Understanding the genetics of asthma and implications for clinical practice

Mammen, Jennifer R.; Arcoleo, Kimberly

doi:10.1097/jxx.0000000000000246

Cited by 5 publications

(3 citation statements)

References 8 publications

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“…These results are in some way in agreement with epidemiological findings that demonstrate high prevalence of asthma and other allergic conditions in our population [34] , [45] , [46] . However, these are complex diseases and likely influenced by dozens or hundreds of genes [47] , [48] . Thus, these results need to be interpreted with caution, so that they do not lead to mistaken conclusions regarding the genetic predisposition of our population to these conditions.…”

Section: Discussionmentioning

confidence: 99%

New variants in NLRP3 inflammasome genes increase risk for asthma and Blomia tropicalis-induced allergy in a Brazilian population

et al. 2020

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Atopic asthma is a chronic lung disease of lower airways caused mainly due to action of T-helper (Th) 2 type cytokines, eosinophilic inflammation, mucus hypersecretion and airway remodelling. Interleukin (IL)-33 increases type 2 immunity polarization in airway playing critical role in eosinophilic asthma. On the other hand, NLRP3 inflammasome activation results in the release of caspase-1 (Casp-1) which, in its turn, promotes IL-33 inactivation. Recent studies have shown associations between NLRP3 variants and inflammatory diseases. However, no study with genes in NLRP3 inflammassome route has been conducted so far with asthma and atopy in any population to date. Blood samples were collected from 1246 asthmatic and non-asthmatic children. Associations were tested for single nucleotide polymorphism (SNP)s in NLRP3 and CASP1 with asthma and markers of atopy and in cultures stimulated with Blomia tropicalis (Bt) mite crude extract. The T allele of rs4925648 ( NLRP3) was associated with increased asthma risk (OR 1.50, P = 0.005). In addition, the T allele of rs12130711 polymorphism, whithin the same gene, acted as a protector factor for asthma (OR 0.78, P = 0.038). On the other hand, the C allele of rs4378247 NLRP3 variant was associated with lower levels of IL-13 production when peripheral blood cells were stimulated with Bt (OR 0.39, P = 4E-04). In addition, the greater the number of risk alleles in IL33 / NLRP3 / CASP1 route the greater was the risk for asthma. The T allele of rs7925706 CASP1 variant was also associated with increased risk for asthma (OR 1.47, P = 0.008). In addition, this same allele increased the eosinophil counts in blood (mm3) in asthmatic individuals compared with non-asthmatic (P = 0.0004). These results suggest that NLRP3 and CASP1 polymorphisms may be associated with susceptibility for asthma and markers of atopy in our population.

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Section: Discussionmentioning

confidence: 99%

New variants in NLRP3 inflammasome genes increase risk for asthma and Blomia tropicalis-induced allergy in a Brazilian population

et al. 2020

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“…The aim is to identify DNA patterns or variations associated with asthma phenotypes or characteristics by comparing the complete DNA sequence of individuals with disease to ethnically matched individuals without disease [ 5 , 6 ]. As GWAS are large-scale population studies that identify polymorphisms in the human genome without the need to genotype the entire genome, they have become the preferred study method in asthma genetics throughout the last decades [ 7 ].…”

Section: Genetics In Asthmamentioning

confidence: 99%

Genetics and Epigenetics in Asthma

Ntontsi

Photiades

Ζervas

et al. 2021

IJMS

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Asthma is one of the most common respiratory disease that affects both children and adults worldwide, with diverse phenotypes and underlying pathogenetic mechanisms poorly understood. As technology in genome sequencing progressed, scientific efforts were made to explain and predict asthma’s complexity and heterogeneity, and genome-wide association studies (GWAS) quickly became the preferred study method. Several gene markers and loci associated with asthma susceptibility, atopic and childhood-onset asthma were identified during the last few decades. Markers near the ORMDL3/GSDMB genes were associated with childhood-onset asthma, interleukin (IL)33 and IL1RL1 SNPs were associated with atopic asthma, and the Thymic Stromal Lymphopoietin (TSLP) gene was identified as protective against the risk to TH2-asthma. The latest efforts and advances in identifying and decoding asthma susceptibility are focused on epigenetics, heritable characteristics that affect gene expression without altering DNA sequence, with DNA methylation being the most described mechanism. Other less studied epigenetic mechanisms include histone modifications and alterations of miR expression. Recent findings suggest that the DNA methylation pattern is tissue and cell-specific. Several studies attempt to describe DNA methylation of different types of cells and tissues of asthmatic patients that regulate airway remodeling, phagocytosis, and other lung functions in asthma. In this review, we attempt to briefly present the latest advancements in the field of genetics and mainly epigenetics concerning asthma susceptibility.

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“…Nowadays, it is widely recognized that genetic component is a crucial contributor to asthma susceptibility [7].…”

Section: Introductionmentioning

confidence: 99%

The associations of circulating inflammatory-related proteins with asthma: a Mendelian randomization study

Xiong,

Sheng,

Zhang

et al. 2024

Preprint

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Background Epidemiological evidence links inflammation to the etiology and pathophysiology of asthma. To assess the causal relationship between circulating inflammation-related proteins and asthma, we performed a two-sample Mendelian randomization (MR) analysis. Methods Protein quantitative trait locis (pQTLs) were derived from twelve genome-wide association studies (GWASs) cohorts on the circulating inflammation-related proteome. Genetic associations with asthma were obtained from a large-scale GWAS, categorized into childhood-onset asthma (COA) and adult-onset asthma (AOA). Bidirectional MR analysis, Bayesian co-localization, and phenotype scanning were employed to confirm the robustness of MR results. Furthermore, pathway enrichment analysis, protein-protein interaction (PPI) network analysis, and molecule docking were conducted to evaluate the druggability of identified proteins and prioritize potential therapeutic targets. These results were further validated in eQTLGen, GTEx Consortium, and two dependent cohorts. Results Collectively, elevated MMP-1 and decreased levels of three proteins (ADA, CD40L, CST5) were associated with an increased risk of both COA and AOA. CXCL6 had an adverse effect specifically on COA. These associations were validated in sensitivity analyses. Apart from CST5, the other proteins interacted with therapeutic targets of asthma medications. Furthermore, therapeutic targeting of three proteins (ADA, CD40L, MMP1) is currently under evaluation, while CST5 and CXCL6 are considered druggable. Molecular docking showed excellent binding between drugs and proteins (ADA and MMP-1) with available structural data. Conclusions This study identified five circulating inflammatory-related protein biomarkers associated with asthma and provided novel insights into its etiology. Drugs targeting these proteins are expected to facilitate future prioritization of drug targets for asthma.

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Understanding the genetics of asthma and implications for clinical practice

Cited by 5 publications

References 8 publications

New variants in NLRP3 inflammasome genes increase risk for asthma and Blomia tropicalis-induced allergy in a Brazilian population

New variants in NLRP3 inflammasome genes increase risk for asthma and Blomia tropicalis-induced allergy in a Brazilian population

Genetics and Epigenetics in Asthma

The associations of circulating inflammatory-related proteins with asthma: a Mendelian randomization study

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