The association of HFE gene H63D polymorphism with endurance athlete status and aerobic capacity: novel findings and a meta-analysis

Ekaterina A Semenova,Eugene V Lekontsev,Eugenia A Boulygina,Liliya B Andryushchenko ,Haruka Murakami,Oleg Borisov ,Mizuki Takaragawa,Andrey K Larin,Е Б Акимов ,Eri Miyamoto‐Mikami ,В П Пушкарев ,Daniil Popov ,Dmitry A Dyatlov,Hisashi Naito,Edward V Generozov,Yuliya E Pushkareva,Motohiko Miyachi,Hirofumi Zempo,Mohamed A Elrayess,Fatima Al‐Khelaifi ,Nikolay A Kulemin,Elena S Kostryukova,Hiroshi Kumagai,Noriyuki Fuku,Ildus I Ahmetov

doi:10.1007/s00421-020-04306-8

Abstract

PurposeIron is an important component of the oxygen-binding proteins and may be critical to optimal athletic performance. Previous studies have suggested that the G allele of C/G rare variant (rs1799945), which causes H63D amino acid replacement, in the HFE is associated with elevated iron indexes and may give some advantage in endurance-oriented sports. The aim of the present study was to investigate the association between the HFE H63D polymorphism and elite endurance athlete status in Japanese and Russian populations, aerobic capacity and to perform a meta-analysis using current findings and three previous studies.MethodsThe study involved 315 international-level endurance athletes (255 Russian and 60 Japanese) and 809 healthy controls (405 Russian and 404 Japanese). Genotyping was performed using micro-array analysis or by PCR. VO2max in 46 male Russian endurance athletes was determined using gas analysis system.ResultsThe frequency of the iron-increasing CG/GG genotypes was significantly higher in Russian (38.0 vs 24.9%; OR 1.85, P = 0.0003) and Japanese (13.3 vs 5.0%; OR 2.95, P = 0.011) endurance athletes compared to ethnically matched controls. The meta-analysis using five cohorts (two French, Japanese, Spanish, and Russian; 586 athletes and 1416 controls) showed significant prevalence of the CG/GG genotypes in endurance athletes compared to controls (OR 1.96, 95% CI 1.58–2.45; P = 1.7 × 10–9). Furthermore, the HFE G allele was associated with high V̇O2max in male athletes [CC: 61.8 (6.1), CG/GG: 66.3 (7.8) ml/min/kg; P = 0.036].ConclusionsWe have shown that the HFE H63D polymorphism is strongly associated with elite endurance athlete status, regardless ethnicities and aerobic capacity in Russian athletes.

Highlights

Iron is an important component of the oxygen-binding proteins, such as hemoglobin and myoglobin
We found that the frequencies of the iron-increasing genotypes (i.e. CG/GG) were significantly higher in Russian and Japanese elite endurance athletes compared to ethnically matched controls
The H63D polymorphism is functional given that the rare G allele has been shown to reduce the ability of the HFE protein to bind to its ligand, thereby preventing the inhibition of transferrin–TFRC binding and resulting in increased transport of iron into circulation and cells (Feder et al 1998)

Summary

Introduction

Iron is an important component of the oxygen-binding proteins, such as hemoglobin and myoglobin. Whereas hemoglobin transports oxygen (via erythrocytes), myoglobin’s function is to store oxygen in working skeletal muscles and to facilitate its transport to mitochondria. 65% of iron is stored in hemoglobin (Wallace 2016), there is a positive correlation between serum iron concentrations and hemoglobin (Ofojekwu et al 2013; Baart et al 2018). Iron can affect many physiological processes, and its deficiency is associated with fatigue, anemia, and decreased exercise performance (DellaValle 2013; Abbaspour et al 2014). There is a balance between iron loss, iron absorption, and iron storage to maintain iron homeostasis (DellaValle 2013; Wallace 2016; Rubeor et al 2018). Endurance athletes have an increased risk for iron loss because of the insufficient dietary intake and training intensity, which leads to increased risk for suboptimal iron status (Hinton 2014)

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