HPSE and sickle cell disease: However, the continued focus on rs1800497 has impeded understanding of the gene, much as if studies of sickle cell anemia had not advanced from use of the Hpa1 RFLP, discovered by Kan et al89 in 1978, to the HBB Val6 missense variant that causes sickle cell anemia and with which the RFLP discovered by Kan et al is in LD.