The heterozygote advantage of the chuvash polycythemia VHL \u3csup\u3eR200W\u3c/sup\u3e mutation may be protection against anemia

The germ-line loss-of-function VHLR200W mutation is common in Chuvashia, Russia and occurs in other parts of the world. VHLR200W homozygotes have elevated hypoxia inducible factor (HIF)-1 and HIF-2 levels, increased hemoglobin concentration, propensity to thrombosis and early mortality. Because the mutation persists from an ancient origin, we hypothesized that there is a heterozygote advantage. Thirty-four VHLR200W heterozygotes and 44 controls over 35 years of age from Chuvashia, Russia were studied. Anemia was defined as hemoglobin less than 130 g/L in men and less than 120 g/L in women. Mild anemia was present in 15% of VHLR200W heterozygotes and 34% of controls without a mutated VHL allele. By multivariate logistic regression, the odds of anemia were reduced an estimated 5.6-fold in the VHLR200W heterozygotes compared to controls (95% confidence interval 1.4-22.7; P=0.017). In conclusion, heterozygosity for VHLR200W may provide protection from anemia; such protection could explain the persistence of this mutation. © 2011 Ferrata Storti Foundation

Endemic polycythemia in Russia: Mutation in the VHL gene

Chuvash polycythemia (CP) is an autosomal recessive condition that is endemic in the Russian mid-Volga River region of Chuvashia. We previously found that CP patients may have increased serum erythropoietin (EPO) levels, ruled out linkage to both the EPO and EPO receptor (EPOR) gene loci, and hypothesized that the defect may lie in the oxygen homeostasis pathway. We now report a study of five multiplex Chuvash families which confirms that CP is associated with significant elevations of serum EPO levels and rules out a location for the CP gene on chromosome 11 as had been reported by other investigators or a mutation of the HIF-1α gene. Using a genome-wide screen, we localized a region on chromosome 3 with a LOD score \u3e2. After sequencing three candidate genes, we identified a C to T transition at nucleotide 598 (an R200W mutation) in the von Hippel-Lindau (VHL) gene. The VHL protein (pVHL) downregulates the alpha subunit of hypoxia-inducible factor 1 (HIF-1α), the main regulator of hypoxia adaptation, by targeting the protein for degradation. In the simplest scenario, disruption of pVHL function causes a failure to degrade HIF-1α resulting in accumulation of HIF-1α, upregulation of downstream target genes such as EPO, and the clinical manifestation of polycythemia. These findings strongly suggest that CP is a congenital disorder of oxygen homeostasis. © 2002 Elsevier Science (USA)

Altered cytokine profiles in patients with Chuvash polycythemia

Chuvash polycythemia results from a homozygous 598C\u3eT mutation in exon 3 of the von Hippel-Lindau (VHL) gene. This disrupts the normoxia pathway for degrading hypoxia inducible factor (HIF)-1α and HIF-2α causing altered expression of HIF-1 and HIF-2 inducible genes. As hypoxia induces expression of proinflammatory cytokines, we hypothesized that there might be an elevation of Th1 cytokines in the setting of Chuvash polycythemia. We analyzed plasma concentrations of Th1 (interleukins-2 and 12, interferon-γ, granulocyte-monocyte colony-stimulating factor, tumor necrosis factor-α) and Th2 cytokines (interleukins-4, 5, 10, and 13) using the Bio-Plex multiplex suspension array system in 34 VHL598C\u3eT homozygotes and 32 VHL wild-type participants from Chuvashia. Concentrations of all the Th1 and Th2 cytokines measured were elevated in the VHL598C\u3eT homozygotes compared with the control wild-type participants, but the ratios of Th1 to Th2 cytokines did not differ by genotype. In parallel, peripheral blood concentrations of CD4 positive T-helper cells and CD4/CD8 ratio were lower in the VHL598C\u3eT homozygotes. In conclusion, the up-regulated hypoxic response in Chuvash polycythemia is associated with increased plasma products of both the Th1 and Th2 pathways, but the balance between the two pathways seems to be preserved. Am. J. Hematol. © 2008 Wiley-Liss, Inc

The phenotype of polycythemia due to Croatian homozygous VHL (571C\u3eG:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C\u3eT:R200W)

Mutations of VHL (a negative regulator of hypoxia-inducible factors) have position-dependent distinct cancer phenotypes. Only two known inherited homozygous VHL mutations exist and they cause polycythemia: Chuvash R200W and Croatian H191D. We report a second polycythemic Croatian H191D homozygote distantly related to the first propositus. Three generations of both families were genotyped for analysis of shared ancestry. Biochemical and molecular tests were performed to better define their phenotypes, with an emphasis on a comparison with Chuvash polycythemia. The VHL H191D mutation did not segregate in the family defined by the known common ancestors of the two subjects, suggesting a high prevalence in Croatians, but haplotype analysis indicated an undocumented common ancestor ~six generations ago as the founder of this mutation. We show that erythropoietin levels in homozygous VHL H191D individuals are higher than in VHL R200W patients of similar ages, and their native erythroid progenitors, unlike Chuvash R200W, are not hypersensitive to erythropoietin. This observation contrasts with a report suggesting that polycythemia in VHL R200W and H191D homozygotes is due to the loss of JAK2 regulation from VHL R200W and H191D binding to SOCS1. In conclusion, our studies further define the hematologic phenotype of VHL H191D and provide additional evidence for phenotypic heterogeneity associated with the positional effects of VHL mutations. © 2013 Ferrata Storti Foundation

Endothelin-1, vascular endothelial growth factor and systolic pulmonary artery pressure in patients with Chuvash polycythemia

Background and Objectives. Endothelin-1 has been associated with development of hypoxia-related pulmonary hypertension and vascular endothelial growth factor (VEGF) with protection from this complication. In Chuvash polycythemia, homozygous germline von Hippel-Lindau (VHL) 598C→T leads to up-regulation during normoxia of hypoxia inducible factor-1α and several hypoxia-controlled genes including erythropoietin and VEGF. We postulated that endothelin-1 and pulmonary artery pressure may be elevated in Chuvash polycythemia. Design and Methods. Systolic pulmonary artery blood pressure was estimated by Doppler echocardiography and plasma concentrations of endothelin-1, VEGF and erythropoietin were determined in 14 patients with Chuvash polycythemia and 14 controls. Results. Plasma endothelin-1 (p=0.010), VEGF (p=0.022) and erythropoietin (p\u3c0.0005) concentrations and Doppler-estimated systolic pulmonary artery pressures (p\u3c0.0005) were higher in the patients while systolic systemic blood pressures were lower (P=0.001). Five (36%) patients and no controls had mild pulmonary hypertension defined as systolic pulmonary artery pressure ≥35 mmHg. Among the patients with Chuvash polycythemia, the trends of association of estimated pulmonary artery pressure with plasma concentrations of endothelin-1 (R = +0.236), VEGF (R = -0.389) and erythropoietin (R = +0.220) were not statistically significant. Interpretations and Conclusions. Estimated systolic pulmonary artery pressure and plasma concentrations of endothelin-1 and VEGF are increased in patients with Chuvash polycythemia patients. The lack of significant associations of estimated systolic pulmonary artery pressure with plasma endothelin-1 and VEGF levels could conceivably be due to the small sample size. Further studies are indicated, especially in view of the reported efficacy of endothelin-1 receptor blockers in treating hypoxia-associated pulmonary hypertension. ©2006 Ferrata Storti Foundation

Congenital disorder of oxygen sensing: Association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors

Adaptation to hypoxia is critical for survival and regulates multiple processes, including erythropoiesis and vasculogenesis. Chuvash polycythemia is a hypoxia-sensing disorder characterized by homozygous mutation (598C\u3eT) of von Hippel-Lindau gene (VHL), a negative regulator of hypoxia sensing. Although endemic to the Chuvash population of Russia, this mutation occurs worldwide and originates from a single ancient event. That VHL 598C\u3eT homozygosity causes elevated normoxic levels of the transcription factor hypoxia inducible factor-1α (HIF-1α), serum erythropoietin and hemoglobin is known, but the disease phenotype has not been documented in a controlled manner. In this matched cohort study, WL 598C\u3eT homozygosity was associated with vertebral hemangiomas, varicose veins, lower blood pressures, and elevated serum vascular endothelial growth factor (VEGF) concentrations (P \u3c .0005), as well as premature mortality related to cerebral vascular events and peripheral thrombosis. Spinocerebellar hemangloblastomas, renal carcinomas, and pheochromocytomas typical of classical VHL syndrome were not found, suggesting that overexpression of HIF-1α and VEGF is not sufficient for tumorigenesis. Although hemoglobin-adjusted serum erythropoietin concentrations were approximately 10-fold higher in VHL 598C\u3eT homozygotes than in controls, erythropoietin response to hypoxia was identical. Thus, Chuvash polycythemia is a distinct VHL syndrome manifested by thrombosis, vascular abnormalities, and intact hypoxic regulation despite increased basal expression of hypoxia-regulated genes. © 2004 by The American Society of Hematology