polymorphism (rs4606). Two separate Norwegian study populations were used; a large population based study and a smaller, but clinically well-described pregnancy biobank. A descriptive study of 43 women with eclampsia was additionally included. In the population-based study, an increased odds of preeclampsia (odds ratio, 1.21; [95% confidence interval, 1.05–1.40]; P =0.009) and recurrent preeclampsia (odds ratio, 1.43; [95% confidence interval, 1.06–1.92];, P =0.017) was found in women carrying the rs4606 CG or GG genotype. In early-onset preeclamptic patients with decidual spiral artery biopsies available (n=24), the rs4606 CG or GG genotype was more frequent in those with acute atherosis (resembling early stage of atherosclerosis) compared with those without: odds ratio, 15.0; (95% confidence interval, 2.02–111.2); P =0.004. No association was found between preeclampsia and the rs5443 or the rs5186. The genotype distribution in eclamptic women was not different from preeclamptic women. In conclusion, RGS2 rs4606 may affect the risk and progression of preeclampsia.

Angiotensin II Type 1 Receptor Mechanoactivation Involves RGS5 (Regulator of G Protein Signaling 5) in Skeletal Muscle Arteries

“…Genetic polymorphism, decreased mRNA/protein levels, and deficiency of RGS5 have been reported to cause increased vascular stiffiness, preeclampsia, and hypertension. 16, 17, 22, 50 The current study suggests that impaired translocation of RGS5, effectively removing a ‘brake’ on AT 1 R-dependent vasoconstriction, may be one factor associated with hypertension. In this scenario, increased duration of G q/11 -mediated signaling of the AT 1 R would be expected to augment myogenic and/or Ang II-induced vasoconstriction.…”

Vasopressin: the missing link for preeclampsia?

“…In the nonpregnant state, vasopressin has been associated with each of these mechanisms through actions at its four receptor subtypes (V1A, V1B, V2, and CUL5) (1, 3, 4, 16, 18). Furthermore, the rs4606 single nucleotide polymorphism in the regulator of G protein signaling-2 (RGS2) gene, which acts as an endogenous brake on AVP signaling, results in decreased RGS2 function and correlates with human preeclampsia and its sequelae (5,6). Thus AVP is sufficient to initiate preeclampsia symptoms in mice, and its receptors are known to interact with the identified major midgestational mechanisms of preeclampsia in human patients.…”

Regulator of G Protein Signaling 2

“…Impairment of such adaptive mechanisms potentially could contribute to the pathophysiology of preeclampsia. Indeed, recent studies of G protein signaling pathways associated with blood pressure regulation in preeclamptic and normotensive pregnant women identified the Rgs2 SNP rs4606 in the 3’ untranslated region as associated with risk and progression of preeclampsia[76]. Further evidence indicated that women experiencing preeclampsia and carrying this Rgs 2 SNP have increased risk of developing hypertension after delivery[77].…”

“…Second, what mechanisms functionally shift the GAP activity of RGS2 toward G i/o - as opposed to G q -class Gα proteins in the vascular endothelium? Addressing this question may have significant impact because endothelial dysfunction is a central feature of several cardiovascular disorders, particularly hypertension and preeclampsia, which are also associated with Rgs2 SNPs[33, 76]. Third, what mechanisms regulate RGS2 expression levels, and how are they altered to up- or down-regulate RGS2 in health and disease?…”