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

Abstract

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.

One panel with four single nucleotide polymorphisms for Chinese children with asthma: Integrating public data and whole exome sequencing

“…Another meta‐analysis of 16 publications, comprising 18 studies involving 5005 asthma patients and 9725 controls, demonstrated that the CHI3L1 polymorphisms rs4950928, rs10399931, and rs883125 are vital genetic factors for asthma in East Asian individuals 12 . Using targeted next‐generation sequencing (NGS), Liu et al 13 . analyzed 211 asthma‐related genes selected on the basis of database searches in a cohort of 284 patients with asthma and 205 healthy controls from the Southern Han Chinese population.…”

Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma

“…Previous studies have explored the contribution of rare variants in asthma and allergic diseases and have implicated genes harboring rare variants in asthma using various study designs across diverse ancestries. 5 , 7 – 16 Among the more notable findings are associations between asthma and rare variants in the IL33 9 , 16 and filaggrin 11 , 17 genes. Indeed, the discovery of a rare loss-of-function variant in IL33 that conferred protection from asthma by disrupting binding to its receptor, ST2, led to the identification of astegolimab, an ST2 inhibitor, as an effective therapy for reducing exacerbations in individuals with hard-to-treat asthma.…”