Longitudinal follow-up of the asthma status in a French-Canadian cohort

Abstract

Asthma affects 340 million people worldwide and varies in time. Twenty years ago, in Canada, the Saguenay-Lac-Saint-Jean asthma family cohort was created to study the genetic and environmental components of asthma. This study is a follow-up of 125 participants of this cohort to explore the appearance, persistence, and progression of asthma over 10-20 years. Participants answered a clinical standardized questionnaire. Lung function was assessed (forced expiratory volume in 1 s, forced vital capacity, bronchial reversibility, and methacholine bronchoprovocation), skin allergy testing was performed, blood samples were obtained (immunoglobulin E, white blood cell counts) and phenotypes were compared between recruitment and follow-up. From the participants without asthma at recruitment, 12% developed a phenotype of adult-onset asthma with the presence of risk factors, such as atopy, high body mass index, and exposure to smoking. A decrease of PC₂₀ values in this group was observed and a decrease in the FEV₁/FVC ratio in all groups. Also, 7% of individuals with asthma at recruitment developed chronic obstructive pulmonary disease, presenting risk factors at recruitment, such as moderate-to-severe bronchial hyperresponsiveness, exposure to smoking, and asthma. This study allowed a better interpretation of the evolution of asthma. Fine phenotypic characterization is the first step for meaningful genetic and epigenetic studies.

Figure 1

Timeline of the SLSJ asthma family cohort. Stages in the acquisition of phenotypic, genomic, and epigenomic data for the SLSJ family cohort. Description of approaches used at each stage: 1.–3. Standardized questionnaire, respiratory measurements, blood samples (IgE, differential white blood cell counts, and DNA), 2. Microsatellite markers, 4. Illumina 610 K-Quad chip, 5. Infinium Human Methylation 450 K chip (white blood cells and eosinophils), 6. Isolation of naive CD4⁺ T cells and eosinophils for DNA and RNA extraction for methylome and transcriptome (methylome sequencing with custom methyl capture panel [MCC-Seq] and RNA sequencing), 7. Standardized questionnaire, respiratory measurements, blood samples (IgE, differential white blood cell counts, DNA, RNA, and plasma), 8. MCC-Seq (white blood cells). Between 2001 and 2010, candidate gene studies were performed with genetic variants, expression, and methylation data.

Figure 2

Asthma severity over time. (A) Participants classified the severity of their disease using a self-reported questionnaire. (B) The use of prescription medication for asthma control evolved between recruitment and follow-up. p values < 0.05 are indicated by an asterisk and p values < 0.0001 are indicated by three asterisks.

Figure 3

Variations in lung function. Changes in the forced expiratory volume in 1 s on the forced vital capacity (FEV₁/FVC) ratio were observed between recruitment and follow-up considering values (A) before or (B) after the use of bronchodilators (BDs). The All group includes all participants in the subsample, the No asthma group comprises individuals without asthma at recruitment, and the Asthma group include participants with confirmed asthma diagnosis at recruitment. p values < 0.001 are indicated by two asterisks and p values < 0.0001 are indicated by three asterisks. (C) Representation of participants with asthma at recruitment who exhibited either an increase (from PC₂₀ ≤ 8 mg/ml to ≥ 16 mg/ml; n = 7) or a decrease (from PC₂₀ ≥ 16 mg/ml to ≤ 8 mg/ml; n = 1) in PC₂₀ measurements. (D) Representations of participants with asthma at recruitment who showed an increase (from FEV₁ < 80% to > 80%; n = 5) or a decrease (from FEV₁ > 80% to < 80%; n = 8) in measurements of FEV₁ of predicted values.