F cell numbers are associated with an X‐linked genetic polymorphism and correlate with haematological parameters in patients with sickle cell disease

Summary Patients with sickle cell disease (SCD) with high fetal haemoglobin (HbF) tend to have a lower incidence of complications and longer survival due to inhibition of deoxyhaemoglobin S (HbS) polymerisation by HbF. HbF‐containing cells, namely F cells, are strongly influenced by genetic factors. We measured the percentage of F cells (Fcells%) in 222 patients with SCD to evaluate the association of (i) Fcells% with genetic HbF‐modifier variants and (ii) Fcells% with haematological parameters. There was a different distribution of Fcells% in females compared to males. The association of the B‐cell lymphoma/leukaemia 11A ( BCL11A ) locus with Fcells% (β = 8·238; P  < 0·001) and with HbF% (β = 2·490; P  < 0·001) was significant. All red cell parameters except for Hb and mean corpuscular Hb concentration levels in males and females were significantly different. The Fcells% was positively associated with mean cell Hb, mean cell volume and reticulocytes. To explain the significant gender difference in Fcells%, we tested for associations with single nucleotide polymorphisms on the X chromosomal region Xp22.2, where a genetic determinant of HbF had been previously hypothesised. We found in males a significant association with a SNP in FERM and PDZ domain‐containing protein 4 ( FRMPD4 ) and adjacent to male‐specific lethal complex subunit 3 ( MSL3 ). Thus, we have identified an X‐linked locus that could account for a significant fraction of the Fcells% variation in patients with SCD.