An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos - 06/03/19
, Dara G. Torgerson, PhD c, ∗, Maria Pino-Yanes, PhD c, d, Lawrence H. Uricchio, PhD b, §, Joshua Galanter, MD, MAS b, c, Lindsey A. Roth, MA c, Celeste Eng, BS c, Donglei Hu, PhD c, Elizabeth A. Nguyen, BS c, Scott Huntsman, MS c, Rasika A. Mathias, ScD e, Rajesh Kumar, MD, MSPH f, Jose Rodriguez-Santana, MD g, Neeta Thakur, MD, MPH c, Sam S. Oh, PhD c, Meghan McGarry, MD h, Andres Moreno-Estrada, MD, PhD i, Karla Sandoval, PhD i, Cheryl A. Winkler, PhD j, Max A. Seibold, PhD k, Badri Padhukasahasram, PhD l, David V. Conti, PhD m, Harold J. Farber, MD, MSPH o, Pedro Avila, MD p, Emerita Brigino-Buenaventura, MD q, Michael Lenoir, MD r, Kelley Meade, MD n, Denise Serebrisky, MD s, Luisa N. Borrell, DDS, PhD t, William Rodriguez-Cintron, MD u, Shannon Thyne, MD c, Bonnie R. Joubert, PhD v, Isabelle Romieu, MD w, Albert M. Levin, PhD l, Juan-Jose Sienra-Monge, MD x, Blanca Estela del Rio-Navarro, MD x, Weiniu Gan, PhD y, Benjamin A. Raby, MD, MPH z, Scott T. Weiss, MD z, Eugene Bleecker, MD aa, Deborah A. Meyers, PhD aa, Fernando J. Martinez, MD bb, W. James Gauderman, PhD m, Frank Gilliland, MD m, Stephanie J. London, MD, PhD v, Carlos D. Bustamante, PhD i, Dan L. Nicolae, PhD cc, Carole Ober, PhD dd, Saunak Sen, PhD ee, Kathleen Barnes, PhD e, L. Keoki Williams, MD, MAS l, ff, Ryan D. Hernandez, PhD a, b, Esteban G. Burchard, MD, MPH a, b, cAbstract |
Background |
Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies.
Objective |
We sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility.
Methods |
We leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups.
Results |
We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (P = 6.8 × 10−6), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07-1.34; P = .002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77-0.96; P = .008). Our findings were replicated in an independent childhood asthma study in Latinos (P = 5.3 × 10−3, combined P = 2.6 × 10−7). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5′ of SMAD family member 2 (SMAD2) in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression; OR, 3.93; 95% CI, 2.12-7.28; P < .001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma.
Conclusion |
Ancestry at 18q21 was significantly associated with asthma in Latinos and implicated multiple ancestry-informative noncoding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.
Le texte complet de cet article est disponible en PDF.Key words : Asthma, asthma exacerbations, admixture mapping, meta-analysis, Latinos, SMAD2, gene expression, targeted sequencing, rare variation
Abbreviations used : eQTL, GALA I, GALA II, GWAS, LD, OR, SAGE, SKAT-O, SMAD2, SNP, TDT, ZBTB7C
Plan
| Supported in part by the National Institutes of Health (NIH; AI061774, AI077439, AI079139, CA113710, DK064695, ES015794, HL078885, HL079055, HL087699, HL088133, HL104608, M01-RR00188, and MD006902); ARRA grant RC2 HL101651; the Flight Attendant Medical Research Institute (FAMRI); UCSF Chancellor's Research Fellowship, Dissertation Year Fellowship, and in part by NIH Training Grant T32GM007175 and T32HG000044 (to C.R.G.); an RWJF Amos Medical Faculty Development Award (to E.G.B.); the Sandler Foundation; the American Asthma Foundation (to E.G.B. and L.K.W.); and NHLBI K23 (K23HL111636) and NCATS KL2 (KL2TR000143; to J.M.G.). M.P.-Y. was funded by a Postdoctoral Fellowship from Fundación Ramón Areces. K.B. was supported in part by the Mary Beryl Patch Turnbull Scholar Program. R.A.M. was supported in part by the MOSAIC initiative of Johns Hopkins University. This publication was supported by the National Center for Advancing Translational Sciences, NIH, through UCSF-CTSI grant no. KL2TR000143. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. |
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| Disclosure of potential conflict of interest: C. R. Gignoux receives grant support and travel support from the National Institutes of Health (NIH) and holds stock with 23andMe. M. Pino-Yanes receives payments for lectures from Affymetrix. L. H. Uricchio receives grant support from the NIH. J. Galanter receives grant support from the NIH. R. Kumar receives grant support from the NIH. N. Thakur receives grant support from the National Institute of General Medical Sciences (NIGMS) and National Heart, Lung, and Blood Institute (NHLBI). S. S. Oh receives grant funding from the NIH. M. McGarry receives grant support from the NIH. M. A. Seibold receives research support from Pfizer and MedImmune. H. J. Farber receives grant support from the NIH. P. Avila receives grant and travel support from the NIH. E. Brigino-Buenaventura receives grant support, honorarium, and travel support from the Sandler Foundation. A. M. Levin received research support from the NIH. B. A. Raby receives royalties from UpToDate and holds stock with CureSpark. F. J. Martinez receives grant support from the NIH/NHLBI and Johnson & Johnson and serves as a consultant for Copeval. D. L. Nicolae receives grant support from the NIH. S. Sen has received grants from the NIH. L. Keoki Williams receives grant support from the National Institute of Allergy and Infectious Diseases (NIAID), NHLBI, and NIH. R. D. Hernandez receives grant support from the NIH. The rest of the authors declares that they have no relevant conflicts of interest. |
Vol 143 - N° 3
P. 957-969 - mars 2019 Retour au numéro
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