TY - JOUR
T1 - An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos
AU - Gignoux, Chris 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
N1 - Copyright © 2018. Published by Elsevier Inc.
PY - 2018/9/7
Y1 - 2018/9/7
N2 - BACKGROUND: Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies.OBJECTIVE: Perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility.METHODS: We leveraged the mixed ancestry of 3,902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3,774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of >500 individuals from 3 racial/ethnic groups.RESULTS: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (p=6.8x10-6), where Native American ancestry was associated with increased risk of asthma (OR=1.20, 95% CI=1.07-1.34, p=0.002) and European ancestry with protection (OR=0.86, 95% CI=0.77-0.96, p=0.008). Our findings replicated in an independent childhood asthma study in Latinos (p=5.3x10-3, combined p=2.6x10-7). Fine mapping of 18q21 in 1,978 Latinos identified a significant association with multiple variants 5' of 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<0.001). 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 non-coding 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: Perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility.METHODS: We leveraged the mixed ancestry of 3,902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3,774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of >500 individuals from 3 racial/ethnic groups.RESULTS: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (p=6.8x10-6), where Native American ancestry was associated with increased risk of asthma (OR=1.20, 95% CI=1.07-1.34, p=0.002) and European ancestry with protection (OR=0.86, 95% CI=0.77-0.96, p=0.008). Our findings replicated in an independent childhood asthma study in Latinos (p=5.3x10-3, combined p=2.6x10-7). Fine mapping of 18q21 in 1,978 Latinos identified a significant association with multiple variants 5' of 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<0.001). 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 non-coding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.
U2 - 10.1016/j.jaci.2016.08.057
DO - 10.1016/j.jaci.2016.08.057
M3 - Article
C2 - 30201514
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
ER -