Identification of a new locus at 16q12 associated with time to asthma onset

Abstract

Background Asthma is a heterogeneous disease in which age of onset plays an important role. Objective We sought to identify the genetic variants associated with time to asthma onset (TAO). Methods We conducted a large-scale meta-analysis of 9 genome-wide association studies of TAO (total of 5462 asthmatic patients with a broad range of age of asthma onset and 8424 control subjects of European ancestry) performed by using survival analysis techniques. Results We detected 5 regions associated with TAO at the genome-wide significant level (P < 5 × 10−8). We evidenced a new locus in the 16q12 region (near cylindromatosis turban tumor syndrome gene [CYLD]) and confirmed 4 asthma risk regions: 2q12 (IL-1 receptor–like 1 [IL1RL1]), 6p21 (HLA-DQA1), 9p24 (IL33), and 17q12-q21 (zona pellucida binding protein 2 [ZPBP2]–gasdermin A [GSDMA]). Conditional analyses identified 2 distinct signals at 9p24 (both upstream of IL33) and 17q12-q21 (near ZPBP2 and within GSDMA). Together, these 7 distinct loci explained 6.0% of the variance in TAO. In addition, we showed that genetic variants at 9p24 and 17q12-q21 were strongly associated with an earlier onset of childhood asthma (P ≤ .002), whereas the 16q12 single nucleotide polymorphism was associated with later asthma onset (P = .04). A high burden of disease risk alleles at these loci was associated with earlier age of asthma onset (4 vs 9-12 years, P = 10−4). Conclusion The new susceptibility region for TAO at 16q12 harbors variants that correlate with the expression of CYLD and nucleotide-binding oligomerization domain 2 (NOD2), 2 strong candidates for asthma. This study demonstrates that incorporating the variability of age of asthma onset in asthma modeling is a helpful approach in the search for disease susceptibility genes

Frontline Science: RIP2 promotes house dust mite–induced allergic airway inflammation

“…Despite NOD1, NOD2, or RIP2 not being generally regarded as susceptibility genes for allergic or asthmatic disease, a number of reports suggest an association between polymorphisms in NOD1, NOD2, and RIP2 genes and allergic or asthmatic status . In addition, other studies have reported up‐regulation of these proteins in the setting of allergy or asthma.…”

Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct

“…This hypothesis, which to our knowledge has not been formally tested to date, is supported by the observations that asthma risk alleles are enriched among individuals with early-onset disease. [14][15][16] Moreover, it has been shown that the efficacy of novel anti-cytokine asthma therapies, such as those involving anti-IL-5 17 and the anti-IL-5Ra, 18 is greater in adult-onset disease, again pointing to age-of-onset-dependent disease mechanisms.…”

Genome‐wide interaction study of early‐life smoking exposure on time‐to‐asthma onset in childhood

“…The analysis of time‐to‐asthma onset phenotype requires to specify the event (here, asthma occurrence) and the time to event. Information on occurrence of asthma was based on report of doctor's diagnosis and/or on standardized questionnaires, as used in previous GWAS . Childhood asthma was defined as having asthma at or before 16 years of age.…”

“…Therefore, similar to the previously reported heterogeneity of SNP effect on asthma risk according to age of onset of asthma, the SNP‐smoke exposure interactions may differ between childhood‐onset and later‐onset asthma and may vary according to time of exposure. Only two GWAS have considered either age of asthma onset in asthmatic children or time‐to‐asthma onset (TAO) in asthmatic and non‐asthmatic subjects and have led to the discovery of new asthma loci, but no GWIS has yet taken into account the time‐to‐asthma onset.…”