title: Genetic heterogeneity of asthma phenotypes identified by a clustering approach.
abstract: The aim of the study was to identify genetic variants associated with refined asthma phenotypes enabling multiple features of the disease to be taken into account. Latent class analysis (LCA) was applied in 3001 adults ever having asthma recruited in the frame of three epidemiological surveys (the European Community Respiratory Health Survey (ECRHS), the Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA) and the Epidemiological Study on the Genetics and Environment of Asthma (EGEA)). 14 personal and phenotypic characteristics, gathered from questionnaires and clinical examination, were used. A genome-wide association study was conducted for each LCA-derived asthma phenotype, compared to subjects without asthma (n=3474). The LCA identified four adult asthma phenotypes, mainly characterised by disease activity, age of asthma onset and atopic status. Associations of genome-wide significance (p<1.25 × 10(-7)) were observed between "active adult-onset nonallergic asthma" and rs9851461 flanking CD200 (3q13.2) and between "inactive/mild nonallergic asthma" and rs2579931 flanking GRIK2 (6q16.3). Borderline significant results (2.5 × 10(-7) < p <8.2 × 10(-7)) were observed between three single nucleotide polymorphisms (SNPs) in the ALCAM region (3q13.11) and "active adult-onset nonallergic asthma". These results were consistent across studies. 15 SNPs identified in previous genome-wide association studies of asthma have been replicated with at least one asthma phenotype, most of them with the "active allergic asthma" phenotype. Our results provide evidence that a better understanding of asthma phenotypic heterogeneity helps to disentangle the genetic heterogeneity of asthma.
authors: Inserm, U823, Grenoble.
authors: Valérie
authors: V
authors: Siroux
authors: Juan R
authors: JR
authors: González
authors: Emmanuelle
authors: E
authors: Bouzigon
authors: Ivan
authors: I
authors: Curjuric
authors: Anne
authors: A
authors: Boudier
authors: Medea
authors: M
authors: Imboden
authors: Josep Maria
authors: JM
authors: Anto
authors: Ivo
authors: I
authors: Gut
authors: Deborah
authors: D
authors: Jarvis
authors: Mark
authors: M
authors: Lathrop
authors: Ernst Reidar
authors: ER
authors: Omenaas
authors: Isabelle
authors: I
authors: Pin
authors: Mathias
authors: M
authors: Wjst
authors: Florence
authors: F
authors: Demenais
authors: Nicole
authors: N
authors: Probst-Hensch
authors: Manolis
authors: M
authors: Kogevinas
authors: Francine
authors: F
authors: Kauffmann
mesh_terms: D000328:Adult; D001249:Asthma / Q000175:diagnosis* / Q000235:genetics*; D016000:Cluster Analysis; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D005602:France; D018740:Genetic Heterogeneity; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D013557:Switzerland