The genetic dissection of fetal haemoglobin persistence in sickle cell disease in Nigeria.

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.

In-vivo anti-plasmodial activity of phosphate buffer extract of Calotropis procera latex in mice infected with Plasmodium berghei.

ETHNOPHARMACOLOGICAL RELEVANCE: Malaria is a global health problem with the greatest burden in sub-Saharan Africa (sSA). The resistance to available antimalarial agents necessitate for the development of new and safe drugs for which medicinal plants provides credible alternative sources for discovering new and cheap therapeutic agents. Calotropis procera is used in several folk or traditional medicines for the treatment of various diseases across different regions of the world. In Nigeria traditional medicine, C. procera latex is used either alone or in combination with other herbs to cure common diseases including malaria. In Malaka district (Indonesia), Calotropis gigantea (a member of Apocyanceae), is one of the most used herbs to treat malaria patient via the massage method. AIM OF THE STUDY: This study aimed to evaluate the anti-plasmodial activity of phosphate buffer extract of Calotropis procera latex in mice infected with Plasmodium berghei. MATERIALS AND METHODS: The plant's anti-plasmodial agent was extracted using 0.2 M-phosphate buffer (pH 7.0), followed by precipitation using acetone. 90 (ninety) mice were divided into three main groups of 30 (thirty) mice each, used for the curative, suppressive and prophylactic tests, respectively. The 30 (thirty) mice in each of the main groups were sub-divided into five groups of 6 (six) mice. The mice in the group 1, 2 and 3 (test groups) were made to receive graded doses of 25 mg/kg, 50 mg/kg and 75 mg/kg of the extract of C. procera latex intraperitoneally; group 4 (negative control group) received 0.2 ml of normal saline; while group 5 (positive control group) were administered with 5 mg/kg chloroquine. The phytochemical constituents of the plant and its intraperitoneal median lethal dose (LD50) were also undertaken. RESULTS: The freeze-dried acetone extract exhibited acute toxicity with median lethal dose (LD50) of 745 mg/kg body weight in mice. The highest percentage parasite suppression (61.85%), percentage parasite cure (50.26%), and percentage parasite prophylaxis (65.47%), were obtained for the groups treated with 75 mg/kg bodyweight/day of the extract. The least percentage parasite suppression (44.74%), percentage parasite cure (35.21%), and percentage parasite prophylaxis (45.21%), were obtained for the groups treated with 25 mg/kg body weight of the extract. Also, a dose-dependent percentage parasite suppression (53.03%), percentage parasite cure (39.70%), and percentage parasite prophylaxis (49.82%) were obtained for the groups treated with 50 mg/kg body weight. This is comparable to the groups treated with standard chloroquine. The extract also produced a significant elevation in body weight of the animals for suppressive and curative tests. However, there were observable significant decreases in body weight of the animals in the case of prophylactic test. CONCLUSION: This study showed that the phosphate buffer extract of C. procera latex possess anti-plasmodial activity. The results of this study can be used as a basis for further phytochemical investigations in the search for new and locally affordable antimalarial agents.

Hyperhomocysteinemia and its relations to conventional risk factors for cardiovascular diseases in adult Nigerians: the REMAH study.

BACKGROUND: Evidence linking homocysteine (Hcy) with cardiovascular diseases (CVD) or its risk factors are limited in a sub-Saharan black population. OBJECTIVE: We set out to evaluate the association between Hcy and hypertension and other CVD risk factors in a population of adult Nigerians. METHODS: Data of 156 adults aged 18-70 years was accessed from the North Central study site of the REmoving the MAsk on Hypertension (REMAH) study. Homocysteine, blood glucose and lipid profile in whole blood/serum were measured using standard laboratory methods. Hypertension was diagnosed if average of 5 consecutive blood pressure (BP) measurements obtained using a mercury sphygmomanometer was equal to or higher than 140 systolic and/or 90 mmHg diastolic or the individual is on antihypertensive medication. Hyperhomocysteinemia (HHcy) was defined as Hcy > 10 µmol/L. RESULTS: Of the 156 participants, 72 (43.5%) were hypertensive, of whom 18 had HHcy. Subjects with HHcy were significantly (p < 0.05) older (41.5 vs. 40.6yrs), had lower HDL-cholesterol (0.6 vs. 0.8 mmol/L) and higher systolic (145.5 vs. 126.0 mmHg) and diastolic BP (92.9 vs. 79.6 mmHg), compared to those without HHcy. Intake of alcohol and a 1 yr increase in age were respectively and significantly (p < 0.05) associated with a 1.54 and 0.10 µmol/L increase in Hcy. In a multivariable model adjusted for age, sex and body mass index, a 1 µmol/L increase in Hcy, was associated with a 1.69 mmHg and 1.34 mmHg increase in systolic and diastolic pressure (p < 0.0001) respectively; and a 0.01 mmol/L decrease in HDL-cholesterol (p < 0.05). CONCLUSION: HHcy occurs among hypertensive Nigerians and it is independently associated with age, HDL-cholesterol, systolic and diastolic BP.