RESUMEN
Sexual differentiation of malaria parasites into gametocytes in the vertebrate host and subsequent gamete fertilization in mosquitoes is essential for the spreading of the disease. The molecular processes orchestrating these transitions are far from fully understood. Here, we report the first transcriptome analysis of male and female Plasmodium falciparum gametocytes coupled with a comprehensive proteome analysis. In male gametocytes there is an enrichment of proteins involved in the formation of flagellated gametes; proteins involved in DNA replication, chromatin organization and axoneme formation. On the other hand, female gametocytes are enriched in proteins required for zygote formation and functions after fertilization; protein-, lipid- and energy-metabolism. Integration of transcriptome and proteome data revealed 512 highly expressed maternal transcripts without corresponding protein expression indicating large scale translational repression in P. falciparum female gametocytes for the first time. Despite a high degree of conservation between Plasmodium species, 260 of these 'repressed transcripts' have not been previously described. Moreover, for some of these genes, protein expression is only reported in oocysts and sporozoites indicating that repressed transcripts can be partitioned into short- and long-term storage. Finally, these data sets provide an essential resource for identification of vaccine/drug targets and for further mechanistic studies.
Asunto(s)
Malaria Falciparum/genética , Plasmodium falciparum/genética , Proteoma/genética , Transcriptoma/genética , Cromatina/genética , Replicación del ADN/genética , Femenino , Gametogénesis/genética , Regulación de la Expresión Génica/genética , Humanos , Malaria Falciparum/parasitología , Masculino , Redes y Vías Metabólicas/genética , Plasmodium falciparum/crecimiento & desarrollo , Plasmodium falciparum/patogenicidad , Biosíntesis de Proteínas , Caracteres SexualesRESUMEN
The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (Pâ=â2.32×10(-12), ORâ=â0.75). Also, rs12540874 in GRB10 gene (Pâ=â1.27 × 10(-6), ORâ=â1.15) and rs11047102 in SOX5 gene (Pâ=â1.39×10(-7), ORâ=â1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (Pâ=â1.79×10(-61), ORâ=â2.48), in the HLA-DPA1/B1 loci with ATA (Pâ=â4.57×10(-76), ORâ=â8.84), and in NOTCH4 with ACA Pâ=â8.84×10(-21), ORâ=â0.55) and ATA (Pâ=â1.14×10(-8), ORâ=â0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.
Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/métodos , Esclerodermia Sistémica/genética , Alelos , Autoanticuerpos/inmunología , Femenino , Sitios Genéticos/genética , Marcadores Genéticos , Antígenos HLA/genética , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Esclerodermia Sistémica/clasificación , Esclerodermia Sistémica/inmunologíaRESUMEN
Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22-23, rs2056626, P = 2.09 x 10(-7) in the discovery samples, P = 3.39 x 10(-9) in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 x 10(-18)), IRF5 (P = 1.86 x 10(-13)) and STAT4 (P = 3.37 x 10(-9)) gene regions as SSc genetic risk factors.