Shared genetic and experimental links between obesity-related traits and asthma subtypes in UK Biobank

被引：248

作者：

Zhu, Zhaozhong ^{[1
,2
,8
]}

Guo, Yanjun ^{[1
,9
]}

Shi, Huwenbo ^{[1
]}

Liu, Cong-Lin ^{[10
,11
]}

Panganiban, Ronald Allan ^{[3
,4
,5
]}

Chung, Wonil ^{[1
]}

O'Connor, Luke J. ^{[1
]}

Himes, Blanca E. ^{[12
]}

Gazal, Steven ^{[1
]}

Hasegawa, Kohei ^{[8
]}

Camargo, Carlos A., Jr. ^{[1
,8
]}

Qi, Lu ^{[13
]}

Moffatt, Miriam F. ^{[14
]}

Hu, Frank B. ^{[6
]}

Lu, Quan ^{[3
,4
,5
]}

Cookson, William O. C. ^{[14
]}

Liang, Liming ^{[1
,7
]}

机构：

[1] Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Dept Epidemiol, Boston, MA USA

[2] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA

[3] Harvard TH Chan Sch Publ Hlth, Program Mol & Integrat Physiol Sci, Dept Environm Hlth, Boston, MA USA

[4] Harvard TH Chan Sch Publ Hlth, Program Mol & Integrat Physiol Sci, Dept Genet, Boston, MA USA

[5] Harvard TH Chan Sch Publ Hlth, Program Mol & Integrat Physiol Sci, Dept Complex Dis, Boston, MA USA

[6] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA

[7] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA

[8] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02115 USA

[9] Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Occupat & Environm Hlth, Sch Publ Hlth, Wuhan, Peoples R China

[10] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA

[11] Harvard Med Sch, Boston, MA 02115 USA

[12] Univ Penn, Dept Biostat Epidemiol & Informat, Philadelphia, PA 19104 USA

[13] Tulane Univ, Dept Epidemiol, Sch Publ Hlth & Trop Med, New Orleans, LA 70118 USA

[14] Natl Heart & Lung Inst, Sect Genom Med, London, England

来源：

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | 2020年 / 145卷 / 02期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

Obesity; metabolic disorder; asthma subtypes; shared genetics; genome-wide association study; RNA sequencing; RT-PCR; GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; FATTY-ACID OXIDATION; AIRWAY INFLAMMATION; LUNG-FUNCTION; MURINE MODEL; CELL; LOCI; TGF-BETA/SMAD3; IDENTIFICATION;

D O I：

10.1016/j.jaci.2019.09.035

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

摘要：

Background: Clinical and epidemiologic studies have shown that obesity is associated with asthma and that these associations differ by asthma subtype. Little is known about the shared genetic components between obesity and asthma. Objective: We sought to identify shared genetic associations between obesity-related traits and asthma subtypes in adults. Methods: A cross-trait genome-wide association study (GWAS) was performed using 457,822 subjects of European ancestry from the UK Biobank. Experimental evidence to support the role of genes significantly associated with both obesity-related traits and asthma through a GWAS was sought by using results from obese versus lean mouse RNA sequencing and RT-PCR experiments. Results: We found a substantial positive genetic correlation between body mass index and later-onset asthma defined by asthma age of onset at 16 years or greater (Rg = 0.25, P = 9.56 X 10(-22)). Mendelian randomization analysis provided strong evidence in support of body mass index causally increasing asthma risk. Cross-trait meta-analysis identified 34 shared loci among 3 obesity-related traits and 2 asthma subtypes. GWAS functional analyses identified potential causal relationships between the shared loci and Genotype-Tissue Expression (GTEx) quantitative trait loci and shared immune and cell differentiation related pathways between obesity and asthma. Finally, RNA sequencing data from lungs of obese versus control mice found that 2 genes (acyl-coenzyme A oxidase-like [ACOXL] and myosin light chain 6 [MYL6]) from the cross-trait meta-analysis were differentially expressed, and these findings were validated by using RT-PCR in an independent set of mice. Conclusions: Our work identified shared genetic components between obesity-related traits and specific asthma subtypes, reinforcing the hypothesis that obesity causally increases the risk of asthma and identifying molecular pathways that might underlie both obesity and asthma.

引用

页码：537 / 549

页数：13

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