Genome-wide association studies (GWAS) and their importance in asthma

Asthma is a complex disease determined by the interaction of different genes and environmental factors. The first genetic investigations in asthma were candidate gene association studies and linkage studies. In recent years research has focused on association studies that scan the entire genome without any prior conditioning hypothesis: the so-called genome-wide association studies (GWAS). The first GWAS was published in 2007, and described a new locus associated to asthma in chromosome 17q12-q21, involving the ORMDL3, GSDMB and ZPBP2 genes (a description of the genes named in the manuscript are listed in Table 1). None of these genes would have been selected in a classical genetic association study since it was not known they could be implicated in asthma. To date, a number of GWAS studies in asthma have been made, with the identification of about 1000 candidate genes. Coordination of the different research groups in international consortiums and the application of new technologies such as new generation sequencing will help discover new implicated genes and improve our understanding of the molecular mechanisms underlying the disease

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Genome-wide association studies (GWAS) and their importance in asthma.

Asthma is a complex disease determined by the interaction of different genes and environmental factors. The first genetic investigations in asthma were candidate gene association studies and linkage studies. In recent years research has focused on association studies that scan the entire genome without any prior conditioning hypothesis: the so-called genome-wide association studies (GWAS). The first GWAS was published in 2007, and described a new locus associated to asthma in chromosome 17q12-q21, involving the ORMDL3, GSDMB and ZPBP2 genes (a description of the genes named in the manuscript are listed in Table 1). None of these genes would have been selected in a classical genetic association study since it was not known they could be implicated in asthma. To date, a number of GWAS studies in asthma have been made, with the identification of about 1000 candidate genes. Coordination of the different research groups in international consortiums and the application of new technologies such as new generation sequencing will help discover new implicated genes and improve our understanding of the molecular mechanisms underlying the disease.

Implications of cytokine genes in allergic asthma

Asthma is a complex disease involving numerous mediator molecules and effector cells, in combination with a range of environmental determining factors. Cytokines play a key role in the physiopathological mechanisms of asthma; the study of the structure, regulation and variations of the genes that encode for these molecules is therefore crucial. Cytokines have extremely diverse roles, and exert effects both as activators and inhibitors of the innate and adaptive immune response. Certain modifications in the expression or structure of these molecules, resulting from the presence of polymorphisms, may give rise to deregulation of the mentioned effects, and therefore to a predisposition to develop concrete asthma phenotypes

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Implications of cytokine genes in allergic asthma.

Asthma is a complex disease involving numerous mediator molecules and effector cells, in combination with a range of environmental determining factors. Cytokines play a key role in the physiopathological mechanisms of asthma; the study of the structure, regulation and variations of the genes that encode for these molecules is therefore crucial. Cytokines have extremely diverse roles, and exert effects both as activators and inhibitors of the innate and adaptive immune response. Certain modifications in the expression or structure of these molecules, resulting from the presence of polymorphisms, may give rise to deregulation of the mentioned effects, and therefore to a predisposition to develop concrete asthma phenotypes.

The prostaglandin D2 receptor (PTGDR) gene in asthma and allergic diseases

The prostaglandin D2 receptor (PTGDR) gene has been associated to asthma and related phenotypes by linking and association studies. Functional studies involving animal models and other expression studies based on in vitro cell models also point to a possible role of polymorphisms in the promoter region, in the differential binding of transcription factors, and thus in PTGDR expression, which appear to be associated to the development of asthma or of susceptibility to the disease

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The prostaglandin D2 receptor (PTGDR) gene in asthma and allergic diseases.

The prostaglandin D2 receptor (PTGDR) gene has been associated to asthma and related phenotypes by linking and association studies. Functional studies involving animal models and other expression studies based on in vitro cell models also point to a possible role of polymorphisms in the promoter region, in the differential binding of transcription factors, and thus in PTGDR expression, which appear to be associated to the development of asthma or of susceptibility to the disease.

Polymorphisms of the IL12B, IL1B, and TNFA Genes and Susceptibility to Asthma

Background: Asthma is one of the most common chronic inflammatory diseases in developed countries. Susceptibility to asthma is associated with interaction between multiple genes and environmental factors. Several cytokines play a major role in the pathophysiology of the disease. Objective: We analyzed the distribution of cytokine gene polymorphisms in a group of patients with asthma and a control group in order to determine the effect of these variants, or their combinations, on the development of clinical phenotypes. Methods: We genotyped 22 single-nucleotide polymorphisms (SNPs) corresponding to 13 cytokine genes (IFNG, IL1A, IL1B, IL1R1, IL1RN, IL2, IL4, IL4R, IL6, IL10, IL12B, TGFB1, and TNFA) in 376 individuals (219 asthmatic patients and 157 controls). Genetic association was evaluated using genotype and allele models for different asthma phenotypes. Gene–gene interactions were explored using multifactor dimensionality reduction. Results: Genotype AC of IL12B -1188 was associated with the presence of asthma. A significant association was detected between 2 SNPs analyzed in TNFA (–308 and –238) and atopic asthma and severe-persistent asthma. The IL1B TT haplotype (3962T and –511T) was also associated with atopy and moderate-persistent asthma. Conclusion: Our data show that the presence of SNPs in IL12B, TNFA, and IL1B was significantly associated with asthma, atopy, and severity of asthma. We also highlight the importance of genetic context, haplotype, and gene–gene interaction analysis in genetic association studies (AU)

Introducción: El asma es una de las enfermedades inflamatorias crónicas más frecuentes en los países desarrollados. La susceptibilidad al asma viene determinada por la interacción entre múltiples genes y factores ambientales. En la fisiopatología de esta enfermedad las citocinas desempeñan un papel importante. Objetivo: El objetivo de este estudio fue analizar la distribución de varios polimorfismos en genes de citocinas en un grupo de pacientes con asma y en un grupo control para determinar la influencia que estas variantes, o sus combinaciones génicas, desempeñan en los fenotipos clínicos. Métodos: Se analizaron 22 SNP correspondientes a 13 genes codificantes de citocinas (IFNG, IL1A, IL1B, IL1R1, IL1RN, IL2, IL4, IL4R, IL6, IL10, IL12B, TGFB1, y TNFA) en 376 individuos, 219 sujetos asmáticos y 157 controles. Las asociaciones genéticas fueron evaluadas empleando modelos genotípicos y alélicos para los distintos fenotipos de asma. Las interacciones gen-gen se analizaron mediante la plataforma Multifactor Dimensionality Reduction Platform (MDR). Resultados: El genotipo AC de IL12B -1188 se asoció con la presencia de asma. Dos SNP analizados en el gen TNFA (TNFA-308, and TNFA-238) mostraron una asociación significativa con el asma atópica y con la presencia de asma persistente grave. El haplotipo TT de IL1B (3962T y -511T) también se asoció con la presencia de atopia y con asma persistente moderada. Conclusiones: Nuestros datos muestran que la presencia de estos SNP en los genes IL12B, TNFA y IL1B se asocian significativamente con el asma, la atopia y con la gravedad del asma. También recalcamos la importancia del contexto génico, haplotipos e interacciones gen-gen en los estudios de asociación génica (AU)

Polymorphisms of the IL12B, IL1B, and TNFA genes and susceptibility to asthma.

BACKGROUND: Asthma is one of the most common chronic inflammatory diseases in developed countries. Susceptibility to asthma is associated with interaction between multiple genes and environmental factors. Several cytokines play a major role in the pathophysiology of the disease. OBJECTIVE: We analyzed the distribution of cytokine gene polymorphisms in a group of patients with asthma and a control group in order to determine the effect of these variants, or their combinations, on the development of clinical phenotypes. METHODS: We genotyped 22 single-nucleotide polymorphisms (SNPs) corresponding to 13 cytokine genes (IFNG, IL1A, IL1B, IL1R1, IL1RN, IL2, IL4, IL4R, IL6, IL10, IL12B, TGFB1, and TNFA) in 376 individuals (219 asthmatic patients and 157 controls). Genetic association was evaluated using genotype and allele models for different asthma phenotypes. Gene-gene interactions were explored using multifactor dimensionality reduction. RESULTS: Genotype AC of IL12B-1188 was associated with the presence of asthma. A significant association was detected between 2 SNPs analyzed in TNFA (-308 and -238) and atopic asthma and severe-persistent asthma. The IL1B TT haplotype (3962T and -511T) was also associated with atopy and moderate-persistent asthma. CONCLUSION: Our data show that the presence of SNPs in IL12B, TNFA, and IL1B was significantly associated with asthma, atopy, and severity of asthma.We also highlight the importance of genetic context, haplotype, and gene-gene interaction analysis in genetic association studies.