Abstract
Chuvash polycythemia is a rare autosomal recessive hereditary disease, with affected homozygotes having decreased survival mainly because of increased incidence of stroke and other thrombotic complications. Intriguingly this risk may be augmented, rather than ameliorated, by phlebotomies (Sergueeva et al, Blood, 2015, and Haematologica 2017).
Chuvash polycythemia is characterized by a C to T missense mutation of the von Hippel Lindau (VHL) gene at nucleotide 589 (VHLC589T, encoding VHLR200W). VHL is a negative regulator of hypoxia-inducible factor (HIF) α subunits. Homozygosity for VHLC589T upregulates hypoxic responses through constitutively augmented HIF signaling even in normoxia, resulting in an increase of erythropoiesis. Heterozygosity leads to only mild augmentation of hypoxia sensing.
Chuvash polycythemia was first identified in people of the Chuvash region in Russia, where it has estimated heterozygosity frequency of 1.7%, likely due to a founder effect. The incidence of Chuvash polycythemia elsewhere is sporadic, and the condition is found in other ethnic groups, including northern Indians of Indo-European ethnicity and northern Europeans. Another hot spot of gene frequency was found among Italians on the island of Ischia. We previously published that VHLC589Thomozygotes from various parts of the world share a common VHL haplotype, and from the size of the shared haplotype, we could calculate that it originated from the same founder about 30-50,000 years ago (Liu, et al, Blood 2004). The same shared haplotype was also identified in Ischia in VHLC589Thomozygotes (Perrotta et al, Blood 2006).
A single individual from Turkey had the VHLC589T mutation on a different haplotype (Turkish haplotype, Cario, et al, Heamatologica, 2005) demonstrating the existence of another independent founder of the VHLC589T mutation. Two polycythemic patients with VHLC589T mutation were recently referred to us, one from Afghanistan (among people using the Dravidian language who had frequent historical interactions with Turkey) and the other from southern India (the ethnicity of which is also Dravidian and distinct from Indo-European ethnicity). We hypothesized that the Chuvash polycythemia patients, who originated from Afghanistan and Southern India, might have the Turkish haplotype, strengthening support for two independent founders of this haplotype. We analyzed the VHL haplotype of these 2 individuals using 6 selected single nucleotide polymorphisms.
Genomic DNA was isolated from granulocytes. Haplotype analysis was performed by Sanger Sequencing. We found that the Chuvash polycythemia patients from Afghanistan and Southern India shared the common Chuvash haplotype (Table).
We conclude that the Chuvash haplotype is also present in VHLC589T homozygotes in Afghanistan and Southern India, suggesting that the VHLC589T mutation in these areas arose from the same common founder. The data support the notion that the Chuvash polycythemia VHL mutation originated relatively early in modern human evolution- possibly after humans moved from Africa- as it is present in different ethnic and racial groups (Europeans and Asians). This observation is compatible with the notion that VHLC589T heterozygosity provides some evolutionary advantage (present in various ethnic groups and did not disappear, i.e., absence of negative selection because of increased mortality of homozygotes). It has been shown that heterozygosity for VHLC589T provides some protection from anemia; it is likely that other evolutionary benefits remain to be identified (Miasnikova et al, Haematologica 2011). Yet, such an advantage is very mild (very low gene frequency worldwide of this mutation). These data provide additional evidence that support a VHLC589T origin before Asians and European diverged.
No relevant conflicts of interest to declare.
