ABSTRACT
The clinical severity of sickle cell disease (SCD) is strongly influenced by the level of fetal haemoglobin (HbF) persistent in each patient. Three major HbF loci (BCL11A, HBS1L-MYB, and Xmn1-HBG2) have been reported, but a considerable hidden heritability remains. We conducted a genome-wide association study for HbF levels in 1006 Nigerian patients with SCD (HbSS/HbSß0), followed by a replication and meta-analysis exercise in four independent SCD cohorts (3,582 patients). To dissect association signals at the major loci, we performed stepwise conditional and haplotype association analyses and included public functional annotation datasets. Association signals were detected for BCL11A (lead SNP rs6706648, ß = -0.39, P = 4.96 × 10-34) and HBS1L-MYB (lead SNP rs61028892, ß = 0.73, P = 1.18 × 10-9), whereas the variant allele for Xmn1-HBG2 was found to be very rare. In addition, we detected three putative new trait-associated regions. Genetically, dissecting the two major loci BCL11A and HBS1L-MYB, we defined trait-increasing haplotypes (P < 0.0001) containing so far unidentified causal variants. At BCL11A, in addition to a haplotype harbouring the putative functional variant rs1427407-'T', we identified a second haplotype, tagged by the rs7565301-'A' allele, where a yet-to-be-discovered causal DNA variant may reside. Similarly, at HBS1L-MYB, one HbF-increasing haplotype contains the likely functional small indel rs66650371, and a second tagged by rs61028892-'C' is likely to harbour a presently unknown functional allele. Together, variants at BCL11A and HBS1L-MYB SNPs explained 24.1% of the trait variance. Our findings provide a path for further investigation of the causes of variable fetal haemoglobin persistence in sickle cell disease.
Subject(s)
Anemia, Sickle Cell , GTP-Binding Proteins , Genome-Wide Association Study , Haplotypes , Female , Humans , Male , Alleles , Anemia, Sickle Cell/genetics , Anemia, Sickle Cell/blood , Genetic Predisposition to Disease , Nigeria , Nuclear Proteins/genetics , Polymorphism, Single Nucleotide/genetics , Repressor Proteins/geneticsABSTRACT
The antihyperglycemic effect of the polyherbal combination of the leaves of Momordica balsamina Linn (MB) and Leptadenia hastata (pers) Decne (LH) have been reported in our previous study in addition to its documented dietary usages. However, the bioactive principles are yet to be fully elucidated. In the present study, bioactive antidiabetic compounds from the leaf extracts of Momordica balsamina Linn and Leptadenia hastata (pers) Decne were isolated and characterized. The plant leaves were fractionated with solvents in ascending order of polarity (hexane-chloroform-ethylacetate-methanol) using microwave assisted extraction method. The ethylacetate (MBE) and methanolic (LHM) leaf extracts of MB and LH, having the highest antihyperglycemic effects were purified by column chromatography and preparative thin layer chromatography. The antihyperglycemic activity of the isolated compounds was evaluated in streptozotocin (STZ)-induced diabetic rats and the structures of the most bioactive compounds were elucidated by 1H and 13C Nuclear Magnetic Resonance (NMR) spectroscopy in comparison with reported literature. A pentacyclic triterpenoid (H3) and an isoflavone (LH2b) isolated from MBE and LHM with significant (p < 0.05) antihyperglycemic effects were identified as betulinic acid and 5-methyl genistein respectively. Our study isolated for the first time a triterpenoid and an isoflavone with potential antidiabetic effects from these indigenous antidiabetic plants. This further validates the traditional multi-therapeutic usage of the combination for the management of Diabetes Mellitus (DM) and its complications.