Sickle Cell Anemia

First described clinically almost exactly 100 years ago, sickle cell anemia is an inherited blood disorder due to mutations in the beta globin HBB gene, most commonly SNP rs334. It is found primarily in African and related populations, and one report concludes that everyone alive today carrying the mutation descended from a single ancestor ~7,300 years ago.10.1016/j.ajhg.2018.02.003

The most common allele of rs334 is (A), encoding the Hb A form of (adult) hemoglobin. rs334(T) encodes the sickling form of hemoglobin, Hb S. Only individuals homozygous for this allele, in other words, having the rs334(T;T) genotype, will have sickle cell anemia. The (T) allele appears to have maintained through evolution due to the ~10 fold higher resistance to life-threatening forms of malaria that heterozygotes (rs334(A;T) genotypes) exhibit. Individuals carrying (only) one abnormal beta globin gene are considered to have sickle cell trait.

Sickle cell anemia has several clinical complications beyond the anemia usually arising early in life. These complications may be brought about by additional SNPs, and they include:

• Priapism, which can affect 30% of males with sickle cell anemia; SNPs found to be associated with this complication include [PMID 15638863]:
  • rs2249358, a SNP in the KLOTHO gene
  • rs211239, also in the KLOTHO gene

• Stroke, affecting perhaps 5% of sickle cell anemia patients; a model involving 6+ SNPs has been developed which claims high accuracy in estimating stroke risk for sickle cell anemia patients, involving at least these SNPs [PMID 15778708]:
  • rs11853426, in the ANXA2 gene
  • rs267196, in the BMP6 gene
  • rs408505, also in the BMP6 gene
  • rs3917733, in the SELP gene
  • rs284875, in the TGFBR3 gene
  • rs989554, in the ERG gene
    • The genotypes for these 6 SNPs, in the order listed above and in orientation as in dbSNP, are predicted to have a risk for stroke within 5 years as follows:
      • 0.007: CT, TT, TT, AG, AG, AG
      • 0.060: CT, TT, TT, AG, GG, AG
      • 0.185: TT, TT, CT, GG, GG, AA
      • 0.727: TT, TT, CC, GG, GG, AA
      • 0.868: CC, TT, CC, GG, GG, AA
      • 0.968: CC, TT, CC, AG, GG, AA
• Sickle cell leg ulcers
  • rs736839, adjacent to the SMAD7 gene