Abstract 2869

Chuvash polycythemia (CP) is characterized by homozygosity for the R200W mutation in the von Hippel Lindau gene (VHL). This rare genetic disorder causes elevated levels of hypoxia inducible factor (HIF)-1 and HIF-2 that trigger constitutive hypoxia responses at normoxia. Hypoxia is a recognized cause of pulmonary hypertension. We recently reported that systolic pulmonary artery pressure (SPAP) estimated by echocardiography-determined tricuspid regurgitation velocity (TRV) was elevated in 120 CP patients compared to 31 Chuvash controls (P = 0.005), and that increasing age (P = 0.001), increasing systemic pulse pressure (P = 0.003) and lower serum ferritin concentration (P = 0.009) were independent predictors of higher estimated SPAP in CP patients [Sable et al., 2012]. In this study, we profiled gene expression for 16,642 genes in peripheral blood mononuclear cells (PBMCs) derived from a cohort of 43 CP patients, and measured the TRV for these individuals. Based on a prospectively chosen criterion of TRV ≥2.5 m/sec, 20 patients were classified as having elevated level of estimated SPAP and 23 were normal. Gene expression level between these two SPAP groups appeared to be homogenous. However, we identified 4777 genes at false discovery rate (FDR) <0.05 that exhibit pulse pressure by SPAP group interaction, suggesting a profound difference in pulse pressure regulation between the two SPAP groups.

Further analysis of probe level data revealed a potential genetic polymorphism located within exon 7 of SERPINC1, encoding antithrombin III, at a site where a disease-associated SNP has not been reported. The minor allele of this polymorphism, which we designated “B”, was highly enriched in the elevated estimated SPAP group (P=0.0009), and classification based on the putative SERPINC1 genotypes strengthens the interaction effect with pulse pressure. Analysis of the gene expression data for the 43 CP patients with an additive genetic model of SERPINC1 identified 1902 differential genes at FDR <0.05. The 1120 genes up-regulated by the B allele were highly enriched in the Reactome G-protein coupled receptor pathway (Padjusted < 8×10−10). Several genes involved in smooth muscle contraction, regulation of blood pressure, and angiogenesis were up-regulated by the putative B allele, for example, HTR5A (serotonin receptor 5A), TAC3 (tachykinin 3), ADRA1D (adrenergic alpha-1D- receptor), BDKRB1 (bradykinin receptor B1), BDKRB2 (bradykinin receptor B1), EDN2 (endothelin 2), PTGER1 (prostaglandin E receptor 1), PTGIR (prostaglandin I2 receptor), APLNR (apelin receptor), RAMP2 (receptor activity modifying protein 2), MYH6 (myosin heavy chain 6), MYH7 (myosin heavy chain 7), MYL2 (myosin light chain 2), MYLK2 (myosin light chain kinase 2), MYLK3 (myosin light chain kinase 3), ACE (angiotensin I converting enzyme 1), ATP2A1 (ATPase cardiac muscle fast twitch 1), ADCY4 (adenylate cyclase 4), and PRKAA2 (protein kinase AMP-activated alpha 2 catalytic subunit). On the other hand, genes whose malfunction has been associated with familial pulmonary hypertension, including BMPR2 (bone morphogenetic protein receptor, type II), SMAD5 (SMAD family member 5), and ACVR2A (activin A receptor, type IIA), were among the 782 genes down regulated by the B allele.

These results suggest that alterations in SERPINC1 may be implicated in the development of elevated SPAP in patients with CP. Antithrombin III deficiency is a potential factor in chronic thromboembolic pulmonary hypertension, but our results suggest that the putative B polymorphism may have effects beyond the coagulation cascade. Whether this is due to the SERPINC1 polymorphism itself or to another locus in linkage disequilibrium will require our future planned studies, beginning with sequencing of SERPINC1 exon 7 and identification of the polymorphism.


No relevant conflicts of interest to declare.


Author notes


Asterisk with author names denotes non-ASH members.