Multi-ancestry genome-wide association study of asthma exacerbations

被引：14

作者：

Herrera-Luis, Esther ^{[1
]}

Ortega, Victor E. ^{[2
]}

Ampleford, Elizabeth J. ^{[3
]}

Sio, Yang Yie ^{[4
]}

Granell, Raquel ^{[5
]}

de Roos, Emmely ^{[6
,7
]}

Terzikhan, Natalie ^{[6
,7
]}

Vergara, Ernesto Elorduy ^{[8
]}

Hernandez-Pacheco, Natalia ^{[9
,10
]}

Perez-Garcia, Javier ^{[1
]}

Martin-Gonzalez, Elena ^{[1
]}

Lorenzo-Diaz, Fabian ^{[1
,11
]}

Hashimoto, Simone ^{[12
]}

Brinkman, Paul ^{[12
]}

Jorgensen, Andrea L. ^{[13
]}

Yan, Qi ^{[14
]}

Forno, Erick ^{[15
]}

Vijverberg, Susanne J. ^{[16
,17
,18
]}

Lethem, Ryan ^{[5
]}

Espuela-Ortiz, Antonio ^{[1
]}

Gorenjak, Mario ^{[19
]}

Eng, Celeste ^{[20
]}

Gonzalez-Perez, Ruperto ^{[21
,22
]}

Hernandez-Perez, Jose M. ^{[23
,24
]}

Poza-Guedes, Paloma ^{[21
,22
]}

Sardon, Olaia ^{[25
,26
]}

Corcuera, Paula ^{[25
]}

Hawkins, Greg A. ^{[27
]}

Marsico, Annalisa ^{[28
]}

Bahmer, Thomas ^{[29
,30
]}

Rabe, Klaus F. ^{[29
,30
]}

Hansen, Gesine ^{[31
]}

Kopp, Matthias Volkmar ^{[32
,33
,34
]}

Rios, Raimon ^{[35
]}

Cruz, Maria Jesus ^{[10
,36
]}

Gonzalez-Barcala, Francisco-Javier ^{[37
]}

Maria Olaguibel, Jose ^{[10
,38
]}

Plaza, Vicente ^{[10
,39
]}

Quirce, Santiago ^{[10
,40
]}

Canino, Glorisa ^{[41
]}

Cloutier, Michelle ^{[42
]}

Del Pozo, Victoria ^{[10
,43
]}

Rodriguez-Santana, Jose R. ^{[44
]}

Korta-Murua, Javier ^{[26
]}

Villar, Jesus ^{[10
,45
]}

Potocnik, Uros ^{[46
]}

Figueiredo, Camila ^{[47
]}

Kabesch, Michael ^{[48
]}

Mukhopadhyay, Somnath ^{[49
,50
]}

Pirmohamed, Munir ^{[51
]}

机构：

[1] Univ La Laguna ULL, Dept Biochem Microbiol Cell Biol & Genet, Genom & Hlth Grp, Apartado 456, Tenerife 38200, Spain

[2] Mayo Clin, Div Resp Med, Dept Internal Med, Scottsdale, AZ USA

[3] Wake Forest Sch Med, Ctr Precis Med, Dept Internal Med, Winston Salem, NC 27101 USA

[4] Natl Univ Singapore, Dept Biol Sci, Singapore, Singapore

[5] Univ Bristol, Bristol Med Sch, MRC Integrat Epidemiol Unit IEU, Bristol, Avon, England

[6] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[7] Ghent Univ Hosp, Dept Resp Med, Ghent, Belgium

[8] German Res Ctr Environm Hlth, Inst Computat Biol, Helmholtz Zentrum Munchen, Munich, Germany

[9] Karolinska Inst, Dept Clin Sci & Educ, Sodersjukhuset, Stockholm, Sweden

[10] CIBER Enfermedades Resp CIBERES, Madrid, Spain

[11] Univ La Laguna ULL, Inst Univ Enfermedades Trop & Salud Publ Canarias, Tenerife, Spain

[12] Univ Amsterdam, Amsterdam Univ Med Ctr, Dept Resp Med, Amsterdam, Netherlands

[13] Univ Liverpool, Inst Populat Hlth, Dept Hlth Data Sci, Liverpool, Merseyside, England

[14] Columbia Univ, Dept Obstet & Gynecol, Irving Med Ctr, New York, NY USA

[15] Univ Pittsburgh, UPMC Childrens Hosp Pittsburgh, Div Pediat Pulm Med, Pittsburgh, PA USA

[16] Univ Amsterdam, Dept Resp Med, Amsterdam UMC, Amsterdam, Netherlands

[17] Univ Utrecht, Fac Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands

[18] Univ Amsterdam, Emmas Children Hosp, Dept Paediat Resp Med & Allergy, Amsterdam UMC, Amsterdam, Netherlands

[19] Univ Maribor, Fac Med, Ctr Human Mol Genet & Pharmacogen, Maribor, Slovenia

[20] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA

[21] Hosp Univ Canarias, Allergy Dept, Tenerife, Spain

[22] Hosp Univ Canarias, Allergy Dept, Severe Asthma Unit, Tenerife, Spain

[23] Hosp Univ NS Candelaria, Pulm Med, Santa Cruz De Tenerife, Spain

[24] Hosp Gen La Palma, Pulm Med, La Palma, Santa Cruz De T, Spain

[25] Hosp Univ Donostia, Div Pediat Resp Med, San Sebastian, Spain

[26] Univ Basque Country UPV EHU, Dept Pediat, San Sebastian, Spain

[27] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC 27101 USA

[28] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Computat Hlth Ctr, Munich, Germany

[29] LungenClin Grosshansdorf, Pneumol, Grosshansdorf, Germany

[30] Germany Ctr Lung Res DZL, Airway Res Ctr North ARCN, Grosshansdorf, Germany

[31] Hannover Med Sch, Dept Pediat Pneumol Allergol & Neonatol, Hannover, Germany

[32] Univ Med Ctr Schleswig Holstein, Div Pediat Pneumol & Allergol, Lubeck, Germany

[33] Germany Ctr Lung Res DZL, Airway Res Ctr North ARCN, Lubeck, Germany

[34] Univ Bern, Univ Childrens Hosp Bern, Dept Paediat Resp Med, Inselspital, Bern, Switzerland

[35] Univ Fed Bahia UFBA, Inst Ciencias Saude, Programa Pos Grad Imunol PPGIm, Salvador, BA, Brazil

[36] Hosp Valle De Hebron, Serv Neumol, Barcelona, Spain

[37] Complejo Hosp Univ Santiago, Serv Neumol, Santiago De Compostela, Spain

[38] Complejo Hosp Navarra, Serv Alergol, Navarra, Spain

[39] Inst Invest Biomed St Pau IIB St Pau, Hosp Santa Creu & St Pau, Dept Med Resp, Barcelona, Spain

[40] La Paz Univ Hosp, Dept Allergy, IdiPAZ, Madrid, Spain

[41] Univ Puerto Rico, Behav Sci Res Inst, San Juan, PR USA

[42] Univ Connecticut, Dept Pediat, Farmington, CT USA

[43] Inst Invest Sanitaria Hosp Univ Fdn Jimenez Diaz, Immunol Dept, Madrid, Spain

[44] Ctr Neumol Pediat, San Juan, PR USA

[45] Hosp Univ Dr Negrin, Res Unit, Multidisciplinary Organ Dysfunct Evaluat Res Netw, Las Palmas Gran Canaria, Spain

[46] Univ Maribor, Fac Chem & Chem Engn, Lab Biochem Mol Biol & Genom, Maribor, Slovenia

[47] Univ Fed Bahia, Inst Ciencias Saude, Salvador, BA, Brazil

[48] Univ Childrens Hosp Regensburg KUNO, Dept Paediat Pneumol & Allergy, Regensburg, Germany

[49] Royal Alexandra Childrens Hosp, Acad Dept Paediat, Brighton & Sussex Med Sch, Brighton, E Sussex, England

[50] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Inst, Populat Pharmacogenet Grp, Dundee, Scotland

来源：

PEDIATRIC ALLERGY AND IMMUNOLOGY | 2022年 / 33卷 / 06期

基金：

英国惠康基金; 美国国家卫生研究院; 英国医学研究理事会; 瑞典研究理事会; 欧盟地平线“2020”;

关键词：

asthma exacerbations; EXTL2; GWAS; PANK1; single-nucleotide polymorphism; EFFICIENT; ADHESION; EXTL2; TOOL;

D O I：

10.1111/pai.13802

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

摘要：

Background: Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. Methods: A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p <= 5 x 10(-5)) were assessed for replication in 36,477 European and 1078 non-European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. Results: One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (ORT allele) = 0.82, p = 9.05 x 10(-6) and replication: ORT allele = 0.89, p = 5.35 x 10(-3)) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele = 0.85, p = 3.10 x 10(-5) and replication: ORC allele = 0.89, p = 1.30 x 10(-2)). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. Conclusions: This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.

引用

页数：17

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