The largest study of its kind found that childhood asthma and adult asthma do not have the same genetics — and that the allergy marker doctors have measured for decades is largely beside the point.
Solid lines are connections this site curates. Dashed lines mean the two ends share a research paper — worth knowing, and not a claim that one explains the other.
Asthma is a narrowing of the airways that comes and goes: inflamed, over-reactive tubes that tighten in response to things that leave other people alone. Cold air, exercise, dust, a cat, a virus. It affects children and adults, and for a long time it was treated as one condition arriving at different ages.
The genetics says it is not.
A 2010 study genotyped 10,365 people with physician-diagnosed asthma against 16,110 unaffected people, all matched for ancestry, and analysed the whole group and then subgroups: childhood-onset, later-onset, severe, occupational.
Several positions passed genome-wide significance across the whole group. rs1342326, next to IL33, was one of them — p = 9 × 10⁻¹⁰. IL33 is an alarm signal released by damaged airway lining, and its partner receptor gene, IL1RL1, came up as well. So did the HLA-DQ region.
Read together, those genes describe a single mechanism: damaged epithelium telling the immune system about it, and the immune system responding in the airway.
The 17q21 region — ORMDL3 and GSDMB, next door to the GSDMA gene where rs3894194 sits — produced the strongest signal in the study, at p = 6 × 10⁻²³.
And it was specific to childhood-onset disease. Not stronger in children; specific to them.
Asthma beginning before sixteen and asthma beginning after it are not the same illness wearing different clothes. They share some risk alleles and they do not share this one, which is the largest single genetic signal in the condition.
Total serum IgE is the antibody level measured as a proxy for allergic disease, and it has been part of the asthma workup for decades.
In this study only HLA-DR was associated with total IgE at genome-wide significance — and the loci most strongly associated with IgE levels were not associated with asthma. The authors' conclusion was blunt: elevation of total serum IgE has a minor role in the development of asthma.
The two things travel together in a clinic without one leading to the other. That is a useful thing to know about a number you may have been given.
Not whether you have asthma, and not whether you will. Asthma is diagnosed from symptoms and from lung function that changes — spirometry before and after a bronchodilator — not from genotype, and no guideline uses a variant to choose an inhaler.
What this research changed is the map. IL33 and its receptor are now drug targets, and the biologics aimed at that pathway exist because of findings like this one.
Source. Moffatt et al. (NEJM 2010), the GABRIEL consortium, genotyped 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, matched for ancestry, with random-effects pooled analysis across the whole population and within childhood-onset (before 16 years), later-onset, severe and occupational subgroups. Genome-wide significant associations: rs3771166 (chromosome 2, IL1RL1/IL18R1, p = 3 × 10⁻⁹); rs9273349 (chromosome 6, HLA-DQ, p = 7 × 10⁻¹⁴); rs1342326 (chromosome 9, flanking IL33, p = 9 × 10⁻¹⁰); rs744910 (chromosome 15, SMAD3, p = 4 × 10⁻⁹); rs2284033 (chromosome 22, IL2RB, p = 1.1 × 10⁻⁸). Association at the ORMDL3/GSDMB locus on 17q21 (rs2305480, p = 6 × 10⁻²³) was specific to childhood-onset disease.
Total serum IgE. Only HLA-DR showed genome-wide significant association with total serum IgE concentration, and the loci strongly associated with IgE levels were not associated with asthma. The authors concluded that elevation of total serum IgE has a minor role in the development of asthma — a conclusion about the trait as a causal intermediate, not about allergen-specific IgE in an individual patient's assessment.
The two positions listed here. rs1342326 is the reported IL33-flanking signal from this study. rs3894194 was recorded by the collector against GSDMA, adjacent to the 17q21 ORMDL3/GSDMB region whose association was childhood-onset-specific; the study's own index SNP for that region is rs2305480, which is not in our variant table.
Clinical use. None. Diagnosis rests on a compatible history with demonstrated variable expiratory airflow limitation — typically spirometry with bronchodilator reversibility, peak-flow variability or a bronchial challenge. No genotype directs the choice of inhaled corticosteroid, bronchodilator or biologic. Biologic therapy is selected on phenotype and biomarkers such as blood eosinophils and FeNO, not on genotype.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Asthma comes down to these specific, well-studied positions — not a diagnosis.
near ZNF616 · rs10411428
See detailed info →Genetically, not entirely. The strongest signal in the largest study — the 17q21 region, at p = 6 × 10⁻²³ — was specific to disease starting before sixteen. Other alleles are associated with asthma at all ages. Two overlapping conditions is closer to the truth than one condition with two start dates.
The study that asked this found that the loci most strongly associated with total IgE were not associated with asthma, and concluded that total IgE has a minor role in the development of the disease. High IgE and asthma often appear in the same person without the first explaining the second. Allergen-specific testing in a clinic is a different question and remains useful.
No. No guideline selects an asthma treatment by genotype. Biologics are chosen on phenotype and biomarkers such as blood eosinophil count and FeNO. What the genetics contributed was the target — the IL33 pathway found in studies like this one is now a drug target — not the prescription.
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