Polymorphisme des Beta Thalassemies en Algerie: caracterisation structurale et fonctionnelle d'une mutation nouvelle

SIGLEINIST T 73766 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Variants of the Mannose-Binding Lectin Gene in the Benin Population: Heterozygosity for the p.G57E Allele May Confer a Selective Advantage

Human mannose-binding lectin (MBL) plays an important role in innate immunity.MBLdeficiency is associated with mutations in the promoter region and in exon 1 of the MBL2 gene. Such deficiency has been correlated with elevated incidence of infections in infancy and in immunocompromised adults. We determined the distribution profile of the MBL2 gene variants in the general population of Benin (West Africa) and in a vulnerable subset of children with sickle cell disease (SCD) (SS homozygotes). Five hundred fortytwo healthy individuals (274 newborns, 268 adults) and 128 patients with SCD (35 newborns, 93 children) were screened for the common variant alleles in the MBL2 secretor haplotype region (exon 1 and promoter). The p.G57E variant allele was the most frequent allele compared to p.G54D (27.5% vs. 1.6%, respectively). The p.R52C allele was not found in this population. There was no difference in allele or genotype frequencies between healthy newborns and newborns with SCD. Alleles associated with MBL deficiency were more frequent in adults than in newborns (69.8% vs. 57.3%, respectively; p = 0.002). This enrichment was exclusively due to an elevated proportion of heterozygotes for the p.G57E allele (47.0% vs. 35.3%, respectively; p = 0.004), supporting a potential selective advantage of this genotype. Our results, compared to those reported in other African countries, support the implication of the MBL2 gene in various major infections in Africa, such as meningitis and tuberculosis in HIV-positive patients

Variants of the Mannose-Binding Lectin Gene in the Benin Population: Heterozygosity for the p.G57E Allele May Confer a Selective Advantage

Human mannose-binding lectin (MBL) plays an important role in innate immunity. MBL deficiency is associated with mutations in the promoter region and in exon 1 of the MBL2 gene. Such deficiency has been correlated with elevated incidence of infections in infancy and in immunocompromised adults. We determined the distribution profile of the MBL2 gene variants in the general population of Benin (West Africa) and in a vulnerable subset of children with sickle cell disease (SCD) (SS homozygotes). Five hundred forty-two healthy individuals (274 newborns, 268 adults) and 128 patients with SCD (35 newborns, 93 children) were screened for the common variant alleles in the MBL2 secretor haplotype region (exon 1 and promoter). The p.G57E variant allele was the most frequent allele compared to p.G54D (27.5% vs. 1.6%, respectively). The p.R52C allele was not found in this population. There was no difference in allele or genotype frequencies between healthy newborns and newborns with SCD. Alleles associated with MBL deficiency were more frequent in adults than in newborns (69.8% vs. 57.3%, respectively; p = 0.002). This enrichment was exclusively due to an elevated proportion of heterozy-gotes for the p.G57E allele (47.0% vs. 35.3%, respectively; p = 0.004), supporting a potential selective advantage of this genotype. Our results, compared to those reported in other African countries, support the implication of the MBL2 gene in various major infections in Africa, such as meningitis and tuberculosis in HIV-positive patients

Warfarin Pharmacogenetics: Polymorphisms of the CYP2C9, CYP4F2 , and VKORC1 loci in a genetically admixed Omani Population

This is the first study to evaluate the spectrum and prevalence of dose-predictive genetic polymorphisms of the CYP2C9, CYP4F2 and VKORC1 loci together, in a geographically defined, ethnically admixed healthy adult Omani population sharing common lifestyle/environmental factors. Since the present-day Omani population is the result of an admixture of Caucasian, African and Asian ancestries, we compared the pharmacoge- netic profile of these three loci in this population. Interestingly, the Omani pharmacogenetic profile, in terms of allele and genotype distribution, has values that are intermediate between Caucasians and African Americans, the African admixture further substantiated by the presence of the CYP2C9*8 allele. However, limitations and usefulness of such comparisons warrant caution, as the data from pharmacogenetic literature do not always represent bona fide population categories. Furthermore, definition of study population based on microgeographical scale would be more appropriate in pharmaco- genetic research rather than the flawed racial, ethnic, or social categoriza- tions since pharmacogenetic variation is clinal, and genetic influences will be further altered by lifestyle and environmental factors

Haplotypes in Tribal Indians Bearing the Sickle Gene: Evidence for the Unicentric Origin of the ßs Mutation and the Unicentric Origin of the Tribal Populations of India

To determine the origin of sickle cell anemia (SS) in India, we analyzed haplotypes of the ß gene cluster in ßs-carrying individuals belonging to tribal populations living in the Nilgiris region of southern India and complemented the available data on tribes of east-central India. We found that in the Nilgiris tribes chromosomes bearing the ßs gene are linked in 91% of the cases to the “Asian” (Arab-Indian) haplotype (although 25% of the haplotypes had the c polymorphic site negative, making the 5\u27 portion of the haplotype identical with the African Senegal haplotype). These XmnI (+) chromosomes were associated with high Gɿ expression (67.2 ± 5.9%) and a high percentage of Hb F (15.5 ± 7.9%; range, 6-25.3%). We have similar findings for tribal groups from west-central India (Gujarat). In east-central India we have confirmed the data of others, finding the same haplotype linked to ßs in tribes living in the east (Orissa, Andhra Pradesh). We conclude that the ßs gene in presently isolated and disperse tribal populations in India is associated with one predominant typical haplotype, suggesting a unicentric origin of the mutation in India. In addition, this finding implies a unicentric origin of the tribal populations themselves: The gene must have arisen and spread before tribal dispersion. Furthermore, we find extremely high frequencies of the (—α) haplotype in the Nilgiris (0.89) and in Gujarat (0.95). The ßs gene linkage to a high Hb F-expressing haplotype and the high incidence of α-thalassemia predict a mild phenotypical expression of sickle cell anemia in India

Association of haemolysis markers, blood viscosity and microcirculation function with organ damage in sickle cell disease in <scp>sub‐Saharan</scp> Africa (the <scp>BIOCADRE</scp> study)

International audienceSummary Sickle cell anaemia (SCA) is a monogenic disease with a highly variable clinical course. We aimed to investigate associations between microvascular function, haemolysis markers, blood viscosity and various types of SCA‐related organ damage in a multicentric sub‐Saharan African cohort of patients with SCA. In a cross‐sectional study, we selected seven groups of adult patients with SS phenotype in Dakar and Bamako based on the following complications: leg ulcer, priapism, osteonecrosis, retinopathy, high tricuspid regurgitant jet velocity (TRV), macro‐albuminuria or none. Clinical assessment, echocardiography, peripheral arterial tonometry, laboratory tests and blood viscosity measurement were performed. We explored statistical associations between the biological parameters and the six studied complications. Among 235 patients, 58 had high TRV, 46 osteonecrosis, 43 priapism, 33 leg ulcers, 31 retinopathy and 22 macroalbuminuria, whereas 36 had none of these complications. Multiple correspondence analysis revealed no cluster of complications. Lactate dehydrogenase levels were associated with high TRV, and blood viscosity was associated with retinopathy and the absence of macroalbuminuria. Despite extensive phenotyping of patients, no specific pattern of SCA‐related complications was identified. New biomarkers are needed to predict SCA clinical expression to adapt patient management, especially in Africa, where healthcare resources are scarce

Warfarin pharmacogenetics: development of a dosing algorithm for Omani patients

International audienceThe objective of our present study was to develop a warfarin dosing algorithm for the Omani patients, as performances of warfarin dosing algorithms vary across populations with impact on the daily maintenance dose. We studied the functional polymorphisms of CYP2C9, CYP4F2 and VKORC1 genes to evaluate their impact on the warfarin maintenance dose in an admixed Omani patient cohort with Caucasian, African and Asian ancestries. We observed a 64-fold inter-patient variability for warfarin to achieve stable international normalized ratio in these patients. Univariate analysis revealed that age, gender, weight, atrial fibrillation, deep vein thrombosis/pulmonary embolism and variant genotypes of CYP2C9 and VKORC1 loci were significantly associated with warfarin dose in the studied patient population. However, multiple regression model showed that only the atrial fibrillation, and homozygous CYP2C9 variant genotypes (*2/*3 and *3/*3) and VKORC1 GA and AA genotypes remained significant. A multivariate model, which included demographic, clinical and pharmacogenetic variables together explained 63% of the overall inter-patient variability in warfarin dose requirement in this microgeographically defined, ethnically admixed Omani patient cohort on warfarin. This locally developed model performed much better than the International Warfarin Pharmacogenetics Consortium (IWPC) model as the latter could only explain 34% of the inter-patient variability in Omani patients. VKORC1 3673G&gt;A polymorphism emerged as the single most important predictor of warfarin dose variability, even in this admixed population (partial R(2)=0.45)