Genome-wide association study of inhaled corticosteroid response in admixed children with asthma

被引：52

作者：

Hernandez-Pacheco, Natalia ^{[1
,2
]}

Farzan, Niloufar ^{[3
,4
]}

Francis, Ben ^{[5
]}

Karimi, Leila ^{[6
]}

Repnik, Katja ^{[7
,8
]}

Vijverberg, Susanne J. ^{[3
,4
]}

Soares, Patricia ^{[9
]}

Schieck, Maximilian ^{[10
,11
]}

Gorenjak, Mario ^{[7
]}

Forno, Erick ^{[12
]}

Eng, Celeste ^{[13
]}

Oh, Sam S. ^{[13
]}

Perez-Mendez, Lina ^{[14
,15
]}

Berce, Vojko ^{[7
,16
]}

Tavendale, Roger ^{[17
]}

Samedy, Lesly-Anne ^{[13
,18
]}

Hunstman, Scott ^{[13
]}

Hu, Donglei ^{[13
]}

Meade, Kelley ^{[19
]}

Farber, Harold J. ^{[20
,21
]}

Avila, Pedro C. ^{[22
,23
]}

Serebrisky, Denise ^{[24
]}

Thyne, Shannon M. ^{[25
]}

Brigino-Buenaventura, Emerita ^{[26
]}

Rodriguez-Cintron, William ^{[27
]}

Sen, Saunak ^{[28
]}

Kumar, Rajesh ^{[29
,30
]}

Lenoir, Michael ^{[31
]}

Rodriguez-Santana, Jose R. ^{[32
]}

Celedon, Juan C. ^{[12
]}

Mukhopadhyay, Somnath ^{[9
,17
]}

Potocnik, Uros ^{[7
,8
]}

Pirmohamed, Munir ^{[33
]}

Verhamme, Katia M. ^{[6
]}

Kabesch, Michael ^{[34
]}

Palmer, Colin N. A. ^{[17
]}

Hawcutt, Daniel B. ^{[5
,35
]}

Flores, Carlos ^{[1
,15
,36
]}

Maitland-van der Zee, Anke H. ^{[3
,4
,37
]}

Burchard, Esteban G. ^{[13
,18
]}

Pino-Yanes, Maria ^{[1
,2
,15
]}

机构：

[1] Univ La Laguna, Hosp Univ NS Candelaria, Res Unit, San Cristobal La Laguna, Spain

[2] Univ La Laguna, Dept Biochem Microbiol Cell Biol & Genet, Genom & Hlth Grp, San Cristobal La Laguna, Santa Cruz De T, Spain

[3] Univ Amsterdam, AMC, Dept Resp Med, Amsterdam, Netherlands

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

[5] Univ Liverpool, Dept Womens & Childrens Hlth, Liverpool, Merseyside, England

[6] Erasmus Univ, Med Ctr, Dept Med Informat, Rotterdam, Netherlands

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

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

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

[10] Univ Childrens Hosp Regensburg KUNO, Dept Pediat Pneumol & Allergy, Regensburg, Germany

[11] Hannover Med Sch, Dept Human Genet, Hannover, Germany

[12] Univ Pittsburgh, Childrens Hosp Pittsburgh, Med Ctr, Div Pediat Pulm Med, Pittsburgh, PA 15213 USA

[13] Univ Calif San Francisco, Dept Med, San Francisco, CA USA

[14] Hosp Univ NS Candelaria, Gerencia Atenc Primaria, Dept Clin Epidemiol & Biostat, Res Unit, Santa Cruz De Tenerife, Spain

[15] Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain

[16] Univ Med Ctr Maribor, Dept Pediat, Maribor, Slovenia

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

[18] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA

[19] Childrens Hosp & Res Ctr Oakland, Oakland, CA USA

[20] Baylor Coll Med, Dept Pediat, Sect Pulmonol, Houston, TX 77030 USA

[21] Texas Childrens Hosp, Houston, TX 77030 USA

[22] Northwestern Univ, Dept Med, Chicago, IL 60611 USA

[23] Allergy & ENT Associates, The Woodlands, TX USA

[24] Pediat Pulm Div, New York, NY USA

[25] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA

[26] Dept Allergy & Immunol, Vallejo, CA USA

[27] Vet Caribbean Hlth Care Syst, San Juan, PR USA

[28] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA

[29] Northwestern Univ, Div Allergy & Immunol, Feinberg Sch Med, Chicago, IL 60611 USA

[30] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA

[31] Bay Area Pediat, Oakland, CA USA

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

[33] Univ Liverpool, Inst Translat Med, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England

[34] Univ Childrens Hosp Regensburg KUNO, Dept Pediat Pneumol & Allergy, Regensburg, Germany

[35] Alder Hey Childrens Hosp, Liverpool, Merseyside, England

[36] ITER, Genom Div, Santa Cruz De Tenerife, Spain

[37] Univ Amsterdam, AMC, Emmas Children Hosp, Dept Pediat Resp Med & Allergy, Amsterdam, Netherlands

来源：

CLINICAL AND EXPERIMENTAL ALLERGY | 2019年 / 49卷 / 06期

基金：

美国国家卫生研究院;

关键词：

African American; childhood asthma; exacerbations; Latino; pharmacogenomics; HISPANIC COMMUNITY-HEALTH; GENETIC PROFILES; PHARMACOGENETICS; IDENTIFICATION; EXACERBATIONS; METAANALYSIS; ANCESTRY; MEDICINE; RISK;

D O I：

10.1111/cea.13354

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

摘要：

BackgroundInhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome-wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response. ObjectiveWe aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings. MethodsA meta-analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P <= 5x10(-6) were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations. ResultsA total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P <= 5x10(-6)). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P=7.52x10(-3)) and was also associated with change in lung function after treatment with ICS (P=4.91x10(-3)). Additionally, the reported association of the L3MBTL4-ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified. Conclusions and clinical relevanceThis study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment.

引用

页码：789 / 798

页数：10

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