Juan Liu1, Yanhan Deng1, Bo Yu2, Biwen Mo3, Liman Luo4, Jingping Yang5, Xiaoju Zhang6, Zheng Wang6, Yingnan Wang7, Jing Zhu7, Hua Yang8, Shirong Fang8, Zhenshun Cheng9, Jingping Li10, Ying Shu10, Guangwei Luo11, Weining Xiong1,12, Jianghong Wei3, Zongzhe Li2. 1. Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Key Cite of National Clinical Research Center for Respiratory Disease, Wuhan Clinical Medical Research Center for Chronic Airway Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China. 2. Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 3. Department of Respiratory Medicine, Affiliated Hospital of Guilin Medical University, Guilin, China. 4. Department of Pediatrics, The 306 Hospital of People's Liberation Army, Beijing, China. 5. Department of Respiratory and Critical Care Medicine, The Third Affiliated Hospital of Inner Mongolia Medical University, Baotou, China. 6. Department of Respiratory Medicine, Henan Provincial People's Hospital & the People's Hospital of Zhengzhou University, Zhengzhou, China. 7. Department of Respiratory and Critical Care Medicine, Renmin Hospital of Three Gorges University, Yichang, China. 8. Department of Respiratory Medicine, University Hospital of Hubei University for Nationalities, Enshi, China. 9. Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China. 10. Department of Respiratory Medicine, Qianjiang Central Hospital, Qianjiang, China. 11. Department of Respiratory Medicine, Wuhan No. 1 Hospital, Wuhan, China. 12. Department of Respiratory Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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.
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.
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Authors: Klaus Bønnelykke; Patrick Sleiman; Kasper Nielsen; Eskil Kreiner-Møller; Josep M Mercader; Danielle Belgrave; Herman T den Dekker; Anders Husby; Astrid Sevelsted; Grissel Faura-Tellez; Li Juel Mortensen; Lavinia Paternoster; Richard Flaaten; Anne Mølgaard; David E Smart; Philip F Thomsen; Morten A Rasmussen; Silvia Bonàs-Guarch; Claus Holst; Ellen A Nohr; Rachita Yadav; Michael E March; Thomas Blicher; Peter M Lackie; Vincent W V Jaddoe; Angela Simpson; John W Holloway; Liesbeth Duijts; Adnan Custovic; Donna E Davies; David Torrents; Ramneek Gupta; Mads V Hollegaard; David M Hougaard; Hakon Hakonarson; Hans Bisgaard Journal: Nat Genet Date: 2013-11-17 Impact factor: 38.330