Integrative approach identifies corticosteroid response variant in diverse populations with asthma - 04/05/19
Abstract |
Background |
Although inhaled corticosteroid (ICS) medication is considered the cornerstone treatment for patients with persistent asthma, few ICS pharmacogenomic studies have involved nonwhite populations.
Objective |
We sought to identify genetic predictors of ICS response in multiple population groups with asthma.
Methods |
The discovery group comprised African American participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE) who underwent 6 weeks of monitored ICS therapy (n = 244). A genome-wide scan was performed to identify single nucleotide polymorphism (SNP) variants jointly associated (ie, the combined effect of the SNP and SNP × ICS treatment interaction) with changes in asthma control. Top associations were validated by assessing the joint association with asthma exacerbations in 3 additional groups: African Americans (n = 803 and n = 563) and Latinos (n = 1461). RNA sequencing data from 408 asthmatic patients and 405 control subjects were used to examine whether genotype was associated with gene expression.
Results |
One variant, rs3827907, was significantly associated with ICS-mediated changes in asthma control in the discovery set (P = 7.79 × 10−8) and was jointly associated with asthma exacerbations in 3 validation cohorts (P = .023, P = .029, and P = .041). RNA sequencing analysis found the rs3827907 C-allele to be associated with lower RNASE2 expression (P = 6.10 × 10−4). RNASE2 encodes eosinophil-derived neurotoxin, and the rs3827907 C-allele appeared to particularly influence ICS treatment response in the presence of eosinophilic inflammation (ie, high pretreatment eosinophil-derived neurotoxin levels or blood eosinophil counts).
Conclusion |
We identified a variant, rs3827907, that appears to influence response to ICS treatment in multiple population groups and likely mediates its effect through eosinophils.
Le texte complet de cet article est disponible en PDF.Key words : Pharmacogenetics, EDDM3B, RNASE2, eosinophil-derived neurotoxin, transcriptome, eosinophils
Abbreviations used : ACT, ECP, EDN, eQTL, GALA II, ICS, PE, RNA-seq, SAGE II, SAPPHIRE, SNP
Plan
| Supported by the Fund for Henry Ford Hospital (to A.M.L., D.E.L., and L.K.W.); a fellowship (FI16/00136) from the Instituto de Salud Carlos III (ISCIII) and cofunded by the European Social Funds from the European Union (ESF)–“ESF invests in your future” (to N.H.-P.); the Ramón y Cajal Program (RYC-2015-17205) by the Spanish Ministry of Economy, Industry, and Competitiveness (to M.P.-Y.); an award (AC15/00015) by the ISCIII through Strategic Action for Health Research (AES) and European Community (EC) within the Active and Assisted Living (AAL) Programme framework (to M.P.-Y.); a SysPharmPedia grant from the ERACoSysMed 1st Joint Transnational Call from the European Union under the Horizon 2020 (to M.P.-Y.); the American Asthma Foundation (to L.K.W. and E.G.B.); the Sandler Family Foundation (to E.G.B.); the RWJF Amos Medical Faculty Development Program (to E.G.B.); Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II (to E.G.B.); and the following institutes of the US National Institutes of Health: National Institute of Allergy and Infectious Diseases (U19AI077439 to D.J.E. and R01AI079139 and R01AI061774 to L.K.W.), the National Heart, Lung, and Blood Institute (K99HL135403 to W.L.E., R01HL117004 and X01HL134589 to E.G.B., and R01HL079055, R01HL118267, and X01HL134589 to L.K.W.), the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK064695 and R01DK113003 to L.K.W.), the National Institute of Health and Environmental (R01ES015794 and R21ES024844 to E.G.B.), and the National Institute on Minority Health and Health Disparities (P60MD006902 and R01MD010443 to E.G.B.). |
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| Disclosure of potential conflict of interest: N. Hernandez-Pacheco reports grant funding through a fellowship from the Instituto de Salud Carlos III. W. L. Eckalbar reports grant funding from the National Institutes of Health (NIH). M. Pino-Yanes reports grant funding from the Spanish Ministry of Economy, Industry and Competitiveness and Instituto de Salud Carlos III. D. J. Erle reports grant funding from the National Institute of Allergy and Infectious Diseases (NIAID)/NIH, an honorarium and travel expenses from Boehringer Ingelheim, and consulting and travel expenses from Coherus. L. K. Williams reports grant funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Heart, Lung, and Blood Institute (NHBLI); and NIAID/NIH and the American Asthma Foundation. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 143 - N° 5
P. 1791-1802 - mai 2019 Retour au numéro
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