A survey of genetic fetal-haemoglobin modifiers in Nigerian patients with sickle cell anaemia

Abstract

Genetic variants at three quantitative trait loci (QTL) for fetal haemoglobin (HbF), BCL11A, HBS1L-MYB and the β-globin gene cluster, have attracted interest as potential targets of therapeutic strategies for HbF reactivation in sickle cell anaemia (SCA). We carried out the first systematic evaluation of critical single nucleotide polymorphisms at these disease modifier loci in Nigerian patients with SCA. Common variants for BCL11A and HBS1L-MYB were strongly associated with HbF levels. At both loci, secondary association signals were detected, illustrating the mapping resolution attainable in this population. For BCL11A, the two independent sites of association were represented by rs1427407 (primary site, p = 7.0 x 10−10) and rs6545816 (secondary site, conditioned on rs1427407: p = 0.02) and for HBS1L-MYB by rs9402686 (HMIP-2B, p = 1.23 x 10−4) and rs66650371 (HMIP-2A, p = 0.002). Haplotype analysis revealed similarities in the genetic architecture of BCL11A and HBS1L-MYB in Nigerian patients. Variants at both loci also alleviated anaemia. The variant allele for the γ globin gene promoter polymorphism XmnI-HBG2 was too infrequent in our patients to be evaluated in this relatively small study. Studying the large and diverse SCA patient populations in African countries such as Nigeria will be key for a clearer understanding of how these loci work and for the discovery of new disease modifier genes.

Genetic modulators of fetal hemoglobin expression and ischemic stroke occurrence in African descendant children with sickle cell anemia

“…The participants in this study showed a mean level of Hb F of 8.9 ± 6.4% which is similar to values reported by other studies on African SCA children, e.g., from Nigeria, Uganda, or Congo Republic, who presented 9.9 ± 6.0% [31], 9.0 ± 5.6% [32], and 8.8 ± 5.8% [33], respectively. Nevertheless, in other studies, lower values of Hb F have been reported for African SCA populations [34][35][36][37]. This discrepancy may be the result of several factors, such as the method used for the Hb F estimation, the age of the SCA patients, or due to environmental, cellular, and genetic factor modulators of phenotypic expression of Hb F. A level of Hb F above 10% has been suggested as necessary for reduced SCA clinical severity [30].…”

Sickle cell disease in Sri Lanka: Clinical and molecular basis and the unanswered questions about disease severeity.

“…The Hb F levels are much higher than those found in SCD patients of Sub-Saharan African origin, and levels greater than 20% would typically be associated with less severe clinical picture. Hb F boosting allele "C" of rs6545816 was detected at a much higher frequency in Sri Lankan patients than in patients from the United Kingdom (34%), Tanzania (36%) and Nigeria (35%) [27,28]. Furthermore, "T" allele of rs1427407 was significantly associated with high Hb F levels (p = 0.04).…”

Sickle cell disease in Sri Lanka: Clinical and molecular basis and the unanswered questions about disease severeity.

“…The Hb F levels are much higher than those found in SCD patients of Sub-Saharan African origin, and levels greater than 20% would typically be associated with less severe clinical picture. Hb F boosting allele "C" of rs6545816 was detected at a much higher frequency in Sri Lankan patients than in patients from the United Kingdom (34%), Tanzania (36%) and Nigeria (35%) (18,37). Furthermore, among those who were not on transfusion and hydroxyurea (n=22), "T" allele of rs1427407 was signi cantly associated with high Hb F levels (p 0.046).…”

“…One Hb F modi er (rs7482144 in Xmn1-HBG2) was genotyped by RFLP. These Hb F markers were selected based on their positive association with Hb F levels in SCD patients suggested by several studies (17)(18)(19).…”