RESUMEN
Mobile genetic elements (MEs) are heritable mutagens that recursively generate structural variants (SVs). ME variants (MEVs) are difficult to genotype and integrate in statistical genetics, obscuring their impact on genome diversification and traits. We developed a tool that accurately genotypes MEVs using short-read whole-genome sequencing (WGS) and applied it to global human populations. We find unexpected population-specific MEV differences, including an Alu insertion distribution distinguishing Japanese from other populations. Integrating MEVs with expression quantitative trait loci (eQTL) maps shows that MEV classes regulate tissue-specific gene expression by shared mechanisms, including creating or attenuating enhancers and recruiting post-transcriptional regulators, supporting class-wide interpretability. MEVs more often associate with gene expression changes than SNVs, thus plausibly impacting traits. Performing genome-wide association study (GWAS) with MEVs pinpoints potential causes of disease risk, including a LINE-1 insertion associated with keloid and fasciitis. This work implicates MEVs as drivers of human divergence and disease risk.
Asunto(s)
Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Humanos , Regulación de la Expresión Génica , Sitios de Carácter Cuantitativo , FenotipoRESUMEN
Bone marrow stromal cell antigen-2 (BST-2)/Tetherin is a restriction factor that prevents Human immunodeficiency virus type 1 (HIV-1) release from infected cells and mediates pro-inflammatory cytokine production. This study investigated the risk conferred by single nucleotide polymorphisms (rs919266, rs9192677, and rs9576) at BST-2 coding gene (BST2) in HIV-1 mother-to-child transmission and in disease progression. Initially, 101 HIV-1+ pregnant women and 331 neonates exposed to HIV-1 from Zambia were enrolled. Additional BST2 single nucleotide polymorphism analyses were performed in 2 cohorts with acquired immunodeficiency syndrome (AIDS) progression: an adult Brazilian cohort (37 rapid, 30 chronic and 21 long-term non-progressors) and an Italian pediatric cohort (21 rapid and 67 slow progressors). The rs9576A allele was nominally associated with protection during breastfeeding (P = 0.019) and individuals carrying rs919266 GA showed slower progression to AIDS (P = 0.033). Despite the influence of rs919266 and rs9576 on BST2 expression being still undetermined, a preventive role by BST2 polymorphisms was found during HIV-1 infection.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/genética , Antígenos CD/genética , Progresión de la Enfermedad , VIH-1/fisiología , Transmisión Vertical de Enfermedad Infecciosa , Madres , Polimorfismo Genético , Complicaciones Infecciosas del Embarazo/genética , Síndrome de Inmunodeficiencia Adquirida/fisiopatología , Adulto , Femenino , Proteínas Ligadas a GPI/genética , VIH-1/crecimiento & desarrollo , Humanos , Inmunidad Innata/genética , Recién Nacido , Masculino , Embarazo , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , ZambiaRESUMEN
HLA and other genetic variants, playing an important role in innate and adaptive immunity, are known to influence tuberculosis (TB) development in HIV-1-positive (HIV+) patients. Because inflammasome genes contribute to HIV-1 susceptibility, we investigated the possible association between polymorphisms in inflammasome genes with HIV-1 and Mycobacterium tuberculosis coinfection (HIV+TB+) in a case/control cohort of Brazilian individuals. Nineteen single-nucleotide polymoprhims in 8 inflammasome genes (NLRP1, NLRP3, AIM2, CARD8, CASP1, IL1B, IL1R, and HSP90) were analyzed in HIV+TB+ Brazilian patients (from Recife, Pernambuco). CARD8 rs6509365 polymorphism was associated with HIV+TB+ (P = 5 × 10(-5)), suggesting a predisposing role of this variant in M. tuberculosis susceptibility in HIV+ subjects (odds ratio = 2.45). This effect is even strong when this allele is combined to CARD8 rs2043211 single-nucleotide polymoprhim. The results of this study support the novel association between CARD8 gene and HIV+TB+ coinfection, demonstrating that inflammasome genetics could influence HIV-1 infection and the development of opportunistic infection.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/genética , Proteínas Adaptadoras de Señalización CARD/genética , Infecciones por VIH/genética , Proteínas de Neoplasias/genética , Tuberculosis/genética , Infecciones Oportunistas Relacionadas con el SIDA/complicaciones , Adulto , Alelos , Brasil , Coinfección , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Infecciones por VIH/complicaciones , Humanos , Inflamasomas/genética , Masculino , Mycobacterium tuberculosis , Polimorfismo de Nucleótido Simple , Tuberculosis/complicacionesRESUMEN
The involvement of inflammasome genes in the susceptibility to HIV-1 infection was investigated. Twelve single nucleotide polymorphisms within NLRP1, NLRP3, NLRC4, CARD8, CASP1, and IL1B genes were analyzed in 150 HIV-1-infected Brazilian subjects and 158 healthy controls. The 2 polymorphisms rs10754558 in NLRP3 and rs1143634 in IL1B were significantly associated to the HIV-1 infection. These findings supported the previously hypothesized involvement of NALP3-inflammasome in HIV-1 pathogenesis, underlining once more the key role of inflammation and innate immunity in the susceptibility to HIV-1 infection.
Asunto(s)
Predisposición Genética a la Enfermedad , Infecciones por VIH/genética , VIH-1 , Inflamasomas/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Polimorfismo de Nucleótido Simple , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Proteínas Reguladoras de la Apoptosis/genética , Brasil , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas de Unión al Calcio/genética , Proteínas Portadoras/genética , Caspasa 1/genética , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Interleucina-1beta/genética , Masculino , Persona de Mediana Edad , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas NLR , Proteínas de Neoplasias/genéticaRESUMEN
Recent findings provide evidence of inflammasome critical role in the predisposition to autoimmune disorders. The involvement of inflammasome in the pathogenesis of systemic lupus erythematosus (SLE) has been hypothesized even if no significant association within inflammasome genes mutations or polymorphisms and lupus has been reported yet. We analyzed 14 single nucleotide polymorphisms (SNPs) within 7 inflammasome genes (NLRP1, NLRP3, NLRC4, AIM2, CARD8, CASP1, IL1B) in 144 patients affected by systemic lupus erythematosus and in 158 healthy controls from Southern Brazilian (state of São Paulo) with the aim of disclosing the possible role of inflammasome genes in the susceptibility of SLE. Our results demonstrated that NLRP1 rs2670660 SNP and the NLRP1 rs12150220-rs2670660 A-G haplotype were associated with SLE in our study population, and in particular with the development of nephritis, rash and arthritis. These findings are concordant with previously reported association of NLRP1 with vitiligo and type-1 diabetes underlining once more the involvement of NALP1 inflammasome in the pathogenesis of autoimmune disorders.
