While HIF-2α appears to be the key factor in mediating the response to anemia with an impact on EPO synthesis and iron handling [49,50,52,53,54,55,56,57], the DNA target sequences for HIF-1α and HIF-2α are similar, thus, in vivo there appears to be significant differentiation regarding the downstream effects of the two isoforms [58,59]. This evidence concerns the gene EPO and anemia (phenotype).