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

J Allergy Clin Immunol. 2016 Oct;138(4):1071-1080. doi: 10.1016/j.jaci.2016.03.018. Epub 2016 Apr 6.

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.

Keywords: Asthma; CYLD; NOD2; age of onset; conditional analysis; genetics; genome-wide association study; survival analysis.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Age of Onset
  • Asthma / genetics*
  • Child
  • Chromosomes, Human, Pair 16 / genetics*
  • Deubiquitinating Enzyme CYLD
  • European Continental Ancestry Group / genetics
  • Female
  • Genetic Variation*
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Male
  • Nod2 Signaling Adaptor Protein / genetics
  • Tumor Suppressor Proteins / genetics

Substances

  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • Tumor Suppressor Proteins
  • CYLD protein, human
  • Deubiquitinating Enzyme CYLD