GSDMB/ORMDL3 variants contribute to asthma susceptibility and eosinophil-mediated bronchial hyperresponsiveness

Kang, Mi‐Jin; Yu, Ho-Sung; Seo, Ju-Hee; Kim, Hyung-Young; Jung, Young-Ho; Kim, Young-Joon; Kim, Ha-Jung; Lee, So‐Yeon; Hong, Soo‐Jong

doi:10.1016/j.humimm.2012.06.009

Cited by 44 publications

(30 citation statements)

References 24 publications

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“…These two polymorphisms are in high LD suggesting these associations represent a single locus. The BHR association (rs2305480) is supported by different SNPs in this gene also showing association with this phenotype, albeit in different ethnic populations [23,24]. Interestingly, a recent study has found association between rs2305480 and wheezing phenotypes in asthmatic children, but did not find association with intermediate phenotypes such as atopy or lung function [25].…”

Section: Discussionmentioning

confidence: 99%

Defining the contribution of SNPs identified in asthma GWAS to clinical variables in asthmatic children

2013

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BackgroundAsthma genome-wide association studies (GWAS) have identified several asthma susceptibility genes with confidence; however the relative contribution of these genetic variants or single nucleotide polymorphisms (SNPs) to clinical endpoints (as opposed to disease diagnosis) remains largely unknown. Thus the aim of this study was to firstly bridge this gap in knowledge and secondly investigate whether these SNPs or those that are in linkage disequilibrium are likely to be functional candidates with respect to regulation of gene expression, using reported data from the ENCODE project.MethodsEleven of the key SNPs identified in eight loci from recent asthma GWAS were evaluated for association with asthma and clinical outcomes, including percent predicted FEV1, bronchial hyperresponsiveness (BHR) to methacholine, severity defined by British Thoracic Society steps and positive response to skin prick test, using the family based association test additive model in a well characterised UK cohort consisting of 370 families with at least two asthmatic children.ResultsGSDMB SNP rs2305480 (Ser311Pro) was associated with asthma diagnosis (p = 8.9×10-4), BHR (p = 8.2×10-4) and severity (p = 1.5×10-4) with supporting evidence from a second GSDMB SNP rs11078927 (intronic). SNPs evaluated in IL33, IL18R1, IL1RL1, SMAD3, IL2RB, PDE4D, CRB1 and RAD50 did not show association with any phenotype tested when corrected for multiple testing. Analysis using ENCODE data provides further insight into the functional relevance of these SNPs.ConclusionsOur results provide further support for the role of GSDMB SNPs in determining multiple asthma related phenotypes in childhood asthma including associations with lung function and disease severity.

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Section: Discussionmentioning

confidence: 99%

Defining the contribution of SNPs identified in asthma GWAS to clinical variables in asthmatic children

2013

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“…Both hospital-based and population-based studies were included in the analysis. Eleven studies were excluded because they did not provide the data necessary for calculating odds ratios or they did not provide the data of the 4 SNPs of this review 30,31,32,33,34,35,36,37,38,39,40. According to the prespecified inclusion criteria, in total 13 reports7,8,9,10,11,12,16,17,18,19,20,21,22 were included in this review, including 17 studies (13 case-control studies and 4 TDT studies) with 6,691 subjects with asthma and 9,281 controls.…”

Section: Resultsmentioning

confidence: 99%

The Association ofGSDMBandORMDL3Gene Polymorphisms With Asthma: A Meta-Analysis

Zhao

Huang

et al. 2015

Allergy Asthma Immunol Res

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PurposeORM1-like 3 (ORMDL3) belongs to a highly conserved protein family which is anchored as transmembrane protein in the endoplasmic reticulum. Gasdermin B (GSDMB) is adjacent to ORMDL3 on chromosome 17q21.2 and belongs to the gasdermin-domain containing the protein family (GSDM family). Recent reports suggest that GSDMB and ORMDL3 are associated with asthma in several populations. However, genetic association studies that examined the association of GSDMB and ORMDL3 gene variants with asthma showed conflicting results. To assess whether combined evidence shows the association between GSDMB/ORMDL3 polymorphism and asthma.MethodsA bibliographic search from MEDLINE identified 13 original articles using the search keywords 'GSDMB', 'ORMDL3', and 'asthma'. An updated literature-based meta-analysis involving 6,691 subjects with asthma, 9,281 control individuals, and 1,360 families were conducted. Meta-odds ratios (ORs) and 95% confidence intervals (CIs) based on the fixed effects model or the random effects model depended on Cochran's Q-statistic and I2 values. Data from case-control and TDT studies were analyzed in an allelic model using the Catmap software.ResultsWe selected and identified 3 SNPs of ORMDL3 associated with asthma (rs8076131: OR=1.10; 95% CI, 1.02-1.20; P=0.012. rs12603332: OR=1.15; 95% CI, 1.05-1.25; P=0.002. rs3744246: OR=1.10; 95% CI, 1.02-1.17; P=0.008) and 1 SNP of GSDMB associated with asthma (rs7216389: OR=1.37; 95% CI, 1.27-1.47; P<0.01). Publication bias was estimated using modified Egger's linear regression test proposed by Harbordetal and revealed no evidence of biases. Furthermore, cumulative meta-analysis in chronological order showed the inclination toward significant association for rs7216389 and rs12603332 with continually adding studies, and the inclination toward null-significant association for rs3744246 and rs8076131.ConclusionsModerate evidence exists for associations of the ORMDL3 rs8076131, rs12603332, and rs3744246 and GSDMB rs7216389 variants with asthma. Large sample size and representative population-based studies and TDT studies with homogeneous asthmatic patients and well-matched controls are warranted to confirm this finding.

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“…Evidence regarding genetic susceptibility in HRV infection is beginning to emerge. Genome-wide association studies (GWAS) have consistently linked the asthma susceptibility locus 17q21 to nonatopic childhood-onset asthma3536). Data from 2 birth cohort studies, COAST and Copenhagen Studies on Asthma in Childhood, demonstrated that 17q21 variants were associated with HRV wheezing illness in early life, but not with RSV wheezing illnesses.…”

Section: Role Of Hrv Infection In Asthma Developmentmentioning

confidence: 99%

Rhinovirus and childhood asthma: an update

Song

2016

Korean J Pediatr

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Asthma is recognized as a complex disease resulting from interactions between multiple genetic and environmental factors. Accumulating evidence suggests that respiratory viral infections in early life constitute a major environmental risk factor for the development of childhood asthma. Respiratory viral infections have also been recognized as the most common cause of asthma exacerbation. The advent of molecular diagnostics to detect respiratory viruses has provided new insights into the role of human rhinovirus (HRV) infections in the pathogenesis of asthma. However, it is still unclear whether HRV infections cause asthma or if wheezing with HRV infection is simply a predictor of childhood asthma. Recent clinical and experimental studies have identified plausible pathways by which HRV infection could cause asthma, particularly in a susceptible host, and exacerbate disease. Airway epithelial cells, the primary site of infection and replication of HRV, play a key role in these processes. Details regarding the role of genetic factors, including ORMDL3, are beginning to emerge. This review discusses recent clinical and experimental evidence for the role of HRV infection in the development and exacerbation of childhood asthma and the potential underlying mechanisms that have been proposed.

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GSDMB/ORMDL3 variants contribute to asthma susceptibility and eosinophil-mediated bronchial hyperresponsiveness

Cited by 44 publications

References 24 publications

Defining the contribution of SNPs identified in asthma GWAS to clinical variables in asthmatic children

Defining the contribution of SNPs identified in asthma GWAS to clinical variables in asthmatic children

The Association ofGSDMBandORMDL3Gene Polymorphisms With Asthma: A Meta-Analysis

Rhinovirus and childhood asthma: an update

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