Genetic modifiers of fetal hemoglobin affect the course of sickle cell disease in patients treated with hydroxyurea

Pierre Allard, Nareen Alhaj, Stephan Lobitz, Holger Cario, Andreas Jarisch, Regine Grosse, Lena Oevermann, Dani Hakimeh, Laura Tagliaferri, Elisabeth Kohne, Annette Kopp-Schneider, Andreas E Kulozik, Joachim B Kunz, Pierre Allard, Nareen Alhaj, Stephan Lobitz, Holger Cario, Andreas Jarisch, Regine Grosse, Lena Oevermann, Dani Hakimeh, Laura Tagliaferri, Elisabeth Kohne, Annette Kopp-Schneider, Andreas E Kulozik, Joachim B Kunz

Abstract

The course of sickle cell disease (SCD) is modified by polymorphisms boosting fetal hemoglobin (HbF) synthesis. However, it has remained an open question how these polymorphisms affect patients who are treated with the HbF-inducing drug hydroxyurea/ hydroxycarbamide. The German SCD registry offers the opportunity to answer this question, because >90% of patients are treated according to national guidelines recommending the use of hydroxyurea in all patients above 2 years of age. We analyzed the modifying effect of HbF-related genetic polymorphisms in 417 patients with homozygous SCD >2 years old who received hydroxyurea. HbF levels were correlated with higher total hemoglobin levels, lower rates of hemolysis, a lower frequency of painful crises and of red blood cell transfusions. The minor alleles of the polymorphisms in the γ-globin promoter (rs7482144), BCL11A (rs1427407) and HMIP (rs66650371) were strongly associated with increased HbF levels. However, these associations did not translate into lower frequencies of vaso-occlusive events which did not differ between patients either carrying or not carrying the HMIP and BCL11A polymorphisms. Patients on hydroxyurea carrying the γ-globin promoter polymorphism demonstrated substantially higher hemoglobin levels (P<10-4) but also higher frequencies of painful crises and hospitalizations (P<0.01) when compared to patients without this polymorphism. Taken together, these data indicate that the γ-globin, HMIP and BCL11A polymorphisms correlate with increased HbF in SCD patients on hydroxyurea. While HbF is negatively correlated with the frequency of painful crises and hospitalizations, this was not observed for the presence of known HbF-boosting alleles.

Figures

Figure 1.
Figure 1.
Linear regression of HbF on laboratory parameters.
Figure 2.
Figure 2.
Correlation between HbF level and complications of sickle cell disease. Poisson regression. (A-C) Numbers of patients available for analysis: 193 for hospitalization (A), 194 for pain crises (B), and red blood cell transfusion (C). Thick lines represent the predicted values, thin lines represent the 95% confidence interval.
Figure 3.
Figure 3.
Mean values of laboratory parameters and complications comparing patients positive or negative for the γ-globin promoter polymorphism rs7482144. (A) Mean HbF ± standard deviation (SD): negative patients (n=105) versus positive patients (n=24): 17.5±10% versus 23.6±8.6%; t-test P=0.0061. (B) Mean hemoglobin ± SD: negative patients (n=143) versus positive patients (n=29): 8.9±1.5 g/dL versus 10.1±1.3 g/dL; t-test P<10-. (C) Mean frequency of hospitalizations per year ± SD: negative patients (n=142) versus positive patients (n=27): 0.8±1.3 versus 1.9±2.6; t-test P=0.0011. (D) Mean frequency of pain crises per year ± SD: negative patients (n=143) versus positive patients (n=27): 0.6±1.1 versus 1.7±2.5; t-test P=0.0003. HbF: fetal hemoglobin; Hb: total hemoglobin.

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