Assessing the Reproducibility of Asthma Candidate Gene Associations, Using Genome-wide Data

Rogers, Angela J.; Raby, Benjamin A.; Lasky‐Su, Jessica; Murphy, Amy; Lazarus, Ross; Klanderman, Barbara J.; Sylvia, Jody S.; Ziniti, John; Lange, Christoph; Celedón, Juan C.; Silverman, Edwin K.; Weiss, Scott T.

doi:10.1164/rccm.200812-1860oc

Cited by 101 publications

(95 citation statements)

References 26 publications

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“…At the allele level, even with loose criteria for significance (Po0.05 with genomewide correction) only 10 SNPs in 6 of 39 genes were replicated to be associated with asthma in the population, whereas at the gene level an additional 15 genes, each with at least 1 SNP, showed replications. 37 This consistent gene level replication suggested possible allelic heterogeneity in asthma genetics. Another Japanese genomewide asthma study used multiplex PCR-Invader assay methods at 82 935 SNPs in 288 atopic asthmatics and 1032 controls (Stage 1).…”

Section: Findings In Several Gwa Studies On Asthmamentioning

confidence: 67%

“…This study identified PDE4D as an asthma candidate gene. 36 A recent study by Rogers et al 37 attempted to assess the reproducibility of 39 of these candidate genes previously reported to be associated with asthma using a genome-wide approach in 422 nuclear families (1169 members) participating in the CAMP. They investigated the replications at both allele (SNP) and gene levels.…”

Section: Findings In Several Gwa Studies On Asthmamentioning

confidence: 99%

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The era of genome-wide association studies: opportunities and challenges for asthma genetics

2009

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In the era of genome-wide association (GWA) studies, delineating pathogenic asthma genetic pathways has provided both challenges and opportunities. Initial GWA studies on asthma and asthma-like phenotypes provided some successes in terms of ascertaining new potential asthma candidate genes. However, due to asthma having a heterogeneous etiology, replications of these genotype-phenotype association studies are generally lacking. Furthermore, genes by environment interactions are generally not considered when GWA studies are conducted. Therefore, there is a need for extensive collaborations in multi-disciplinary research fields, including different environments and populations, to investigate the functional importance of variations in the human genome in relation to asthma pathogenesis.

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Section: Findings In Several Gwa Studies On Asthmamentioning

confidence: 67%

Section: Findings In Several Gwa Studies On Asthmamentioning

confidence: 99%

The era of genome-wide association studies: opportunities and challenges for asthma genetics

2009

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“…PtdIns(3,4)P2, in turn, gets degraded by inositol polyphosphate-4-phosphatase (INPP4) to form PtdIns(3)P 4 . Genotypic variations in type I INPP4 (INPP4A), which is a regulatory checkpoint in phosphoinositide signalling, have previously been shown to be associated with increased risk of asthma 5,6 . Although other phosphoinositide phosphatases, PTEN and SHIP, have been shown to importantly regulate T-cell activation 7,8 , suppress B-cell lymphoma 9 and have protective roles in allergic airway inflammation (AAI) 10,11 , the functional role of INPP4A, in this context, is not known.…”

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confidence: 99%

Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation

et al. 2012

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Inositol polyphosphate phosphatases regulate the magnitude of phosphoinositide-3 kinase signalling output. Although inositol polyphosphate-4-phosphatase is known to regulate phosphoinositide-3 kinase signalling, little is known regarding its role in asthma pathogenesis. Here we show that modulation of inositol polyphosphate-4-phosphatase alters the severity of asthma. Allergic airway inflammation in mice led to calpain-mediated degradation of inositol polyphosphate-4-phosphatase. In allergic airway inflammation models, preventing inositol polyphosphate-4-phosphatase degradation by inhibiting calpain activity, or overexpression of inositol polyphosphate-4-phosphatase in mouse lungs, led to attenuation of the asthma phenotype. Conversely, knockdown of inositol polyphosphate-4-phosphatase severely aggravated the allergic airway inflammation and the asthma phenotype. Interestingly, inositol polyphosphate-4-phosphatase knockdown in lungs of naive mice led to spontaneous airway hyper-responsiveness, suggesting that inositol polyphosphate-4-phosphatase could be vital in maintaining the lung homeostasis. We suggest that inositol polyphosphate-4-phosphatase has an important role in modulating inflammatory response in asthma, and thus, uncover a new understanding of the complex interplay between inositol signalling and asthma, which could provide alternative strategies in asthma management. P hosphoinositide signalling, from phosphoinositide-3-kinase (PI3K) activation to Akt phosphorylation, critically regulates cellular functions, such as cell growth, differentiation, proliferation, survival and motility 1 . In response to growth factor stimuli, activation of PI(3)Ks leads to generation of PtdIns(3,4,5)P3 and PtdIns(3,4)P2 at the plasma membrane. The intracellular concentration of PtdIns(3,4,5)P3 is controlled by a 3-phosphatase known as phosphatase and tensin homologue (PTEN) 2 or by 5-phosphatases (SHIP) 3 , resulting in the production of PtdIns(4,5)P2 and PtdIns(3,4)P2, respectively. PtdIns(3,4)P2, in turn, gets degraded by inositol polyphosphate-4-phosphatase (INPP4) to form PtdIns(3)P 4 . Genotypic variations in type I INPP4 (INPP4A), which is a regulatory checkpoint in phosphoinositide signalling, have previously been shown to be associated with increased risk of asthma 5,6 . Although other phosphoinositide phosphatases, PTEN and SHIP, have been shown to importantly regulate T-cell activation 7,8 , suppress B-cell lymphoma 9 and have protective roles in allergic airway inflammation (AAI) 10,11 , the functional role of INPP4A, in this context, is not known. As PtdIns(3,4)P2, but not PtdIns(3,4,5)P3, potently activates Akt 12 , INPP4A effectively terminates the PI3K-Akt signalling cascade.Asthma is characterized by episodic bronchoconstriction due to airway inflammation, remodelling and hyper-responsiveness 13 . Metabolic origins of asthma in obese subjects with minimal inflammatory cell infiltrate are an active topic of research 14 . Current understanding and treatment of asthma focuses on inhibiting airway inflamma...

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“…24 The first genome-wide replication study of 39 asthma candidate genes generated IL4RA results that were consistent with our observations. 25 In the most comprehensive replication study carried out to date, the reproducibility of 93 genes previously associated with asthma and/or asthma intermediate traits was tested. 26 IL13 was associated with asthma, and TBXA2R was associated with atopy, as we also observed in this study.…”

Section: Discussionmentioning

confidence: 99%

“…27 Daley et al concluded that many published associations for asthma and atopy may be false-positive results. Whereas Rogers et al 25 suggested that the poor coverage of genome-wide association study genotyping platforms and lack of statistical power due to insufficient sample size were the main reasons for their low replication. We are more inclined to suspect the 'contextual' bias explaining our failure to replicate all candidate genes.…”

Section: Discussionmentioning

confidence: 99%

Replication of genetic association studies in asthma and related phenotypes

et al. 2010

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In asthma genetics, the association of highly replicated susceptibility genes lacks consistency across populations. To identify genuine associations, we investigated the reproducibility of the 23 most promising asthma and asthma-related candidate genes in a moderately sized sample from the Japanese population. We compared the frequency of 33 polymorphisms in unrelated cases and controls and tested for their association with asthma, atopy and serum total IgE levels using allele frequency, codominant, dominant and recessive genotype models. On the basis of the consistency of our findings with previous metaanalyses and large replication studies, IL13, TNF, ADAM33, IL4RA and TBXA2R might represent common major asthma and asthma-related trait genes. Individual gene assessment was extended to the interactions between two polymorphisms using our original method. Interactions between TBXA2R and ADAM33, and IL4RA and C3 were suggested to increase the risk for childhood and all asthma (adult and childhood asthma combined). The confirmation of previously reported associations between gene polymorphisms and phenotypes was problematic when as few as several hundred samples per group were used. Stratification of the subjects by environmental factors or other confounding factors may be necessary to improve the sensitivity and reliability of association results. Keywords: association; asthma; atopy; polymorphism; replication INTRODUCTIONAsthma is a heritable trait 1 and investigations to determine the genetic components underlying asthma using linkage mapping and the candidate gene approach have been carried out. By 2006, more than 100 genes were associated with asthma and asthma-related phenotypes; 2 25 of these genes have been replicated in more than six independent association studies. In 2008, this list was complemented with an additional three genes, FLG, NAT2 and CCL15. 3 However, no single polymorphic marker or gene locus has been unanimously labeled as a strong and independent genetic determinant of asthma, and the results for the highly replicated genes have been inconsistent across the tested populations. 3 To identify true associations, it is of critical importance to comprehensively replicate the initial finding. 4 To this aim, we investigated whether the 23 most replicated genes for asthma and asthma-related phenotypes were positively associated with extrinsic childhood and adult asthma, atopy and total serum IgE levels in a moderately sized sample drawn from the Japanese population.We also tested eight genes that were significantly associated with asthma in our subjects: IL13, 5 TBXA2R, 6 GSTP1, 7 ADAM33, 8 MMP9, 9 IL12B, 10 C3 11 and SOCS1. 12 The re-evaluation of these associations is

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Assessing the Reproducibility of Asthma Candidate Gene Associations, Using Genome-wide Data

Cited by 101 publications

References 26 publications

The era of genome-wide association studies: opportunities and challenges for asthma genetics

The era of genome-wide association studies: opportunities and challenges for asthma genetics

Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation

Replication of genetic association studies in asthma and related phenotypes

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