An association study of asthma and related phenotypes with polymorphisms in negative regulator molecules of the TLR signaling pathway

Nakashima, Kazuko; Hirota, Tomomitsu; Obara, Kazuhiko; Shimizu, Makiko; Jodo, Aya; Kameda, Makoto; Doi, Satoru; Fujita, Kimie; Shirakawa, Taro; Enomoto, Tadao; Kishi, Fumio; Yoshihara, Shigemi; Matsumoto, Kenji; Saito, Hirohisa; Suzuki, Yôichi; Nakamura, Yusuke; Tamari, Mayumi

doi:10.1007/s10038-005-0358-1

Cited by 30 publications

(22 citation statements)

References 25 publications

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“…Therefore, genes/pathways involved in the development of other complex diseases are likely to be relevant in the onset, course, or severity of ALI. The IRAK3 gene is critical for the early recognition of bacterial products by the Toll-like family of receptors (7,20), and although it has been poorly studied for associations with susceptibility to other complex diseases and no published reports have associated IRAK3 polymorphisms with sepsis or ALI (http://geneticassociationdb.nih.gov; accessed May 2010), the IRAK3 gene was recently studied in association with susceptibility to chronic inflammatory conditions such as asthma (38,39) and inflammatory bowel disease (40). In fact, strong evidence for the role of IRAK3 variants in susceptibility to asthma was found by Balaci and colleagues (39), who positionally cloned the gene in asthma after using successive linkage and association analyses of samples from families and unrelated casecontrol subjects from Southern European populations.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1 Receptor–Associated Kinase 3 Gene Associates with Susceptibility to Acute Lung Injury

Pino-Yanes

Fan

Sun

et al. 2011

Am J Respir Cell Mol Biol

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Sepsis is the most common cause of acute lung injury (ALI), leading to organ dysfunction and death in critically ill patients. Previous studies associated variants of interleukin-1 receptor-associated kinase genes (IRAKs) with differential immune responses to pathogens and with outcomes during sepsis, and revealed that increased expression levels of the IRAK3 gene were correlated with poor outcomes during sepsis. Here we explored whether common variants of the IRAK3 gene were associated with susceptibility to, and outcomes of, severe sepsis. After our discovery of polymorphism, we genotyped a subset of seven single-nucleotide polymorphisms (SNPs) in 336 population-based control subjects and 214 patients with severe sepsis, collected as part of a prospective study of adults from a Spanish network of intensive care units. Whereas IRAK3 SNPs were not associated with susceptibility to severe sepsis, rs10506481 showed a significant association with the development of ALI among patients with sepsis (P 5 0.007). The association remained significant after adjusting for multiple comparisons, population stratification, and clinical variables (odds ratio, 2.50; 95% confidence interval, 1.15-5.47; P 5 0.021). By imputation, we revealed three additional SNPs independently associated with ALI (P , 0.01). One of these (rs1732887) predicted the disruption of a putative human-mouse conserved transcription factor binding site, and demonstrated functional effects in vitro (P 5 0.017). Despite the need for replication in independent studies, our data suggest that common SNPs in the IRAK3 gene may be determinants of sepsis-induced ALI.

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Section: Discussionmentioning

confidence: 99%

Interleukin-1 Receptor–Associated Kinase 3 Gene Associates with Susceptibility to Acute Lung Injury

Pino-Yanes

Fan

Sun

et al. 2011

Am J Respir Cell Mol Biol

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“…Interactions of Toll-like receptors (TLRs), also known to be immune-related, were observed. The TLR4 signaling pathway is associated with an immune response by interacting with MYD88 and IRAK1 [34,35] in the network (Figure 4). They were linked to proteins in the nucleus through MAPKs.…”

Section: Biological Functions Of Pathways and Nodes In The Networkmentioning

confidence: 99%

Protein interaction network related to Helicobacter pylori infection response

Kim¹,

Kim²

2009

WJG

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AIM:To understand the complex reaction of gastric inflammation induced by Helicobacter pylori (H pylori ) in a systematic manner using a protein interaction network. METHODS:The expression of genes significantly changed on microarray during H pylori infection was scanned from the web literary database and translated into proteins. A network of protein interactions was constructed by searching the primary interactions of selected proteins. The constructed network was mathematically analyzed and its biological function was examined. In addition, the nodes on the network were checked to determine if they had any further functional importance or relation to other proteins by extending them. RESULTS:The scale-free network showing the relationship between inflammation and carcinogenesis was constructed. Mathematical analysis showed hub and bottleneck proteins, and these proteins were mostly related to immune response. The network contained pathways and proteins related to H pylori infection, such as the JAK-STAT pathway triggered by interleukins. Activation of nuclear factor (NF)-kB, TLR4, and other proteins known to function as core proteins of immune response were also found. These immune-related proteins interacted on the network with pathways and proteins related to the cell cycle, cell maintenance and proliferation, and transcription regulators such as BRCA1, FOS, REL, and zinc finger proteins. The extension of nodes showed interactions of the immune proteins with cancerrelated proteins. One extended network, the core network, a summarized form of the extended network, and cell pathway model were constructed. CONCLUSION:Immune-related proteins activated by H pylori infection interact with proto-oncogene proteins. The hub and bottleneck proteins are potential drug targets for gastric inflammation and cancer.

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“…Details of these patients are described in a previous report [27], with a summary of the cases and controls shown in table 1. All participants with asthma were diagnosed and selected by physicians according to the American Thoracic Society criteria [28].…”

Section: Methodsmentioning

confidence: 99%

The GSTP1 Gene Is a Susceptibility Gene for Childhood Asthma and the GSTM1 Gene Is a Modifier of the GSTP1 Gene

Kamada¹,

Mashimo

Inoue

et al. 2007

Int Arch Allergy Immunol

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Background: Bronchial asthma is a chronic airway disorder characterized by bronchial inflammation. Oxidative stress is a key component of inflammation. Glutathione S-transferase P1 (GSTP1), the abundant isoform of glutathione S-transferases (GSTs) in lung epithelium, plays a key role in cellular protection against oxidative stress. Several studies have shown that the GSTP1 geneis involved in the pathogenesis of asthma and a gene-gene interaction may occur within the GST gene superfamily. Methods: We screened single-nucleotide polymorphisms (SNPs) at the GSTP1 locus and performed an association study in the Japanese population using two independent case-control groups (group 1: 391 pediatric patients with asthma, 462 adult patients with asthma, and 639 controls, and group 2: 115 pediatric patients with asthma and 184 controls). The effect of GSTM1 null/present genotype on the association between GSTP1 Ile105Val and asthma was also investigated. Results: We identified 20 SNPs at this locus and found this region consisted of one linkage disequilibrium block represented by four SNPs (tag SNPs). The association between the Ile105Val polymorphism in the GSTP1 gene and childhood asthma was significant in both groups (p = 0.047 in group 1, and p = 0.021 in group 2). This association was only significant in patients with GSTM1-positive genotype in both groups (group 1: GSTM1 present p = 0.013 and GSTM1 null p = 0.925, and group 2: GSTM1 present p = 0.015 and GSTM1 null p = 0.362). Conclusions: These findings suggest that the GSTP1 gene is a childhood asthma susceptible gene, and the GSTM1 gene is a modifier gene of GSTP1 for the risk of childhood asthma in the Japanese population.

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An association study of asthma and related phenotypes with polymorphisms in negative regulator molecules of the TLR signaling pathway

Cited by 30 publications

References 25 publications

Interleukin-1 Receptor–Associated Kinase 3 Gene Associates with Susceptibility to Acute Lung Injury

Interleukin-1 Receptor–Associated Kinase 3 Gene Associates with Susceptibility to Acute Lung Injury

Protein interaction network related to Helicobacter pylori infection response

The <i>GSTP1</i> Gene Is a Susceptibility Gene for Childhood Asthma and the <i>GSTM1</i> Gene Is a Modifier of the <i>GSTP1</i> Gene

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