RESUMEN
Despite high rates of exposure, only 5-10% of people infected with Mycobacterium tuberculosis will develop active tuberculosis (TB) disease, suggesting a significant role for genetic variation in the human immune response to this infection. Here, we studied TB association and expression of 18 genes involved in the Toll-like receptor (TLR) pathways. Initially, we genotyped 149 sequence polymorphisms in 375 pulmonary TB patients and 387 controls from Indonesia. We found that four polymorphisms in the TLR8 gene on chromosome X showed evidence of association with TB susceptibility in males, including a non-synonymous polymorphism rs3764880 (Met1Val; P = 0.007, odds ratio (OR) = 1.8, 95% c.i. = 1.2-2.7). We genotyped these four TLR8 polymorphisms in an independent collection of 1,837 pulmonary TB patients and 1,779 controls from Russia and again found evidence of association in males (for rs3764880 P = 0.03, OR = 1.2, 95% c.i. = 1.02-1.48). Combined evidence for association is P = 1.2x10(-3)-6x10(-4). In addition, a quantitative PCR analysis indicated that TLR8 transcript levels are significantly up-regulated in patients during the acute phase of disease (P = 9.36x10(-5)), relative to baseline levels following successful chemotherapy. A marked increase in TLR8 protein expression was also observed directly in differentiated macrophages upon infection with M. bovis bacille Calmette-Guérin (BCG). Taken together, our results provide evidence, for the first time, of a role for the TLR8 gene in susceptibility to pulmonary TB across different populations.
Asunto(s)
Receptor Toll-Like 8/genética , Tuberculosis Pulmonar/genética , Tuberculosis Pulmonar/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Línea Celular , Cromosomas Humanos X/genética , Femenino , Expresión Génica , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Indonesia , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , ARN Mensajero/genética , ARN Mensajero/metabolismo , Caracteres Sexuales , Receptor Toll-Like 8/metabolismoAsunto(s)
Ligamiento Genético , Glicoproteínas de Membrana/genética , Polimorfismo de Nucleótido Simple , Receptores de Interleucina-1/genética , Tuberculosis Pulmonar/genética , Estudios de Casos y Controles , Análisis Mutacional de ADN , Frecuencia de los Genes , Ghana , Humanos , Indonesia , Leucina/genética , Federación de Rusia , Serina/genéticaRESUMEN
The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods-recursive partitioning and regression-to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; P(combined) = 2.01 x 10(-19) and 2.35 x 10(-13), respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Genes MHC Clase I/genética , Predisposición Genética a la Enfermedad/genética , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Alelos , Estudios de Casos y Controles , Bases de Datos Genéticas , Frecuencia de los Genes , Genes MHC Clase II/genética , Genotipo , Antígenos HLA-DQ/genética , Cadenas beta de HLA-DQ , Antígenos HLA-DR/genética , Cadenas HLA-DRB1 , Humanos , Polimorfismo de Nucleótido Simple/genética , Tamaño de la Muestra , Población Blanca/genéticaRESUMEN
The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 x 10(-7) between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (P(follow-up) Asunto(s)
Mapeo Cromosómico
, Diabetes Mellitus Tipo 1/genética
, Predisposición Genética a la Enfermedad
, Genoma Humano
, Adolescente
, Estudios de Casos y Controles
, Humanos
, Polimorfismo de Nucleótido Simple
RESUMEN
Recently, the Intracellular pathogen resistance 1 (Ipr1) gene was shown to control susceptibility to Mycobacterium tuberculosis in mice. We examined whether common sequence variants of its human orthologue, the SP110 gene, are associated with susceptibility to tuberculosis in a human population. We resequenced SP110 exons in 96 individuals and identified new polymorphisms. Then, we combined our sequence and HapMap data for 83 distinct polymorphisms and selected tags that capture information for all common variants in the 100 kb region around SP110. We genotyped 29 single nucleotide polymorphisms including seven amino-acid changing variants in 1,912 HIV-negative culture-confirmed adult pulmonary tuberculosis patients and 2,104 adult healthy controls from Russia and found no evidence of association. Our results indicate that common polymorphisms of the SP110 gene have no major effect on susceptibility to tuberculosis in this population.
Asunto(s)
Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Polimorfismo Genético , Análisis de Secuencia de ADN/métodos , Tuberculosis Pulmonar/genética , Alelos , Exones , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Intrones , Antígenos de Histocompatibilidad Menor , Mutación , Mycobacterium tuberculosis/metabolismo , Oportunidad Relativa , Federación de Rusia , Tuberculosis Pulmonar/microbiologíaRESUMEN
Recently, the interleukin-18 cytokine gene (IL18) was reported to be associated with type 1 diabetes. In the present report, we calculated that the reported genotypes of the two 5' region/promoter single nucleotide polymorphisms (SNPs), -607 (C-->A) (rs1946518) and -137 (G-->C) (rs187238), were not in Hardy-Weinberg equilibrium (HWE). We therefore investigated the association of the -607 and -137 SNPs in a U.K. type 1 diabetic Caucasian case-control collection (1,560 case and 1,715 control subjects tested at -607 and 4,323 case and 4,610 control subjects tested at -137) as well as a type 1 diabetic Caucasian collection comprised of families of European ancestry (1,347 families tested at -137 and 1,356 families tested at -607). No evidence for association with type 1 diabetes was found, including for the -607 A/A and C/A genotypes. To evaluate whether common variation elsewhere in the gene was associated with disease susceptibility, we analyzed eight IL18 tag SNPs in a type 1 diabetic case-control collection (1,561 case and 1,721 control subjects). No evidence for association was obtained (P = 0.11). We conclude that common allelic variation in IL18 is unlikely to contribute substantially to type 1 diabetes susceptibility in the populations tested and recommend routine application of tests for HWE in population-based studies for genetic association.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Frecuencia de los Genes , Interleucina-18/genética , Polimorfismo de Nucleótido Simple/genética , Alelos , Población Negra/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Obesidad/genética , Población Blanca/genéticaRESUMEN
Susceptibility to the autoimmune disease type 1 diabetes has been linked to human chromosome 6q27 and, moreover, recently associated with one of the genes in the region, TATA box-binding protein (TBP). Using a much larger sample of T1D families than those studied by others, and by extensive re-sequencing of nine other genes in the proximity, in which we identified 279 polymorphisms, 83 of which were genotyped in up to 725 T1D multiplex and simplex families, we obtained no evidence for association of the TBP CAG/CAA (glutamine) microsatellite repeat sequence with disease, or for nine other genes, PDCD2, PSMB1, KIAA1838, DLL1, dJ894D12.4, FLJ25454, FLJ13162, FLJ11152, PHF10 and CCR6. This study also provides an exon-based tag single nucleotide polymorphism map for these 10 genes that can be used for analysis of other diseases.