An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos

Christopher R. Gignoux; Dara G. Torgerson; Maria Pino-Yanes; Lawrence H. Uricchio; Joshua Galanter; Lindsey A. Roth; Celeste Eng; Donglei Hu; Elizabeth A. Nguyen; Scott Huntsman; Rasika A. Mathias; Rajesh Kumar; Jose Rodriguez-Santana; Neeta Thakur; Sam S. Oh; Meghan McGarry; Andres Moreno-Estrada; Karla Sandoval; Cheryl A. Winkler; Max A. Seibold; Badri Padhukasahasram; David V. Conti; Harold J. Farber; Pedro Avila; Emerita Brigino-Buenaventura; Michael Lenoir; Kelley Meade; Denise Serebrisky; Luisa N. Borrell; William Rodriguez-Cintron; Shannon Thyne; Bonnie R. Joubert; Isabelle Romieu; Albert M. Levin; Juan Jose Sienra-Monge; Blanca Estela del Rio-Navarro; Weiniu Gan; Benjamin A. Raby; Scott T. Weiss; Eugene Bleecker; Deborah A. Meyers; Fernando J. Martinez; W. James Gauderman; Frank Gilliland; Stephanie J. London; Carlos D. Bustamante; Dan L. Nicolae; Carole Ober; Saunak Sen; Kathleen Barnes; L. Keoki Williams; Ryan D. Hernandez; Esteban G. Burchard

doi:10.1016/j.jaci.2016.08.057

An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos

Christopher R. Gignoux^*, Dara G. Torgerson, Maria Pino-Yanes, Lawrence H. Uricchio, Joshua Galanter, Lindsey A. Roth, Celeste Eng, Donglei Hu, Elizabeth A. Nguyen, Scott Huntsman, Rasika A. Mathias, Rajesh Kumar, Jose Rodriguez-Santana, Neeta Thakur, Sam S. Oh, Meghan McGarry, Andres Moreno-Estrada, Karla Sandoval, Cheryl A. Winkler, Max A. SeiboldBadri Padhukasahasram, David V. Conti, Harold J. Farber, Pedro Avila, Emerita Brigino-Buenaventura, Michael Lenoir, Kelley Meade, Denise Serebrisky, Luisa N. Borrell, William Rodriguez-Cintron, Shannon Thyne, Bonnie R. Joubert, Isabelle Romieu, Albert M. Levin, Juan Jose Sienra-Monge, Blanca Estela del Rio-Navarro, Weiniu Gan, Benjamin A. Raby, Scott T. Weiss, Eugene Bleecker, Deborah A. Meyers, Fernando J. Martinez, W. James Gauderman, Frank Gilliland, Stephanie J. London, Carlos D. Bustamante, Dan L. Nicolae, Carole Ober, Saunak Sen, Kathleen Barnes, L. Keoki Williams, Ryan D. Hernandez, Esteban G. Burchard

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	957-969
Number of pages	13
Journal	Journal of Allergy and Clinical Immunology
Volume	143
Issue number	3
DOIs	https://doi.org/10.1016/j.jaci.2016.08.057
State	Published - Mar 2019

Funding

We thank the families and patients for their participation and the numerous health care providers and community clinics for their support and participation in all the EVE Consortium and replication studies. In particular, we thank GALA I, GALA II, and SAGE study coordinator Sandra Salazar and the recruiters who obtained the data: Duanny Alva, MD; Gaby Ayala-Rodriguez; Lisa Caine; Elizabeth Castellanos; Jaime Colon; Denise DeJesus; Blanca Lopez; Brenda Lopez, MD; Louis Martos; Vivian Medina; Juana Olivo; Mario Peralta; Esther Pomares, MD; Jihan Quraishi; Johanna Rodriguez; Shahdad Saeedi; Dean Soto; Emmanuel Viera; and Ana Taveras. Resequencing services were kindly provided through the Resequencing and Genotyping Service by the Northwest Genomics Center at the University of Washington, Department of Genome Sciences, under US Federal Government contract no. HHSN268201100037C from the National Heart, Lung, and Blood Institute. Some computations were performed with the UCSF Biostatistics High Performance Computing System. Finally, the authors would like to thank Dean Sheppard, MD; David Erle, MD; and Amy J. Markowitz for helpful edits, comments and advice on early versions of the manuscript. 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 Fundaci?n Ram?n 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.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. 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. 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. 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.

Keywords

Asthma
Latinos
SMAD2
admixture mapping
asthma exacerbations
gene expression
meta-analysis
rare variation
targeted sequencing

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1016/j.jaci.2016.08.057

Cite this

Gignoux, C. R., Torgerson, D. G., Pino-Yanes, M., Uricchio, L. H., Galanter, J., Roth, L. A., Eng, C., Hu, D., Nguyen, E. A., Huntsman, S., Mathias, R. A., Kumar, R., Rodriguez-Santana, J., Thakur, N., Oh, S. S., McGarry, M., Moreno-Estrada, A., Sandoval, K., Winkler, C. A., ... Burchard, E. G. (2019). An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos. Journal of Allergy and Clinical Immunology, 143(3), 957-969. https://doi.org/10.1016/j.jaci.2016.08.057

@article{659182eb607d42e0a53979b532d2ecab,

title = "An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos",

abstract = " 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.",

keywords = "Asthma, Latinos, SMAD2, admixture mapping, asthma exacerbations, gene expression, meta-analysis, rare variation, targeted sequencing",

author = "Gignoux, {Christopher R.} and Torgerson, {Dara G.} and Maria Pino-Yanes and Uricchio, {Lawrence H.} and Joshua Galanter and Roth, {Lindsey A.} and Celeste Eng and Donglei Hu and Nguyen, {Elizabeth A.} and Scott Huntsman and Mathias, {Rasika A.} and Rajesh Kumar and Jose Rodriguez-Santana and Neeta Thakur and Oh, {Sam S.} and Meghan McGarry and Andres Moreno-Estrada and Karla Sandoval and Winkler, {Cheryl A.} and Seibold, {Max A.} and Badri Padhukasahasram and Conti, {David V.} and Farber, {Harold J.} and Pedro Avila and Emerita Brigino-Buenaventura and Michael Lenoir and Kelley Meade and Denise Serebrisky and Borrell, {Luisa N.} and William Rodriguez-Cintron and Shannon Thyne and Joubert, {Bonnie R.} and Isabelle Romieu and Levin, {Albert M.} and Sienra-Monge, {Juan Jose} and {del Rio-Navarro}, {Blanca Estela} and Weiniu Gan and Raby, {Benjamin A.} and Weiss, {Scott T.} and Eugene Bleecker and Meyers, {Deborah A.} and Martinez, {Fernando J.} and Gauderman, {W. James} and Frank Gilliland and London, {Stephanie J.} and Bustamante, {Carlos D.} and Nicolae, {Dan L.} and Carole Ober and Saunak Sen and Kathleen Barnes and Williams, {L. Keoki} and Hernandez, {Ryan D.} and Burchard, {Esteban G.}",

note = "Publisher Copyright: {\textcopyright} 2018",

year = "2019",

month = mar,

doi = "10.1016/j.jaci.2016.08.057",

language = "English (US)",

volume = "143",

pages = "957--969",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

number = "3",

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Gignoux, CR, Torgerson, DG, Pino-Yanes, M, Uricchio, LH, Galanter, J, Roth, LA, Eng, C, Hu, D, Nguyen, EA, Huntsman, S, Mathias, RA, Kumar, R, Rodriguez-Santana, J, Thakur, N, Oh, SS, McGarry, M, Moreno-Estrada, A, Sandoval, K, Winkler, CA, Seibold, MA, Padhukasahasram, B, Conti, DV, Farber, HJ, Avila, P, Brigino-Buenaventura, E, Lenoir, M, Meade, K, Serebrisky, D, Borrell, LN, Rodriguez-Cintron, W, Thyne, S, Joubert, BR, Romieu, I, Levin, AM, Sienra-Monge, JJ, del Rio-Navarro, BE, Gan, W, Raby, BA, Weiss, ST, Bleecker, E, Meyers, DA, Martinez, FJ, Gauderman, WJ, Gilliland, F, London, SJ, Bustamante, CD, Nicolae, DL, Ober, C, Sen, S, Barnes, K, Williams, LK, Hernandez, RD & Burchard, EG 2019, 'An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos', Journal of Allergy and Clinical Immunology, vol. 143, no. 3, pp. 957-969. https://doi.org/10.1016/j.jaci.2016.08.057

TY - JOUR

T1 - An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos

AU - Gignoux, Christopher R.

AU - Torgerson, Dara G.

AU - Pino-Yanes, Maria

AU - Uricchio, Lawrence H.

AU - Galanter, Joshua

AU - Roth, Lindsey A.

AU - Eng, Celeste

AU - Hu, Donglei

AU - Nguyen, Elizabeth A.

AU - Huntsman, Scott

AU - Mathias, Rasika A.

AU - Kumar, Rajesh

AU - Rodriguez-Santana, Jose

AU - Thakur, Neeta

AU - Oh, Sam S.

AU - McGarry, Meghan

AU - Moreno-Estrada, Andres

AU - Sandoval, Karla

AU - Winkler, Cheryl A.

AU - Seibold, Max A.

AU - Padhukasahasram, Badri

AU - Conti, David V.

AU - Farber, Harold J.

AU - Avila, Pedro

AU - Brigino-Buenaventura, Emerita

AU - Lenoir, Michael

AU - Meade, Kelley

AU - Serebrisky, Denise

AU - Borrell, Luisa N.

AU - Rodriguez-Cintron, William

AU - Thyne, Shannon

AU - Joubert, Bonnie R.

AU - Romieu, Isabelle

AU - Levin, Albert M.

AU - Sienra-Monge, Juan Jose

AU - del Rio-Navarro, Blanca Estela

AU - Gan, Weiniu

AU - Raby, Benjamin A.

AU - Weiss, Scott T.

AU - Bleecker, Eugene

AU - Meyers, Deborah A.

AU - Martinez, Fernando J.

AU - Gauderman, W. James

AU - Gilliland, Frank

AU - London, Stephanie J.

AU - Bustamante, Carlos D.

AU - Nicolae, Dan L.

AU - Ober, Carole

AU - Sen, Saunak

AU - Barnes, Kathleen

AU - Williams, L. Keoki

AU - Hernandez, Ryan D.

AU - Burchard, Esteban G.

PY - 2019/3

Y1 - 2019/3

N2 - 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.

AB - 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.

KW - Asthma

KW - Latinos

KW - SMAD2

KW - admixture mapping

KW - asthma exacerbations

KW - gene expression

KW - meta-analysis

KW - rare variation

KW - targeted sequencing

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DO - 10.1016/j.jaci.2016.08.057

M3 - Article

C2 - 30201514

AN - SCOPUS:85055913043

SN - 0091-6749

VL - 143

SP - 957

EP - 969

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 3

ER -

An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos

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