Patients' recruitment and data collection
Patients were recruited through the nationwide German
SCD registry (NCT03327428) which collects prospective
and retrospective data on patients with SCD in Germany.All patients
for whom the complete set of genetic traits of interest (a-
thalassemia, HBG2-polymorphism rs7482144, BCL11A poly-
morphisms rs1427407 and rs7606173, HMIP polymorphism
rs66650371) was available in combination with the respect-
ive laboratory parameter (n=121 for HbF to n=164 for MCV)
(Table 2) were included in the analyses that correlated gen-
etics with laboratory parameters and clinical course.Data on complications and treatment
of SCD were documented annually, together with routine
laboratory parameters (hemoglobin, mean corpuscular vol-
ume [MCV], reticulocytes, lactate dehydrogenase [LDH], bili-
rubin and HbF) (Table 1).In the case of insuf-
ficient efficacy, a dose escalation up to the maximum tol-
erated dose or to 35 mg/kg/day is recommended.In order to investigate geographic and ethnic differences in
the phenotypic expression of SCD, we categorized patients
according to the origins of their parents from one of the
three regions Mediterranean Sea, Sub-Saharan Africa and
"rest of the world".Treatment guidelines implemented in 2014 recommend
parental education, the use of penicillin prophylaxis at
least until the age of 5 years, and annual screening with
transcranial Doppler ultrasound starting from 2 until 18
years of age.The data collected included demographic information, di-
agnosis and genotype, treatment, laboratory parameters
and clinical events.For the analysis of the frequency and distribution of genetic
modifiers, patients with homozygous SCD of all ages and ir-
respective of treatment were included.For the analysis of laboratory parameters
and complications of SCD, only patients at least 2 years of
age and with ongoing treatment with hydroxyurea were con-
sidered.The study was performed according to the Declaration of
Helsinki and approved by the institutional review board of
the Medical Faculty of Heidelberg University (S 416/2014).At the time of the data cutoff, May 13,
2020, 425 patients with homozygous SCD from 28 different
institutions were enrolled in the registry.