Olympic Games: When the haematocrit does not fit, the athlete is not always a cheat

Dear Editor,

The upcoming Olympic Games will be accompanied by intense testing for doping, which is unfortunately not uncommon in top-level sporting circles. Among classic doping products used in endurance sports, erythropoietin (EPO) drug, the biological copy of the main EPO hormone responsible for substantial increases in haemoglobin (Hb) concentration and haematocrit (Ht), is one of the originals, both in terms of its age (available since the 1980s) and frequency of use (61 doping cases worldwide in 2022) [1].

The history of the Olympic Games is associated with the discovery of mutations in the EPO receptor gene, EPOR, in the 1990s. The first mutation was identified in Eero Mäntyranta, who won multiple Olympic and world champion medals in cross-country skiing [2]. At that time, no technique was available to identify blood doping using EPO drug, or transfusion, for which methods were validated in the early 2000s [3].

Here, we report two cases in which top-level athletes were disqualified solely on the basis of high Hb and Ht values. These athletes were found to be carriers of familial polycythaemia associated with functionally tested pathogenic mutations in genes involved in the hypoxia-sensing pathway several years after their disqualification from the sporting world, underlining the importance of having recourse to specialized testing before making serious accusations.

A 34-year-old male, who started playing soccer at a young age, applied to enter a sports-study high school when he was 16 years old. His application was rejected due to the presence of high Hb and Ht values (Table 1). The doctor overseeing his case suspected doping, leading to the man's subsequent ban from sports study in high school and competitions. Eighteen years later, his son was diagnosed with polycythaemia, suggesting familial erythrocytosis and samples from the father and son were analysed using NGS sequencing with a gene panel dedicated to the exploration of polycythaemia. A pathogenic mutation (p.Asp525Gly) in EPAS1 was identified in the father and son and three other relatives segregating with a polycythaemia phenotype. The EPAS1 gene encodes the hypoxia-inducible factor HIF2α, which regulates the expression of EPO when oxygen concentrations go down.

The second medical record concerns a top-level national Taekwondo athlete, for whom a routine examination revealed high Ht and Hb values (Table 1), leading to definitive banishment from competition. Ten years later, the patient's sister was referred to the hospital for absolute idiopathic polycythaemia. Given the sister's history of polycythaemia, the hypoxia-regulating genes were sequenced, which revealed a pathogenic mutation in the EGLN1 gene (p.Trp334Arg). EGLN1 encodes the PHD2 protein, which plays a major role in the degradation of HIF2α. This mutation was found in the athlete and her sister, as well as in three other relatives, confirming the segregation of the mutation with the systematic presence of polycythaemia.

Although these two case reports sadly emphasize the difficulties in the past to differentiate blood doping from atypically high Hb, they also show how progress in science, in particular genetic analyses, can now bring answers to uncommon cases. Since 2009, the longitudinal follow-up of the haematological parameters of high-level athletes has been performed, and high Hb could not be confused with doping anymore [4]. Recently, a single-nucleotide polymorphism (c.577del) found in the EPO gene was linked to atypical EPO profiles of Asian athletes and is now taken into account before concluding to doping [5].

Elite sports performance has been shown to be influenced by heritable components. The germline mutation in EPOR is the first mutation shown to increase athletic performance in relation to red blood cell production. We show here that the oxygen-related genes EGLN1/PHD2 and EPAS1/HIF2A should also be added to the growing list of genes predisposing to sports performance. In our opinion, high Hb or Ht values in athletes need to be tested using NGS sequencing with a dedicated panel of genes, in order to identify genetic abnormalities related to hereditary erythrocytosis.

François Girodon recruited patients. Nada Maaziz and Betty Gardie performed genetic analyses. François Girodon, Nada Maaziz and Betty Gardie wrote the manuscript. Laurent Martin and Alexandre Marchand reviewed the manuscript. François Girodon directed the study. All authors contributed to the research and approved the final manuscript.

The authors declare no potential conflicts of interest regarding the present work.

This research received no external funding.

Written informed consent has been obtained from the patients to publish this paper.