Pathways to asthma severity are distinct from asthma susceptibility

Published Online: March 29, 2013

Genome-wide association studies (GWAS) of asthma susceptibility have consistently identified ORMDL3-GSDMB, IL33, IL1RL1-IL18R1, RAD50-IL13, TSLP-WDR36, and HLA-DR/DQ regions. Except ORMDL3 (with unknown relevant function), other asthma genes are related to allergy and Th2 pathways. While multiple GWAS have been performed in subjects with asthma versus healthy controls, genetic analyses of asthma severity and related phenotypes such as lung function are extremely rare. Although severe asthma affects about 10% of all asthmatics and accounts for the majority of morbidity and health care use, the etiology of severe asthma is poorly understood. In contrast to patients with mild-to-moderate asthma who achieve good symptom control with low doses of inhaled corticosteroids, those with severe asthma have persistent symptoms despite the use of high doses of inhaled or oral corticosteroids and require extensive use of healthcare resources.

In an original article in The Journal of Allergy & Clinical Immunology (JACI), Li et al reports results of meta-analysis of lung function (percent predicted FEV1) in four European American populations with asthma (SARP, CSGA, TENOR, and ACRN (n=1,544)). The researchers confirmed seven of 28 lung function loci (HHIP, FAM13A, THSD4, GSTCD, NOTCH4-AGER, RARB, and ZNF323) previously identified in the general population. More importantly, they identified that four loci (IL12A, IL12RB1, STAT4, and IRF2) associated with percent predicted FEV1 belong to Th1 or IL12-cytokine family pathway. These four Th1 pathway SNPs cumulatively explained 2.9%-7.8% of the variance of percent predicted FEV1 (P=3x10-11) and were associated with the ATS severe asthma classification (P=0.005). In contrast, Th2 pathway genes (IL13, TSLP, IL33, and IL1RL1) conferring asthma susceptibility were not associated with lung function.

The authors’ findings suggest 1) Genes involved in airway structure/remodeling are associated with lung function in both general populations and in subjects with asthma; 2) Th1 pathway genes involved in anti-virus/bacterial-infection and inflammation modify lung function in asthma; and 3) Genes associated with lung function that may affect asthma severity are distinct from those genes associated with asthma susceptibility. Their findings indicate that the optimized treatment of severe asthma may be quite different from mild asthma. Differences in individual ‘genetic profiles’ of asthma will be increasingly important in the development of personalized medicine.


The Journal of Allergy and Clinical Immunology (JACI) is the official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

AAAAI - American Academy of Allergy Asthma & Immunology