Objective
To evaluate the spectrum of genetic defects in Indian patients with unexplained erythrocytosis.
Methods
Fifteen families (18 patients) with unexplained erythrocytosis were enrolled after excluding polycythemia vera and secondary erythrocytosis. Focused Sanger sequencing from genomic DNA was performed for EPOR (exon 8), VHL (exons 2‐3), EGLN1 (exons 2‐5), EPAS1 (exon 12), and all exons of HBB, HBA1, and HBA2 genes.
Results
Eleven of the 18 patients (including two pairs of brothers) had Chuvash polycythemia, that is, homozygosity for VHL:c.598C > T (p.Arg200Trp). Three patients (two of whom were brothers) had HBB mutations associated with increased oxygen‐affinity hemoglobin—one had a heterozygous Hb McKees Rocks HBB:c.438T > A (p.Tyr146*), and two brothers showed heterozygous Hb Rainier HBB:c.437A > G (p.Tyr146Cys). No pathogenic variants were found in the remaining four cases.
Conclusion
A gene‐by‐gene Sanger sequencing approach could determine a genetic basis for erythrocytosis in 11 of the 15 (73%) Indian families, with homozygous VHL:c.598C > T (p.Arg200Trp) being the commonest pathogenic variant. This first study from the Indian subcontinent provides a rationale for analyzing this variant in patients with suspected congenital erythrocytosis from this region.
Rare first occurrences of Hb McKees Rocks and Hb Rainier in Indians are also being reported.
Coumarin derivatives such as warfarin and acenocoumarol are used in various disorders such as deep venous thrombosis, pulmonary embolism, atrial fibrillation and artificial heart valves. They have improved prognosis of patients with thromboembolic disease. An individual's response to coumarins depends on several factors. The non-genetic factors include age, gender, body mass index, diet and interacting drugs. Among the genetic factors, the cytochrome P450 system and vitamin K epoxide reductase complex subunit 1 play a key role in drug metabolism. This was a prospective hospital based study in which allele and genotypic frequencies of CYP2C9 gene polymorphisms; 430C>T and 1075A>C and VKORC1 gene polymorphisms; 1639G>A, 9041G>A and 6009C>T in 106 alleles of north Indian patients with valve replacement on acenocoumarol were determined and their effect on acenocoumarol dosing was studied. To the best of our knowledge, this is first report of VKORC1 9041G>A and 6009C>T gene polymorphisms and their effect on acenocoumarol dosing from north India. In 53 patients with valve replacement on acenocoumarol with stable INR, the allele frequency of CYP2C9*2 and CYP2C9*3 gene polymorphisms was 0.05 and 0.17 respectively and that of VKORC1 *2,*3 and *4 gene polymorphisms was 0.15, 0.72 and 0.11 respectively. The presence of CYP2C9*3 or VKORC1*2 gene polymorphism were associated with decrease in acenocoumarol dose requirements (p values 0.03 and 0.02 respectively).This study confirmed the association of lower mean weekly dosages of acenocoumarol in patients with CYP2C9*3 and VKORC1*2 gene polymorphisms. An unusually high frequency of 9041A polymorphism in VKORC1 was found in study population.
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