Targeted resequencing showing novel common and rare genetic variants increases the risk of asthma in the Chinese Han population

• Main Authors: Cheng, Z. (Author), Deng, Y. (Author), Fang, S. (Author), Li, J. (Author), Li, Z. (Author), Liu, J. (Author), Luo, G. (Author), Luo, L. (Author), Mo, B. (Author), Shu, Y. (Author), Wang, Y. (Author), Wang, Z. (Author), Wei, J. (Author), Xiong, W. (Author), Yang, H. (Author), Yang, J. (Author), Yu, B. (Author), Zhang, X. (Author), Zhu, J. (Author)
• Format: Article
• Language: English
• Published: John Wiley and Sons Inc 2021
• Subjects: adolescent; Adolescent; adult; Adult; aged; Aged; Aged, 80 and over; Article; asthma; Asthma; bioinformatics; biological marker; Biomarkers; case control study; Case-Control Studies; child; Child; Child, Preschool; China; cohort analysis; Cohort Studies; common variant; controlled study; female; Female; follow up; Follow-Up Studies; gene frequency; gene interaction; gene sequence; genetic predisposition; Genetic Predisposition to Disease; genetic risk; genetic selection; genetic variability; genetics; genome-wide association study; Genome-Wide Association Study; genotype; Han Chinese; high throughput sequencing; High-Throughput Nucleotide Sequencing; human; Humans; infant; Infant; Infant, Newborn; loss of function mutation; major clinical study; male; Male; metabolism; middle aged; Middle Aged; newborn; next-generation sequencing; pathology; Polymorphism, Single Nucleotide; population research; preschool child; procedures; prognosis; Prognosis; rare variant; risk factor; risk stratification; Sanger sequencing; single nucleotide polymorphism; very elderly; young adult; Young Adult
• Online Access: View Fulltext in Publisher

 Background: Although studies have identified hundreds of genetic variants associated with asthma risk, a large fraction of heritability remains unexplained, especially in Chinese individuals. Methods: To identify genetic risk factors for asthma in a Han Chinese population, 211 asthma-related genes were first selected based on database searches. The genes were then sequenced for subjects in a Discovery Cohort (284 asthma patients and 205 older healthy controls) using targeted next-generation sequencing. Bioinformatics analysis and statistical association analyses were performed to reveal the associations between rare/common variants and asthma, respectively. The identified common risk variants underwent a validation analysis using a Replication Cohort (664 patients and 650 controls). Results: First, we identified 18 potentially functional rare loss-of-function (LOF) variants in 21/284 (7.4%) of the asthma cases. Second, using burden tests, we found that the asthma group had nominally significant (p < 0.05) burdens of rare nonsynonymous variants in 10 genes. Third, 23 common single-nucleotide polymorphisms were associated with the risk of asthma, 7/23 (30.4%) and 9/23 (39.1%) of which were modestly significant (p < 9.1 × 10−4) in the Replication Cohort and Combined Cohort, respectively. According to our cumulative risk model involving the modestly associated alleles, middle- and high-risk subjects had a 2.0-fold (95% CI: 1.621–2.423, p = 2.624 × 10−11) and 6.0-fold (95% CI: 3.623–10.156, p = 7.086 × 10−12) increased risk of asthma, respectively, compared with low-risk subjects. Conclusion: This study revealed novel rare and common genetic risk factors for asthma, and provided a cumulative risk model for asthma risk prediction and stratification in Han Chinese individuals. © 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC