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.
N1 - Publisher Copyright:
© 2018
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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U2 - 10.1016/j.jaci.2016.08.057
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 -