Clinical characteristics and risk factors of relative systemic hypertension and hypertension among sickle cell patients in Cameroon.

Increased blood pressure (BP) has been associated with higher risk of stroke and mortality in Sickle Cell Disease (SCD). We investigated risk factors associated with Relative Systemic Hypertension (RSH) or systemic hypertension in SCD patients in Cameroon. Using R, Multivariate multinomial logistic regression modeling was used to examine the effects of the demographic, anthropometric, clinical, and laboratory factors to determine risk factors. A total of 815 individuals with SCD, including 380 (46.6%) males were analyzed. At baseline, the median age [interquartile range] was 18.0 [12.0-25.0] years, ranging from 3 to 66 years. Approximately three-quarters of the patients (n = 645; 79.1%) had normal BP, 151 (18.5%) had RSH and 19 (2.3%) had hypertension. Age (P < 0.001) and gender (P = 0.022) were significantly different across the BP categories. Weight (P < 0.001), height (P < 0.001), BMI (P < 0.001), pulse pressure (P = 0.020), history of stroke (P = 0.012), hemoglobin level (P = 0.002), red blood cell count (P = 0.031), creatinine (P < 0.001), and (estimated glomerular filtration rate) eGFR (P = 0.002) was also significantly different across the three BP categories. After adjustment, the significantly associated factors of RSH in the SCD patients were age [OR = 1.03, (95% CI = 1.01-1.06), P < 0.010], male gender [OR = 1.54, (95% CI = 1.04-2.27), P = 0.029], BMI [OR = 1.10, (95% CI = 1.04-1.17), P = 0.001]. After adjustment, the independent variables significantly associated factors of Hypertension in the SCD patients were age [OR = 1.05, (95% CI = 1.01-1.10), P = 0.034], male gender [OR = 3.31, (95% CI = 1.04-10.52), P = 0.042], BMI [OR = 1.14, (95% CI = 1.01-1.29), P = 0.027]. Creatinine was significantly associated with RSH [OR =1.31 (1.05-1.63), P = 0.016]. SCD patients with RSH or hypertension maybe at increased risk of renal dysfunction. We found relatively high prevalence of RSH and hypertension (20.8%) in SCD patients in Cameroon. Tailored Interventions that consider major risk factors (age, gender, and BMI) may lower BP pressure and prevent severe complications.

Genetic modifiers of long-term survival in sickle cell anemia.

BACKGROUND: Sickle cell anemia (SCA) is a clinically heterogeneous, monogenic disorder. Medical care has less-than-optimal impact on clinical outcomes in SCA in Africa due to several factors, including patient accessibility, poor access to resources, and non-availability of specific effective interventions for SCA. METHODS: Against this background, we investigated 192 African participants who underwent whole exome sequencing. Participants included 105 SCA patients spanning variable clinical expression: a "long survivor" group (age over 40 years), a "stroke" group (at least one episode of overt stroke), and a "random" group (patients younger than 40 years without overt cerebrovascular disease). Fifty-eight ethnically matched homozygous hemoglobin A controls were also studied. Findings were validated in an independently recruited sample of 29 SCA patients. Statistical significance of the mutational burden of deleterious and loss-of-function variants per gene against a null model was estimated for each group, and gene-set association tests were conducted to test differences between groups. RESULTS: In the "long survivor" group, deleterious/loss-of-function variants were enriched in genes including CLCN6 (a voltage-dependent chloride channel for which rare deleterious variants have been associated with lower blood pressure) and OGHDL (important in arginine metabolism, which is a therapeutic target in SCA). In the "stroke" group, significant genes implicated were associated with increased activity of the blood coagulation cascade and increased complement activation, for example, SERPINC1, which encodes antithrombin. Oxidative stress and glutamate biosynthesis pathways were enriched in "long survivors" group. Published transcriptomic evidence provides functional support for the role of the identified pathways. CONCLUSIONS: This study provides new gene sets that contribute to variability in clinical expression of SCA. Identified genes and pathways suggest new avenues for other interventions.

Association between Variants at BCL11A Erythroid-Specific Enhancer and Fetal Hemoglobin Levels among Sickle Cell Disease Patients in Cameroon: Implications for Future Therapeutic Interventions.

Variants in BCL11A were previously associated with fetal hemoglobin (HbF) levels among Cameroonian sickle cell disease (SCD) patients, however explaining only ∼2% of the variance. In the same patients, we have investigated the relationship between HbF and two SNPs in a BCL11A erythroid-specific enhancer (N=626). Minor allele frequencies in rs7606173 and rs1427407 were 0.42 and 0.24, respectively. Both variants were significantly associated with HbF levels (p=3.11e-08 and p=6.04e-06, respectively) and explained 8% and 6.2% variations, respectively. These data have confirmed a stronger effect on HbF of genomic variations at the BCL11A erythroid-specific enhancer among patients with SCD in Cameroon, the first report on a West African population. The relevance of these findings is of prime importance because the disruption of this enhancer would alter BCL11A expression in erythroid precursors and thus HbF expression, while sparing the induced functional challenges of any alterations on the expression of this transcription factor in non-erythroid lineages, thus providing an attractive approach for new treatment strategies of SCD.

Perspectives in Genetics and Sickle Cell Disease Prevention in Africa: Beyond the Preliminary Data from Cameroon.

Management of sickle cell disease (SCD) in Africa needs to be accompanied by various preventive strategies, including early detection via prenatal genetic diagnosis (PND). Contrary to Cameroonian doctors who considered termination of an affected pregnancy (TAP) for SCD in 36.1%, the majority of parents (62.5%) with affected children accepted TAP in principle. In practice, most women opted for TAP (90%), justified by a huge psycho-social burden. The ethical and legal challenges of PND prompted the need to explore the use of genetics for secondary prevention of SCD. In 610 Cameroonian SCD patients, the genomic variations in two principal foetal haemoglobin-promoting loci were significantly associated with foetal haemoglobin levels. In addition, the co-inheritance of a 3.7-kb α-globin gene deletion and SCD was associated with a late disease onset and possibly improved survival: there was a much higher allele frequency of the 3.7-kb α-globin gene deletion in SCD patients (∼ 40%) than in haemoglobin AA controls (∼ 10%). The data indicate the urgent need to develop and implement policy actions in sub-Saharan Africa on at least four levels: (1) the implementation of SCD screening practices and early neonatal follow-up; (2) the development and incorporating of socio-economic support to alleviate the burden of SCD on affected families; (3) the exploration of the appropriateness of the medical abortion laws for SCD, and (4) the development of national plans for genetic medicine, including research on genomic variants that affect the phenotypes of SCD, in order to potentially use them for anticipatory guidance.

The co-inheritance of alpha-thalassemia and sickle cell anemia is associated with better hematological indices and lower consultations rate in Cameroonian patients and could improve their survival.

BACKGROUND: Co-inheritance of α-thalassemia was reported to be associated with a delayed age of disease onset among Cameroonian Sickle Cell Anemia (SCA) patients. The present study aimed to explore the correlation between α-thalassemia, hematological indices, and clinical events in these patients. METHODS AND FINDINGS: We studied 161 Cameroonian SCA patients and 103 controls (59.1% HbAA) with median ages of 17.5 and 23 years. RFLP-PCR was used to confirm SCA genotype and to describe haplotypes in the HBB-like genes cluster. Multiplex Gap-PCR was performed to investigate the 3.7 kb α-globin gene deletions. SNaPshot PCR, capillary electrophoresis and cycle sequencing were used for the genotyping of 10 SNPs in BCL11A, HMIP1/2, OR51B5/6 and HBG loci, known to influence HbF levels. Generalised linear regression models adjusted for age, sex and SNPs genotypes was used to investigate effects of α-thalassemia on clinical and hematological indices. The median rate of vaso-occlusive painful crisis and hospitalisations was two and one per year, respectively. Stroke was reported in eight cases (7.4%). Benin haplotype was the most prevalent (66.3%; n = 208 chromosomes). Among patients, 37.3% (n = 60) had at least one 3.7 kb deletion, compared to 10.9% (n = 6) among HbAA controls (p<0.001). Among patients, the median RBC count increased with the number of 3.7 kb deletions [2.6, 3.0 and 3.4 million/dl, with no, one and two deletions (p = 0.01)]. The median MCV decreased with the number of 3.7 kb deletion [86, 80, and 68fl, with no, one and two deletions (p<0.0001)], as well as median WBC counts [13.2, 10.5 and 9.8×109/L (p<0.0001. The co-inheritance of α-thalassemia was associated with lower consultations rate (p = 0.038). CONCLUSION: The co-inheritance of α-thalassemia and SCA is associated with improved hematological indices, and lower consultations rate in this group of patients. This could possibly improve their survival and explain the higher proportion of α-thalassemia among patients than controls.