Polymorphism in the Angiotensin II Type 1 Receptor (AGTR1) is Associated With Age at Diagnosis in Pulmonary Arterial Hypertension

Abstract

Background Pulmonary arterial hypertension (PAH) is a rare, lethal disease associated with single gene disorders, connective tissue disease, exposures to anorexigens, and often idiopathic etiology. There is evidence that genes can modify the risk of PAH: 1) monogenic disorders associated with PAH are incompletely penetrant, and 2) not all patients with associated conditions at increased risk for PAH develop the disease. The renin angiotensin aldosterone system (RAAS) provides a set of candidate genes that could modulate pulmonary vascular disease similar to its effects on renal and peripheral vasculature. Methods We studied 247 subjects with PAH (177 subjects with idiopathic PAH (IPAH); 63 subjects with PAH/connective tissue disease (CTD); and 7 subjects with PAH associated with anorexigens). Subjects were genotyped for five common polymorphisms in angiotensinogen (AGT), angiotensin converting enzyme (ACE), cardiac chymase A (CMA1), angiotensin II type 1 receptor (AGTR1) and aldosterone synthase (CYP11B2). Genotypes were tested for associations with age at diagnosis, hemodynamic parameters at diagnosis, and/or response to acute pulmonary vasodilator testing at diagnosis. Results Associations were demonstrated for AGTR1 and age at diagnosis in IPAH (p=0.005). Homozygotes for the C1166 allele (n=13) were associated with an age at diagnosis 26 years later than subjects with A/A (n=139) or A/C (n=90) genotypes. No associations were demonstrated for AGT, ACE, CMA1, or CYP11B2. Conclusions The 1166C polymorphism in AGTR1 appears to be associated with a later age at diagnosis in IPAH suggesting that this pathway could be involved in the biologic variability that is known to occur in PAH.

Association of polymorphisms in prolylcarboxypeptidase and chymase genes with essential hypertension in the Chinese Han population

“…36 Other studies also did not show the positive association between rs1800875 and hypertension among Japanese, Russian, and American populations. [37][38][39] In the present study, no significant difference was found between the case group and the control group in the genotype as well as allele distributions of rs1800875 in the Chinese Han population. This finding was consistent with previous results among other populations.…”

Interleukin 13– and Interleukin 17A–Induced Pulmonary Hypertension Phenotype Due to Inhalation of Antigen and Fine Particles from Air Pollution

“…Endothelin 1 and angiotensin are major arterial constrictors and play significant roles in pulmonary hypertension. 2,75,76 Our data showed a significant downregulation of these molecules (Fig. 7D-7H), constituting a molecular protection profile for pulmonary arterial constriction.…”

Pulmonary arterial hypertension (ascites syndrome) in broilers: A review

“…The most likely candidate genes are Gga9:13.5-14.8: AGTR1, angiotensin II type 1 receptor; and UTS2D, urotensin receptor 2 D; Gga9:16-5HT2B, serotonin receptor/transporter type 2B; and Gga27:2-ACE, angiotensinogen cleaving enzyme. Each of these genes has been implicated in some aspect of hypertension or hypoxic response in mouse or humans (Simonneau et al, 2004;Watanabe et al, 2006;Djordjevic and Görlach, 2007;MacLean, 2007;Chung et al, 2009). Genes that we did not find include BMPR2, which has been implicated in human hypertension (De Caestecker Figure 4.…”