RESUMEN
BACKGROUND: Staphylococcus aureus (S. aureus) has been implicated in the pathogenesis of chronic rhinosinusitis (CRS). However, host factors contributing to susceptibility to S. aureus colonization in CRS remain unknown. We wish to investigate, using a pooled genomewide association study (pGWAS), single-nucleotide polymorphisms (SNPs) associated with S. aureus carriage in CRS patients. METHODS: An existing population of 408 CRS patients and 190 controls was prospectively recruited for genetic association studies. All CRS patients had an endoscopic swab culture as part of phenotyping. A pGWAS compared DNA pools from patients with and without S. aureus colonization using the Illumina HumanHap 1M BeadChip, which interrogates 1 million SNPs. Top-ranked SNPs associated with S. aureus colonization were selected according to biallelic differences and silhouette rank, and confirmed by individual genotyping using the Sequenom platform. PLINK software was used for genetic association tests. Ingenuity pathway analysis was used to identify canonical and signaling pathways enriched for genes neighboring associated SNPs, as well as identification of the underlying biological mechanisms. RESULTS: Thirty-nine top priority SNPs were selected for individual genotyping. Out of 39 SNPs, 23 were associated (p < 0.05) with S. aureus colonization in CRS patients. These SNPs are located within or near 21 genes reported to be implicated in several diseases, endocytic internalization, and bacterial recognition. CONCLUSION: These results suggest novel host genetic factors influencing susceptibility to S. aureus colonization in CRS. Identifying implicated mechanisms may offer new insights into pathogenesis of CRS.
Asunto(s)
Rinitis/genética , Sinusitis/genética , Infecciones Estafilocócicas/genética , Staphylococcus aureus/inmunología , Adulto , Canadá , Adhesión Celular/genética , Movimiento Celular/genética , Enfermedad Crónica , Análisis Mutacional de ADN , Femenino , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Humanos , Queratinas Específicas del Pelo/genética , Queratinas Tipo II/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Rinitis/complicaciones , Transducción de Señal/genética , Sinusitis/complicaciones , Infecciones Estafilocócicas/complicaciones , Proteína de Unión al GTP rac1/genéticaRESUMEN
OBJECTIVE: To replicate and extend recent findings in a Turkish population of associations between chronic rhinosinusitis (CRS) with nasal polyposis and single-nucleotide polymorphisms (SNPs) in the IL1A (rs17561 and Ser114Ala), IL1B (rs16944), and TNF (rs361525 and rs1800629) genes. DESIGN: In a case-control replication study, DNA samples were obtained from 206 patients with severe CRS (cases) and from 196 postal code-matched controls. For IL1A and TNF, the 3 reported SNPs were complemented with tagging SNPs using an International HapMap genotyping data set to ensure complete genetic coverage. For IL1B, only the single reported SNP was assessed. A total of 24 SNPs (7 in IL1A, 1 in IL1B, and 16 in TNF) were individually genotyped. The PLINK software package was used to perform genetic association tests. SETTING: Academic research. PATIENTS: Canadian population of individuals with severe CRS. MAIN OUTCOME MEASURES: Allelic differences between cases and controls. RESULTS: Significant allelic differences between cases and controls were obtained for IL1A rs17561 (odds ratio [OR], 1.48; P = .02). The following 3 additional SNPs in this gene were associated with CRS: rs2856838 (OR, 0.63; P = .003), rs2048874 (OR, 0.57; P = .01), and rs1800587 (OR, 1.49; P = .02). These 3 SNPs remained significant after correction for multiple testing. No association was found with IL1B or TNF. CONCLUSIONS: We replicated the previously reported association between the IL1A polymorphism and severe CRS and identified 3 potential new associations in the same gene. This further supports the potential contribution of IL1A to the development of CRS. We were unable to replicate previous reports of associations with IL1B or TNF.
Asunto(s)
Interleucina-1alfa/genética , Interleucina-1beta/genética , Pólipos Nasales/genética , Rinitis/genética , Sinusitis/genética , Factor de Necrosis Tumoral alfa/genética , Adulto , Anciano , Canadá , Estudios de Casos y Controles , Enfermedad Crónica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Alpha-1-antitrypsin (AAT) is a serine protease inhibitor that blocks the protease, neutrophil elastase. Previous population studies have suggested that heterozygote status for the AAT gene (SERPINA1) is a risk factor for chronic rhinosinusitis with nasal polyposis (CRSwNP). This implies a potential genetic predisposition to CRS tied to AAT deficiency. The purpose of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in the SERPINA1 gene and CRS. METHODS: DNA extracted from a population of 206 patients diagnosed with CRSwNPs and 196 postal code-matched controls was used. A maximally informative set of tagging SNPs from SERPINA1 on chromosome 14q were selected from the HapMap data set (International HapMap Consortium, Nature 437:1299-1320, 2005) and genotyped on the Sequenom platform (Sequenom, San Diego, CA). RESULTS: Successful genotyping was performed for 32 of 33 SNPs. Two SNPs (rs1243168 and rs4900229) located upstream of the SERPINA1gene, were associated with CRS. Individuals homozygous (TT) for these SNPs had an increased probability of having CRS with an odds ratio of 5.95 and 1.49, respectively. Subgroup analysis according to severity of disease identified each SNP to be increasingly common in individuals as disease severity increased (p < 0.001). These individuals were also less likely to be responsive to medical therapy (p < 0.001). CONCLUSION: Polymorphisms of the SERPINA1 gene are associated with clinically severe CRS. These results, from a small subset of individuals with CRS, suggest that defects in AAT may be implicated in a subset of individuals unresponsive to conventional therapy and suggests that alternate therapies may be required for their management.
Asunto(s)
Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Rinitis/genética , Sinusitis/genética , alfa 1-Antitripsina/genética , Adulto , Anciano , Enfermedad Crónica , Análisis Mutacional de ADN , Progresión de la Enfermedad , Resistencia a Medicamentos/genética , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Pólipos Nasales , Rinitis/tratamiento farmacológico , Rinitis/fisiopatología , Sinusitis/tratamiento farmacológico , Sinusitis/fisiopatología , alfa 1-Antitripsina/inmunología , alfa 1-Antitripsina/metabolismoRESUMEN
RATIONALE: Stimulation of interleukin-22 receptor alpha-1 (IL22RA1) was reported to increase the innate immune responses in inflammatory diseases. Moreover, a reduced level of IL22RA1 was found in patients with recalcitrant CRS with nasal polyps. OBJECTIVE: To explore association between single nucleotide polymorphisms (SNPs) in IL22RA1 and severe CRS. METHODS: We extracted DNA from 206 cases with severe CRS and 196 postal code-matched controls. Twenty-three SNPs in the IL22RA1 gene were selected from the pooling-based genome-wide association study and from the CEU HapMap dataset and genotyped. PLINK software was used to determine association. RESULTS: After Bonferroni correction, three SNPs (rs4292900 P(nom) = 0.0006, OR = 1.757; rs4648936 P(nom) = 0.0011, OR = 1.716; rs16829225 P(nom) = 0.0014, OR = 1.977) show significant differences in allelic frequencies between cases and controls. CONCLUSION: Polymorphisms in IL22RA1 are associated with severe CRS. Replication and functional studies are involved to better understand the mechanism by which these polymorphisms contribute to the pathogenesis of CRS.
Asunto(s)
Receptores de Interleucina/genética , Rinitis/genética , Sinusitis/genética , Estudios de Casos y Controles , Enfermedad Crónica , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Historia del Siglo XVII , Humanos , Modelos Logísticos , Masculino , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Encuestas y CuestionariosRESUMEN
BACKGROUND: Factors conferring susceptibility to chronic rhinosinusitis remain unknown. However, advances in genomics offer powerful tools to explore this disorder. Tumour necrosis factor (TNF) is a crucial proinflammatory cytokine that exerts inflammatory and immunomodulatory activities important in host defense. Our objective was to determine whether polymorphisms in genes in the TNF superfamily (TNF, TNF-alpha-induced protein 3, TNF-alpha-induced protein 6) were associated with chronic rhinosinusitis. METHODS: Deoxyribonucleic acid (DNA) extracted from a population of 206 patients with severe chronic rhinosinusitis and 196 postal code-matched controls was used. Three candidate genes related to the TNF inflammatory pathway were assessed. For each gene, an informative set of single nucleotide polymorphisms was genotyped. RESULTS: Thirty-five single nucleotide polymorphisms were genotyped. Two polymorphisms located within the TNF-alpha-induced protein 3 gene (TNFAIP3) reached the nominal p value threshold (p < .05) for association with chronic rhinosinusitis. However, none of these polymorphisms resist multiple testing adjustments. CONCLUSIONS: Our data suggest that two polymorphisms in TNFAIP3 are weakly associated with severe chronic rhinosinusitis but do not support an association with genetic variants in TNF or TNF-alpha-induced protein 6. Although these results do not support correction for multiple testing and have to be validated in a second population, they nevertheless suggest that further studies of the role of TNFAIP3 in the pathogenesis of disease are warranted.
