RT Book, Section
A1 Steinberg, Martin H.
A1 Thein, Swee Lay
A2 Gladwin, Mark T.
A2 Kato, Gregory J.
A2 Novelli, Enrico M.
SR Print(0)
ID 1179337842
T1 Genetic Basis of Sickle Cell Disease
T2 Sickle Cell Disease
YR 2021
FD 2021
PB McGraw-Hill Education
PP New York, NY
SN 9781260458596
LK hemonc.mhmedical.com/content.aspx?aid=1179337842
RD 2024/04/20
AB Subsequent  to  its  ancient  origin  in  Africa,  the  sickle  hemoglobin  (HbS)  gene  spread  to  the  Western  Hemisphere,  Europe,  the  Middle  East,  and  the  Indian  subcontinent  by  slave  trading,  war,  and  migration  (Figure  1-1).  The  phenotype  of  sickle  cell  disease  is  caused  by  several  common  and  many  rare  genotypes.  All  have  in  common  at  least  50%  HbS  in  the  blood.  Among  these  genotypes,  the  most  frequent  and  severe  clinically  is  homozygosity  for  the  HbS  gene  (HbSS  or  sickle  cell  anemia),  followed  by  compound  heterozygosity  for  the  HbS  and  the  hemoglobin  C  (HbC)  gene  (HbSC  disease)  and  compound  heterozygosity  for  HbS  and  various  β  thalassemia  genes  (HbS-β  thalassemia).  The  HbS  gene  is  associated  with  5  common  β-globin  gene  haplotypes,  named  after  regions  of  high  gene  frequency  in  Africa,  the  Middle  East,  and  India.  These  haplotypes  have  a  loose  association  with  the  severity  of  disease  that  is  explained  by  the  characteristic  fetal  hemoglobin  (HbF)  level  of  each  haplotype.  HbF  is  the  major  modulator  of  the  phenotype  of  sickle  cell  disease;  it  inhibits  the  polymerization  of  HbS  that  initiates  the  pathophysiology  of  disease,  and  it  also  dilutes  the  intraerythrocytic  HbS  concentration,  a  key  factor  in  the  sickling  kinetics.  Because  HbS  polymerization  is  the  key  mechanism  that  triggers  all  other  pathophysiologic  events,  preventing  polymerization  has  been  of  prime  therapeutic  interest.  Decades  have  been  devoted  to  understanding  how  the  HbF  genes  are  almost  totally  turned  off  after  birth  and  whether  and  how  this  switch  from  fetal  to  adult  hemoglobin  gene  expression  can  be  reversed  by  drugs  or  cellular  therapeutics.  In  this  chapter,  we  prepare  the  reader  for  understanding  the  pathophysiologic  basis  of  the  complications  of  sickle  cell  disease  and  the  future  therapeutic  landscape  by  discussing  the  origin  and  genetic  background  of  the  HbS  mutation,  the  most  common  genotypes  of  this  disease,  the  regulation  of  gene  expression  within  the  globin  gene  clusters,  and  genetic  variants  that  might  explain  disease  heterogeneity.