Association of asthma genetic variants with asthma‐associated traits reveals molecular pathways of eosinophilic asthma

Abstract

IntroductionAsthma is a complex, polygenic, heterogenous inflammatory disease. Recently, we generated a list of 128 independent single nucleotide polymorphisms (SNPs) associated with asthma in genome‐wide association studies. However, it is unknown if asthma SNPs are associated with specific asthma‐associated traits such as high eosinophil counts, atopy, and airway obstruction, revealing molecular endotypes of this disease. Here, we aim to identify the association between asthma SNPs and asthma‐associated traits and assess expression quantitative trait locus (e‐QTLs) to reveal their downstream functional effects and find drug targets.MethodsAssociation analyses between 128 asthma SNPs and associated traits (blood eosinophil numbers, atopy, airway obstruction, airway hyperresponsiveness) were conducted using regression modelling in population‐based studies (Lifelines N = 32,817/Vlagtwedde‐Vlaardingen N = 1554) and an asthma cohort (Dutch Asthma genome‐wide association study N = 917). Functional enrichment and pathway analysis were performed with genes linked to the significant SNPs by e‐QTL analysis. Genes were investigated to generate novel drug targets.ResultsWe identified 69 asthma SNPs that were associated with at least one trait, with 20 SNPs being associated with multiple traits. The SNP annotated to SMAD3 was the most pleiotropic. In total, 42 SNPs were associated with eosinophil counts, 18 SNPs with airway obstruction, and 21 SNPs with atopy. We identified genetically driven pathways regulating eosinophilia. The largest network of eosinophilia contained two genes (IL4R, TSLP) targeted by drugs currently available for eosinophilic asthma. Several novel targets were identified such as IL‐18, CCR4, and calcineurin.ConclusionMany asthma SNPs are associated with blood eosinophil counts and genetically driven molecular pathways of asthma‐associated traits were identified.

IL18 Gene Polymorphism Is Associated with Total IgE in Adult Subjects with Asthma

“…However, these results are not fully comparable with ours due to differences in the study population and age distribution and have not been replicated in other populations. In addition, other studies have identified SNPs in the IL18 receptor gene cluster and in the IL1 family that are linked to asthma-associated biomarkers (i.e., serum IgE, blood eosinophilic counts) in asthma or other allergic disorders [ 36 , 37 , 38 , 39 , 40 ].…”

CC Chemokine Family Members’ Modulation as a Novel Approach for Treating Central Nervous System and Peripheral Nervous System Injury—A Review of Clinical and Experimental Findings

“…The role of this receptor in the CNS was suggested in many animal studies after CNS injury (in a mouse MCAO model [312]), after PNS injury (in mouse/rat CCI models [92,230]), and in diabetes in monkeys [314] and mice [315]. Furthermore, CCR4 has been shown to play an important role in the pathogenesis of many diseases in patients, such as TBI [309], asthma [316,317], dermatitis [318], and cancer [319]. The presence of CCR4 in the CNS [320,321] and PNS [186] suggests that CCR4 plays a role after injury; however, further studies are needed.…”

Severe Allergy as a Chronic Inflammatory Condition From a Systems Biology Perspective

“…Interestingly, numerous SNPs linked to asthma onset and its characteristics have been identified [205]. SNPs in noncoding regions of the ORMDL3 gene lead to an increase in ORMDL3/ GSDMB expression that is associated with childhood-onset asthma [129,206] through the alteration of SL synthesis [207].…”