Search for genetic determinants of individual variability of the erythropoietin response to high altitude

There is marked variability in the erythropoietin (Epo) and erythrocytic response to extreme high altitude among mountain dwellers, as well as to hypoxic training among athletes, at least in part because of the variation in the erythropoietic response to hypoxia. We hypothesized that this may be genetically determined. Forty-eight athletes were exposed to 24 h of simulated altitude to 2800 m in a hypobaric chamber. Serum Epo concentrations were determined at baseline and after 24 h. The Epo responses ranged from -41 to 433% of baseline values after 24 h at simulated altitude. The association of the Epo response to hypoxia with the EPO gene and eight genes involved in Epo regulation utilizing 16 polymorphic dinucleotide repeats was examined. Initial analysis showed a possible association between the EPO gene (marker D7S477) and the increase of the Epo level (P = 0.018). We then tested the possibility that sequence abnormalities in the 3′ and 5′ hypoxia response elements (3′ HRE) and (5′ HRE) of the EPO gene could explain the differences in Epo response. We found a 3434 C → T polymorphism in the 3′ HRE sequence. However, this polymorphism showed no correlation with the differences in Epo levels. Further, when we analyzed two additional markers flanking the EPO gene by less than 0.3 cM, we found no association of the allelic variants at these loci with the Epo hypoxic response. In conclusion, we could find not convincing association between markers tightly linked to EPO or eight genes involved in Epo regulation and Epo differential responses to hypoxia.