Sickle cell trait in São Tomé e Príncipe: a population-based prevalence study in women of reproductive age.

BACKGROUND: Sickle Cell Disorder is Africa's most prevalent genetic disease. Yet, it remains a neglected condition, with high mortality under-five, and a lack of population-based studies in the region. This is the first of its kind in São Tomé e Príncipe, aiming to estimate the prevalence of sickle cell trait and other haemoglobin variants in women of reproductive age and its associated factors. METHODS: We conducted a cluster survey in 35 neighbourhoods. Haemoglobin was assessed through point-of-care capillary electrophoresis or high-performance liquid chromatography, and sociodemographic data through questionnaires. The weighted prevalence of sickle cell trait (HbAS) and HbC carriers was estimated with a 95% confidence interval (95% CI). We calculated weighted prevalence ratios (95% CI) through robust Poisson regression for its association with age and individual and collective genetic heritage. FINDINGS: The prevalence of sickle cell trait in women of reproductive age in São Tomé e Príncipe (n = 376) was 13.45% (95% CI: 9.05-19.00). The prevalence of HbC carriers was 8.00% (95% CI: 4.71-12.00). Older age and speaking Forro or Angolar were positively associated with having sickle cell trait. INTERPRETATION: The prevalence of sickle cell trait in São Tomé e Príncipe ranks high in the West African region. The country should follow international guidelines, implementing newborn screening and comprehensive healthcare management.

NOS2 variants reveal a dual genetic control of nitric oxide levels, susceptibility to Plasmodium infection, and cerebral malaria.

Nitric oxide (NO) is a proposed component of malaria pathogenesis, and the inducible nitric oxide synthase gene (NOS2) has been associated to malaria susceptibility. We analyzed the role of NOS2 polymorphisms on NO bioavailability and on susceptibility to infection, Plasmodium carrier status and clinical malaria. Two distinct West African sample collections were studied: a population-based collection of 1,168 apparently healthy individuals from the Príncipe Island and a hospital-based cohort of 269 Angolan children. We found that two NOS2 promoter single-nucleotide polymorphism (SNP) alleles associated to low NO plasma levels in noninfected individuals were also associated to reduced risk of pre-erythrocytic infection as measured anti-CSP antibody levels (6.25E-04 < P < 7.57E-04). In contrast, three SNP alleles within the NOS2 cistronic region conferring increased NO plasma levels in asymptomatic carriers were strongly associated to risk of parasite carriage (8.00E-05 < P < 7.90E-04). Notwithstanding, three SNP alleles in this region protected from cerebral malaria (7.90E-4 < P < 4.33E-02). Cohesively, the results revealed a dual regimen in the genetic control of NO bioavailability afforded by NOS2 depending on the infection status. NOS2 promoter variants operate in noninfected individuals to decrease both NO bioavailability and susceptibility to pre-erythrocytic infection. Conversely, NOS2 cistronic variants (namely, rs6505469) operate in infected individuals to increase NO bioavailability and confer increased susceptibility to unapparent infection but protect from cerebral malaria. These findings corroborate the hypothesis that NO anti-inflammatory properties impact on different steps of malaria pathogenesis, explicitly by favoring infection susceptibility and deterring severe malaria syndromes.

SLC40A1 Q248H allele frequencies and associated SLC40A1 haplotypes in three West African population samples.

BACKGROUND: Ferroportin is a transmembrane protein responsible for iron export from enterocytes and macrophages. Mutation c.744G → T (Q248H), located in exon 6 of the ferroportin gene SLC40A1, is found as a polymorphism in populations of African origin. This mutation has been extensively analysed in African-Americans, but poorly studied in native African populations. AIM: To increase information about Q248H mutation frequency in native sub-Saharan populations examining three West African populations. SUBJECTS AND METHODS: Samples from S. Tomé e Príncipe (n = 115), Angola (n = 156) and Republic of Guinea (n = 170) were analysed for Q248H mutation and for two polymorphisms, IVS1( - 24)G → C and microsatellite (CGG)(n), using standard molecular methodology. RESULTS: The estimated frequencies of Q248H allele were 2.2% in S. Tomé e Príncipe, 3.5% in Angola and 4.1% in Republic of Guinea. Analysis of polymorphisms IVS1( - 24)G → C and (CGG)(n) showed mutation allele c.744T to be strongly associated with haplotype IVS1( - 24)G/(CGG)(7). CONCLUSIONS: This study confirmed the presence of Q248H mutation at polymorphic frequencies in three native sub-Saharan populations. Analysis of two additional markers in the same gene support a single origin of the mutant allele c.744T in the haplotype background IVS1( - 24)G/(CGG)(7).

Analysis of TPI gene promoter variation in three sub-Saharan Africa population samples.

Population samples from Angola, Mozambique, and S. Tomé e Príncipe were screened for the TPI gene promoter variants -5A-->G, -8G-->A and -24T-->G. Three haplotypes were identified in the three populations: the haplotype -5A-8G-24T (average frequency 65.3%) and two less common haplotypes -5G-8G-24T (average frequency 24.7%) and -5G-8A-24T (average frequency 10.0%). A population sample from Central Portugal showed the haplotype -5A-8G-24T in 139 chromosomes and one subject heterozygous for haplotype -5G-8A-24G. The exact test of sample differentiation among three groups of malaria-infected individuals classified according to the severity of the disease showed no significant differences. We confirmed TPI gene diversity in sub-Saharan Africa, but we could not detect any association between TPI promoter variation and a malarial protective effect. Larger scale epidemiological studies are thus required to clarify this putative mechanism of natural host defense against this worldwide public health problem.