Attempted Replication of 50 Reported Asthma Risk Genes Identifies a SNP in RAD50 as Associated with Childhood Atopic Asthma

Murk, William; Walsh, Kyle M.; Hsu, Ling‐I; Zhao, Linlu; Bracken, Michael B.; DeWan, Andrew T.

doi:10.1159/000319536

Cited by 39 publications

(32 citation statements)

References 60 publications

(30 reference statements)

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“…Although three SNPs, rs1801275 (−1902G/A), rs1805012 (1291T/C) and rs1805010 (−223G/A) demonstrated associations with asthma in previous studies (11–13), only rs1805012 exhibited an association with asthma (dominant model; P=0.03) in the current study. To further investigate the effect of IL-4R SNPs in asthma, eight tag SNPs of the IL-4R region were investigated for an association with asthma, to the best of our knowledge, for the first time.…”

Section: Discussioncontrasting

confidence: 76%

Palm dermatoglyphs and interleukin-4 receptor polymorphisms in asthma

Sun

Wang

et al. 2016

Biomedical Reports

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Single nucleotide polymorphisms (SNPs) in the interleukin-4 receptor (IL-4R) gene have been identified as having a close association with asthma severity in different populations. In our previous studies, a close association between asthma and a distinctive palm dermatoglyphic pattern was observed; however, the clinical implication and underlying genetic mechanisms of this particular palm pattern have not been clarified. Whether this particular palm pattern is associated with asthma severity and IL-4R SNPs was assessed in the present study. A case cohort study was conducted in 400 patients with allergic asthma and in 200 healthy controls. DNA was extracted from peripheral blood leukocytes for analysis of 11 IL-4R SNPs associated with asthma via polymerase chain reaction. There are two SNPs, rs1805012 and rs3024608, which are associated with asthma (rs1805012, dominant model; P=0.03 and rs3024608, codominant model; P=0.029), and two SNPs, rs1805010 and rs3024608, which are associated with the positive palm pattern (rs1805010, log-additive model; P=0.031 and rs3024608, codominant model; P=0.016). The SNP of rs3024608 is associated with asthma and the positive palm pattern. Thus, genetic variation in IL-4R may be associated with the development of asthma and the distinctive palm pattern; however, further investigations are required to identify the connection between asthma and palm dermatoglyphic patterns.

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Section: Discussioncontrasting

confidence: 76%

Palm dermatoglyphs and interleukin-4 receptor polymorphisms in asthma

Sun

Wang

et al. 2016

Biomedical Reports

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“…[2526] The IL-4Rα gene is highly polymorphic and several SNPs have been associated with different immune-related disorders, including atopy and asthma, although not without discrepancies. [810272829] The rs1805010 polymorphism (A→G) is a type of ‘gain-of-function’ mutation, which results in substitution of isoleucine for valine (I75V) in the extracellular domain of IL-4Rα subunit; in vitro , this mutant receptor with enhanced IL-4 signaling appears to promote a sustained phosphorylation and hence, keep STAT6 transcription factor abnormally active, even upon withdrawal of IL-4 stimulation. [2830] The rs1801275 (A→G) is another gain-of-function mutation also aberrantly enhancing signal transduction, which results in glutamine being substituted by arginine (Q576R) in the intracellular domain of IL-4Rα; it is situated beside the critically important tyrosine-2 residue, which is part of the docking site for STAT6.…”

Section: Introductionmentioning

confidence: 99%

IL-4 receptor alpha single-nucleotide polymorphisms rs1805010 and rs1801275 are associated with increased risk of asthma in a Saudi Arabian population

et al. 2014

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BACKGROUND:The IL-4 receptor alpha subunit (IL-4Rα), when associated with the common gamma chain receptor, or the IL-13Rα1 subunit, transduces signals to STAT6 in response to IL-4 and IL-13 stimulations. This results in a number of cell-specific responses including Th2 differentiation, lymphocyte proliferation and IgE production. Given the prominent role of IL-4Rα in allergic disorders, several single-nucleotide polymorphisms (SNPs) have been found associated with asthma and other atopic disorders, including rs1805010 (I75V) and rs1801275 (Q576R) SNPs; however, lack of significant association have also been reported for some ethnic groups. The objective of this study was to determine whether IL-4Rα rs1805010 and rs1801275 polymorphisms are associated with asthma in patients from Saudi Arabia.MATERIALS AND METHODS:One hundred and ninety severe asthmatic patients (11-70 years old) and 194 healthy subjects of equivalent age range were recruited for blood donation. DNA was purified and genotyping for rs1801275 and rs1805010 polymorphisms in the IL-4Rα gene was performed by PCR amplification, followed by cycle sequencing of the purified PCR fragments using BigDye chain terminator and capillary electrophoresis.RESULTS:Pearson's Chi-square tests showed that the minor alleles, G, for both rs1805010 and rs1801275 SNPs, were significantly more frequent in asthmatics than in the healthy group (Yates’ P < 0.05); conversely, the major alleles, A, were significantly more frequent in healthy than in asthmatics (P < 0.05). Concerning association analysis, odds for A/G-G/G genotypes were significantly higher to be associated with asthma predisposition (rs1801275: OR = 2.12; 95% CI = 1.39-3.22; P < 0.001*; rs1805010: OR = 1.6; 95% CI = 1.01-2.53; P < 0.05*; dominant model). Analysis of gender-genotype interactions, with genders nested within A/G-G/G, indicated higher odds for females than males of significant association with asthma (rs1801275: OR = 5.19, 95% CI = 2.09-12.94*; rs1805010: OR = 3.73, 95% CI = 2.06-6.74*). Rs1805010 and rs1801275 were in linkage disequilibrium (D’ = 0.27; P < 0.0004*), with G-G haplotype being more frequent in asthmatics than in healthy subjects (OR = 2.43, 95% CI = 1.59-3.71*).CONCLUSIONS:The risk alleles, G, of IL-4Rα rs1805010 and rs1801275 SNPs and corresponding A/G-G/G genotypes were significantly associated with asthma predisposition in asthmatics from Saudi Arabia.

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“…Asthma runs in families and is clearly heritable, but patterns of inheritance are complex and genetic studies have shown poor replication, and loci which have been replicated generally explain a very small proportion of the heritability, with small effect sizes [5,6]. The rapid increase in the prevalence of asthma seen in the later part of the last century strongly indicates that environmental exposures are highly relevant in the aetiology of wheezing illnesses.…”

Section: Introductionmentioning

confidence: 99%

Characterizing wheeze phenotypes to identify endotypes of childhood asthma, and the implications for future management

Belgrave

Čustović

Simpson

2013

Expert Review of Clinical Immunology

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It is now a commonly held view that asthma is not a single disease, but rather a set of heterogeneous diseases sharing common symptoms. One of the major challenges to treating asthma is understanding these different asthma phenotypes and their underlying biological mechanisms.This review gives an epidemiological perspective of our current understanding of the different phenotypes that develop from birth to childhood that come under the umbrella term "asthma". The review focuses mainly on publications from longitudinal birth cohort studies where the natural history of asthma symptoms is observed over time in the whole population. Identifying distinct pathophysiological mechanisms for these different phenotypes will potentially elucidate different asthma endotypes, ultimately leading to more effective treatment and management strategies.

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Attempted Replication of 50 Reported Asthma Risk Genes Identifies a SNP in RAD50 as Associated with Childhood Atopic Asthma

Cited by 39 publications

References 60 publications

Palm dermatoglyphs and interleukin-4 receptor polymorphisms in asthma

Palm dermatoglyphs and interleukin-4 receptor polymorphisms in asthma

IL-4 receptor alpha single-nucleotide polymorphisms rs1805010 and rs1801275 are associated with increased risk of asthma in a Saudi Arabian population

Characterizing wheeze phenotypes to identify endotypes of childhood asthma, and the implications for future management

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