28 results on '"Burchard, Esteban G."'
Search Results
2. Multi-omic approach associates blood methylome with bronchodilator drug response in pediatric asthma.
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Perez-Garcia, Javier, Herrera-Luis, Esther, Li, Annie, Mak, Angel C.Y., Huntsman, Scott, Oh, Sam S., Elhawary, Jennifer R., Eng, Celeste, Beckman, Kenneth B., Hu, Donglei, Lorenzo-Diaz, Fabian, Lenoir, Michael A., Rodriguez-Santana, Jose, Zaitlen, Noah, Villar, Jesús, Borrell, Luisa N., Burchard, Esteban G., and Pino-Yanes, Maria
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[Display omitted] Albuterol is the drug most widely used as asthma treatment among African Americans despite having a lower bronchodilator drug response (BDR) than other populations. Although BDR is affected by gene and environmental factors, the influence of DNA methylation is unknown. This study aimed to identify epigenetic markers in whole blood associated with BDR, study their functional consequences by multi-omic integration, and assess their clinical applicability in admixed populations with a high asthma burden. We studied 414 children and young adults (8-21 years old) with asthma in a discovery and replication design. We performed an epigenome-wide association study on 221 African Americans and replicated the results on 193 Latinos. Functional consequences were assessed by integrating epigenomics with genomics, transcriptomics, and environmental exposure data. Machine learning was used to develop a panel of epigenetic markers to classify treatment response. We identified 5 differentially methylated regions and 2 CpGs genome-wide significantly associated with BDR in African Americans located in FGL2 (cg08241295, P = 6.8 × 10
−9 ) and DNASE2 (cg15341340, P = 7.8 × 10−8 ), which were regulated by genetic variation and/or associated with gene expression of nearby genes (false discovery rate < 0.05). The CpG cg15341340 was replicated in Latinos (P = 3.5 × 10−3 ). Moreover, a panel of 70 CpGs showed good classification for those with response and nonresponse to albuterol therapy in African American and Latino children (area under the receiver operating characteristic curve for training, 0.99; for validation, 0.70-0.71). The DNA methylation model showed similar discrimination as clinical predictors (P >.05). We report novel associations of epigenetic markers with BDR in pediatric asthma and demonstrate for the first time the applicability of pharmacoepigenetics in precision medicine of respiratory diseases. [ABSTRACT FROM AUTHOR]- Published
- 2023
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3. Multiomics analysis identifies BIRC3 as a novel glucocorticoid response–associated gene.
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Kan, Mengyuan, Diwadkar, Avantika R., Shuai, Haoyue, Joo, Jaehyun, Wang, Alberta L., Ong, Mei-Sing, Sordillo, Joanne E., Iribarren, Carlos, Lu, Meng X., Hernandez-Pacheco, Natalia, Perez-Garcia, Javier, Gorenjak, Mario, Potočnik, Uroš, Burchard, Esteban G., Pino-Yanes, Maria, Wu, Ann Chen, and Himes, Blanca E.
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Inhaled corticosteroid (ICS) response among patients with asthma is influenced by genetics, but biologically actionable insights based on associations have not been found. Various glucocorticoid response omics data sets are available to interrogate their biological effects. We sought to identify functionally relevant ICS-response genetic associations by integrating complementary multiomics data sets. Variants with P values less than 10
−4 from a previous ICS-response genome-wide association study were reranked on the basis of integrative scores determined from (1) glucocorticoid receptor– and (2) RNA polymerase II–binding regions inferred from ChIP-Seq data for 3 airway cell types, (3) glucocorticoid response element motifs, (4) differentially expressed genes in response to glucocorticoid exposure according to 20 transcriptomic data sets, and (5) expression quantitative trait loci from GTEx. Candidate variants were tested for association with ICS response and asthma in 6 independent studies. Four variants had significant (q value < 0.05) multiomics integrative scores. These variants were in a locus consisting of 52 variants in high linkage disequilibrium (r2 ≥ 0.8) near glucocorticoid receptor–binding sites by the gene BIRC3. Variants were also BIRC3 expression quantitative trait loci in lung, and 2 were within/near putative glucocorticoid response element motifs. BIRC3 had increased RNA polymerase II occupancy and gene expression, with glucocorticoid exposure in 2 ChIP-Seq and 13 transcriptomic data sets. Some BIRC3 variants in the 52-variant locus were associated (P <.05) with ICS response in 3 independent studies and others with asthma in 1 study. BIRC3 should be prioritized for further functional studies of ICS response. [ABSTRACT FROM AUTHOR]- Published
- 2022
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4. A genome-wide association study of asthma hospitalizations in adults.
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Yan, Qi, Forno, Erick, Herrera-Luis, Esther, Pino-Yanes, Maria, Yang, Ge, Oh, Sam, Acosta-Pérez, Edna, Hu, Donglei, Eng, Celeste, Huntsman, Scott, Rodriguez-Santana, José R., Cloutier, Michelle M., Canino, Glorisa, Burchard, Esteban G., Chen, Wei, and Celedón, Juan C.
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Little is known about the genetic determinants of severe asthma exacerbations. We aimed to identify genetic variants associated with asthma hospitalizations. We conducted a genome-wide association study of asthma hospitalizations in 34,167 white British adults with asthma, 1,658 of whom had at least 1 asthma-related hospitalization. This analysis was conducted by using logistic regression under an additive genetic model with adjustment for age, sex, body mass index, smoking status, and the first 5 principal components derived from genotypic data. We then analyzed data from 2 cohorts of Latino children and adolescents for replication and conducted quantitative trait locus and functional annotation analyses. At the chromosome 6p21.3 locus, the single-nucleotide polymorphism (SNP) rs56151658 (8 kb from the promoter of HLA-DQB1) was most significantly associated with asthma hospitalizations (for test allele A, odds ratio = 1.36 [95% CI = 1.22-1.52]; P = 3.11 × 10
–8 ); 21 additional SNPs in this locus were associated with asthma hospitalizations at a P value less than 1 × 10–6 . In the replication cohorts, multiple SNPs in strong linkage disequilibrium with rs56151658 were associated with severe asthma exacerbations at a P value of.01 or less in the same direction of association as in the discovery cohort. Three HLA genes (HLA-DQA2 , HLA-DRB6 , and HLA-DOB) were also shown to mediate the estimated effects of the SNPs associated with asthma hospitalizations through effects on gene expression in lung tissue. We identified strong candidate genes for asthma hospitalizations in adults in the region for class II HLA genes through genomic, quantitative trait locus, and summary data–based mendelian randomization analyses. [ABSTRACT FROM AUTHOR]- Published
- 2021
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5. Functional genomics of CDHR3 confirms its role in HRV-C infection and childhood asthma exacerbations.
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Everman, Jamie L., Sajuthi, Satria, Saef, Benjamin, Rios, Cydney, Stoner, Ari M., Numata, Mari, Hu, Donglei, Eng, Celeste, Oh, Sam, Rodriguez-Santana, Jose, Vladar, Eszter K., Voelker, Dennis R., Burchard, Esteban G., and Seibold, Max A.
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Research in transformed immortalized cell lines indicates the cadherin-related family member 3 (CDHR3) protein serves as a receptor for human rhinovirus (HRV)–C. Similar experiments indicate that the CDHR3 coding variant rs6967330 increases CDHR3 protein surface expression. We sought to determine whether CDHR3 is necessary for HRV-C infection of primary airway epithelial cells (AECs) and to identify molecular mechanisms by which CDHR3 variants confer risk for asthma exacerbations. CDHR3 function and influence on HRV-C infection were investigated by using single-cell transcriptomics, CRISPR-Cas9 gene knockout, and genotype-specific donor experiments performed in primary AECs. Nasal airway epithelium cis–expression quantitative trait locus (eQTL) analysis of CDHR3 was performed, followed by association testing for asthma hospitalization in minority children. CDHR3 lung expression is exclusive to ciliated AECs and associated with basal bodies during and after motile ciliogenesis. Knockout of CDHR3 in human AECs did not prevent ciliated cell differentiation but was associated with a decrease in transepithelial resistance and an 80% decrease in HRV-C infection of the mucociliary epithelium. AECs from subjects homozygous for the risk-associated rs6967330 single nucleotide polymorphism (SNP) exhibited greater HRV-C infection compared with cells homozygous for the nonrisk allele. AEC cis-eQTL analysis indicated that rs6967330 and other SNPs are eQTLs for CDHR3. Only the eQTL block containing the rs6967330 SNP showed a significant association with childhood asthma hospitalization. Genetic deletion and genotype-specific studies in primary AECs indicate CDHR3 is critical to HRV-C infection of ciliated cells. The rs6967330 SNP confers risk of severe childhood asthma exacerbations, likely through increasing HRV-C infection levels and protein surface localization. [ABSTRACT FROM AUTHOR]
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- 2019
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6. Integrative approach identifies corticosteroid response variant in diverse populations with asthma.
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Levin, Albert M., Gui, Hongsheng, Hernandez-Pacheco, Natalia, Yang, Mao, Xiao, Shujie, Yang, James J., Hochstadt, Samantha, Barczak, Andrea J., Eckalbar, Walter L., Rynkowski, Dean, Samedy, Lesly-Anne, Kwok, Pui-Yan, Pino-Yanes, Maria, Erle, David J., Lanfear, David E., Burchard, Esteban G., and Williams, L. Keoki
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Although inhaled corticosteroid (ICS) medication is considered the cornerstone treatment for patients with persistent asthma, few ICS pharmacogenomic studies have involved nonwhite populations. We sought to identify genetic predictors of ICS response in multiple population groups with asthma. 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. 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). We identified a variant, rs3827907, that appears to influence response to ICS treatment in multiple population groups and likely mediates its effect through eosinophils. [ABSTRACT FROM AUTHOR]- Published
- 2019
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7. Acculturation is associated with asthma burden and pulmonary function in Latino youth: The GALA II study.
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Thakur, Neeta, Borrell, Luisa N., Ye, Morgan, Oh, Sam S., Eng, Celeste, Meade, Kelley, Avila, Pedro C., Farber, Harold J., Serebrisky, Denise, Brigino-Buenaventura, Emerita, Rodriguez-Cintron, William, Kumar, Rajesh, Bibbins-Domingo, Kirsten, Thyne, Shannon, Sen, Saunak, Rodriguez-Santana, Jose R., and Burchard, Esteban G.
- Abstract
Acculturation is an important predictor of asthma in Latino youth, specifically Mexican Americans. Less is known about acculturation and pulmonary function measures. We sought to estimate the association of acculturation measures with asthma and pulmonary function in Latino youth and determine whether this association varies across Latino subgroups. We included 1849 Latinos (302 Caribbean Spanish, 193 Central or South Americans, 1136 Mexican Americans, and 218 other Latino children) aged 8 to 21 years from 4 urban regions in the United States. Acculturation measures include nativity status, age of immigration, language of preference, and generation in the United States. We used multivariable logistic and linear regression models to quantify the association of acculturation factors with the presence of asthma (case-control study) and pulmonary function (case-only study), adjusting for demographic, socioenvironmental, and clinical variables. For all acculturation measures (nativity status, age of immigration, language of preference, and generation in the United States), greater levels of acculturation were associated with greater odds of asthma. Among cases, high (English preference) and medium (equal preference for Spanish and English) levels of language acculturation were associated with decreased bronchodilator response compared with low (Spanish preference) levels (P =.009 and.02, respectively). Similarly, high language acculturation was associated with increased FEV 1 compared with low language acculturation (P =.02). There was insufficient evidence of heterogeneity for associations across Latino subgroups. Acculturation was associated with diagnosed asthma and pulmonary function in Latino children and is an important factor to consider in the management of Latino youth with asthma. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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8. Human genetics influences microbiome composition involved in asthma exacerbations despite inhaled corticosteroid treatment.
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Perez-Garcia, Javier, Espuela-Ortiz, Antonio, Hernández-Pérez, José M., González-Pérez, Ruperto, Poza-Guedes, Paloma, Martin-Gonzalez, Elena, Eng, Celeste, Sardón-Prado, Olaia, Mederos-Luis, Elena, Corcuera-Elosegui, Paula, Sánchez-Machín, Inmaculada, Korta-Murua, Javier, Villar, Jesús, Burchard, Esteban G., Lorenzo-Diaz, Fabian, and Pino-Yanes, Maria
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- 2023
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9. Atopic dermatitis, race, and genetics.
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Kumar, Rajesh, Seibold, Max A., and Burchard, Esteban G.
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- 2020
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10. An epigenome-wide association study of total serum IgE in Hispanic children.
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Chen, Wei, Wang, Ting, Pino-Yanes, Maria, Forno, Erick, Liang, Liming, Yan, Qi, Hu, Donglei, Weeks, Daniel E., Baccarelli, Andrea, Acosta-Perez, Edna, Eng, Celeste, Han, Yueh-Ying, Boutaoui, Nadia, Laprise, Catherine, Davies, Gwyneth A., Hopkin, Julian M., Moffatt, Miriam F., Cookson, William O.C.M., Canino, Glorisa, and Burchard, Esteban G.
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Background Total IgE is a therapeutic target in patients with allergic diseases. DNA methylation in white blood cells (WBCs) was associated with total IgE levels in an epigenome-wide association study of white subjects. Whether DNA methylation of eosinophils explains these findings is insufficiently understood. Methods We tested for association between genome-wide DNA methylation in WBCs and total IgE levels in 2 studies of Hispanic children: the Puerto Rico Genetics of Asthma and Lifestyle Study (PR-GOAL; n = 306) and the Genes-environments and Admixture in Latino Americans (GALA II) study (n = 573). Whole-genome methylation of DNA from WBCs was measured by using the Illumina Infinium HumanMethylation450 BeadChip. Total IgE levels were measured by using the UniCAP 100 system. In PR-GOAL WBC types (ie, neutrophils, eosinophils, basophils, lymphocytes, and monocytes) in peripheral blood were measured by using Coulter Counter techniques. In the GALA II study WBC types were imputed. Multivariable linear regression was used for the analysis of DNA methylation and total IgE levels, which was first conducted separately for each cohort, and then results from the 2 cohorts were combined in a meta-analysis. Results CpG sites in multiple genes, including novel findings and results previously reported in white subjects, were significantly associated with total IgE levels. However, adjustment for WBC types resulted in markedly fewer significant sites. Top findings from this adjusted meta-analysis were in the genes ZFPM1 ( P = 1.5 × 10 −12 ), ACOT7 ( P = 2.5 × 10 −11 ), and MND1 ( P = 1.4 × 10 −9 ). Conclusions In an epigenome-wide association study adjusted for WBC types (including eosinophils), methylation changes in genes enriched in pathways relevant to asthma and immune responses were associated with total IgE levels among Hispanic children. [ABSTRACT FROM AUTHOR]
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- 2017
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11. COMT Val158Met polymorphism is associated with post-traumatic stress disorder and functional outcome following mild traumatic brain injury.
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Winkler, Ethan A., Yue, John K., Ferguson, Adam R., Temkin, Nancy R., Stein, Murray B., Barber, Jason, Yuh, Esther L., Sharma, Sourabh, Satris, Gabriela G., McAllister, Thomas W., Rosand, Jonathan, Sorani, Marco D., Lingsma, Hester F., Tarapore, Phiroz E., Burchard, Esteban G., Hu, Donglei, Eng, Celeste, Wang, Kevin K.W., Mukherjee, Pratik, and Okonkwo, David O.
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Mild traumatic brain injury (mTBI) results in variable clinical trajectories and outcomes. The source of variability remains unclear, but may involve genetic variations, such as single nucleotide polymorphisms (SNPs). A SNP in catechol-o-methyltransferase ( COMT ) is suggested to influence development of post-traumatic stress disorder (PTSD), but its role in TBI remains unclear. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val 158 Met polymorphism is associated with PTSD and global functional outcome as measured by the PTSD Checklist – Civilian Version and Glasgow Outcome Scale Extended (GOSE), respectively. Results in 93 predominately Caucasian subjects with mTBI show that the COMT Met 158 allele is associated with lower incidence of PTSD (univariate odds ratio (OR) of 0.25, 95% CI [0.09–0.69]) and higher GOSE scores (univariate OR 2.87, 95% CI [1.20–6.86]) 6-months following injury. The COMT Val 158 Met genotype and PTSD association persists after controlling for race (multivariable OR of 0.29, 95% CI [0.10–0.83]) and pre-existing psychiatric disorders/substance abuse (multivariable OR of 0.32, 95% CI [0.11–0.97]). PTSD emerged as a strong predictor of poorer outcome on GOSE (multivariable OR 0.09, 95% CI [0.03–0.26]), which persists after controlling for age, GCS, and race. When accounting for PTSD in multivariable analysis, the association of COMT genotype and GOSE did not remain significant (multivariable OR 1.73, 95% CI [0.69–4.35]). Whether COMT genotype indirectly influences global functional outcome through PTSD remains to be determined and larger studies in more diverse populations are needed to confirm these findings. [ABSTRACT FROM AUTHOR]
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- 2017
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12. Novel locus for atopic dermatitis in African Americans and replication in European Americans.
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Almoguera, Berta, Vazquez, Lyam, Mentch, Frank, March, Michael E., Connolly, John J., Peissig, Peggy L., Linneman, James G., Plaza-Serón, María del Carmen, Pino-Yanes, Maria, Burchard, Esteban G., Brilliant, Murray, Sleiman, Patrick, and Hakonarson, Hakon
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- 2019
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13. Factors predicting inhaled corticosteroid responsiveness in African American patients with asthma.
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Gould, Wendy, Peterson, Edward L., Karungi, Gloria, Zoratti, Amanda, Gaggin, John, Toma, Ghazwan, Yan, Shiqing, Levin, Albert M., Yang, James J., Wells, Karen, Wang, Mingqun, Burke, Robert R., Beckman, Kenneth, Popadic, Danijela, Land, Susan J., Kumar, Rajesh, Seibold, Max A., Lanfear, David E., Burchard, Esteban G., and Williams, L. Keoki
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DISEASES in African Americans ,ASTHMA treatment ,CORTICOSTEROIDS ,GENETIC disorders ,BECLOMETHASONE dipropionate ,HEALTH outcome assessment ,PULMONARY function tests - Abstract
Background: African American patients disproportionately experience uncontrolled asthma. Treatment with an inhaled corticosteroid (ICS) is considered first-line therapy for persistent asthma. Objective: We sought to determine the degree to which African American patients respond to ICS medication and whether the level of response is influenced by other factors, including genetic ancestry. Methods: Patients aged 12 to 56 years who received care from a large health system in southeast Michigan and who resided in Detroit were recruited to participate if they had a diagnosis of asthma. Patients were treated with 6 weeks of inhaled beclomethasone dipropionate, and pulmonary function was remeasured after treatment. Ancestry was determined by genotyping ancestry-informative markers. The main outcome measure was ICS responsiveness defined as the change in prebronchodilator FEV
1 over the 6-week course of treatment. Results: Among 147 participating African American patients with asthma, average improvement in FEV1 after 6 weeks of ICS treatment was 11.6%. The mean proportion of African ancestry in this group was 78.4%. The degree of baseline bronchodilator reversibility was the only factor consistently associated with ICS responsiveness, as measured by both an improvement in FEV1 and patient-reported asthma control (P = .001 and P = .021, respectively). The proportion of African ancestry was not significantly associated with ICS responsiveness. Conclusions: Although baseline pulmonary function parameters appear to be associated with the likelihood to respond to ICS treatment, the proportion of genetic African ancestry does not. This study suggests that genetic ancestry might not contribute to differences in ICS controller response among African American patients with asthma. [ABSTRACT FROM AUTHOR]- Published
- 2010
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14. Racial/ethnic differences in eligibility for asthma biologics among pediatric populations.
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Wohlford, Eric M., Huang, Peter F., Elhawary, Jennifer R., Millette, Lauren A., Contreras, Maria G., Witonsky, Jonathan, Holweg, Cécile T.J., Oh, Sam S., Lee, Christine, Merenda, Christine, Rabin, Ronald L., Araojo, Richardae, Mak, Angel C.Y., Eng, Celeste S., Hu, Donglei, Huntsman, Scott, LeNoir, Michael A., Rodríguez-Santana, Jose R., Borrell, Luisa N., and Burchard, Esteban G.
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Asthma is a heterogeneous disease. Clinical blood parameters differ by race/ethnicity and are used to distinguish asthma subtypes and inform therapies. Differences in subtypes may explain population-specific trends in asthma outcomes. However, these differences in racial/ethnic minority pediatric populations are unclear. We investigated the association of blood parameters and asthma subtypes with asthma outcomes and examined population-specific eligibility for biologic therapies in minority pediatric populations. Using data from 2 asthma case-control studies of pediatric minority populations, we performed case-control (N = 3738) and case-only (N = 2743) logistic regressions to quantify the association of blood parameters and asthma subtypes with asthma outcomes. Heterogeneity of these associations was tested using an interaction term between race/ethnicity and each exposure. Differences in therapeutic eligibility were investigated using chi-square tests. Race/ethnicity modified the association between total IgE and asthma exacerbations. Elevated IgE level was associated with worse asthma outcomes in Puerto Ricans. Allergic asthma was associated with worse outcomes in Mexican Americans, whereas eosinophilic asthma was associated with worse outcomes in Puerto Ricans. A lower proportion of Puerto Ricans met dosing criteria for allergic asthma–directed biologic therapy than other groups. A higher proportion of Puerto Ricans qualified for eosinophilic asthma–directed biologic therapy than African Americans. We found population-specific associations between blood parameters and asthma subtypes with asthma outcomes. Our findings suggest that eligibility for asthma biologic therapies differs across pediatric racial/ethnic populations. These findings call for more studies in diverse populations for equitable treatment of minority patients with asthma. [ABSTRACT FROM AUTHOR]
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- 2021
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15. Relationship between recent short-acting beta-agonist use and subsequent asthma exacerbations.
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Paris J, Peterson EL, Wells K, Pladevall M, Burchard EG, Choudhry S, Lanfear DE, Williams LK, Paris, Jason, Peterson, Edward L, Wells, Karen, Pladevall, Manel, Burchard, Esteban G, Choudhry, Shweta, Lanfear, David E, and Williams, L Keoki
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- 2008
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16. Differences in allergic sensitization by self-reported race and genetic ancestry.
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Yang, James J., Burchard, Esteban G., Choudhry, Shweta, Johnson, Christine C., Ownby, Dennis R., Favro, David, Chen, Justin, Akana, Matthew, Ha, Connie, Kwok, Pui-Yan, Krajenta, Richard, Havstad, Suzanne L., Joseph, Christine L., Seibold, Max A., Shriver, Mark D., and Williams, L. Keoki
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MAN-woman relationships ,ETHNIC groups ,MULTICULTURALISM ,REGRESSION analysis - Abstract
Background: Many allergic conditions occur more frequently in African American patients when compared with white patients; however, it is not known whether this represents genetic predisposition or disparate environmental exposures. Objective: We sought to assess the relationship of self-reported race and genetic ancestry to allergic sensitization. Methods: We included 601 women enrolled in a population-based cohort study whose self-reported race was African American or white. Genetic ancestry was estimated by using markers that differentiate West African and European ancestry. We assessed the relationship between allergic sensitization (defined as ≥1 allergen-specific IgE results) and both self-reported race and genetic ancestry. Regression models adjusted for sociodemographic variables, environmental exposures, and location of residence. Results: The average proportion of West African ancestry in African American participants was 0.69, whereas the mean proportion of European ancestry in white participants was 0.79. Self-reported African American race was associated with allergic sensitization when compared with those who reported being white (adjusted odds ratio, 2.19; 95% CI, 1.22–3.93), even after adjusting for other variables. Genetic ancestry was not significantly associated with allergic sensitization after accounting for location of residence (adjusted odds ratio, 2.09 for urban vs suburban residence; 95% CI, 1.32–3.31). Conclusion: Self-reported race and location of residence appeared to be more important predictors of allergic sensitization when compared with genetic ancestry, suggesting that the disparity in allergic sensitization by race might be primarily a result of environmental factors rather than genetic differences. [Copyright &y& Elsevier]
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- 2008
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17. Gene-environment interactions between CD14 C-260T and endotoxin exposure on Foxp3+ and Foxp3- CD4+ lymphocyte numbers and total serum IgE levels in early childhood.
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Williams LK, Oliver J, Peterson EL, Bobbitt KR, McCabe MJ Jr, Smolarek D, Havstad SL, Wegienka G, Burchard EG, Ownby DR, Johnson CC, Williams, L Keoki, Oliver, Jennifer, Peterson, Edward L, Bobbitt, Kevin R, McCabe, Michael J Jr, Smolarek, Derek, Havstad, Suzanne L, Wegienka, Ganesa, and Burchard, Esteban G
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- 2008
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18. NLRP1 variant M1184V decreases inflammasome activation in the context of DPP9 inhibition and asthma severity.
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Moecking, Jonas, Laohamonthonkul, Pawat, Chalker, Katelyn, White, Marquitta J., Harapas, Cassandra R., Yu, Chien-Hsiung, Davidson, Sophia, Hrovat-Schaale, Katja, Hu, Donglei, Eng, Celeste, Huntsman, Scott, Calleja, Dale J., Horvat, Jay C., Hansbro, Phil M., O'Donoghue, Robert J.J., Ting, Jenny P., Burchard, Esteban G., Geyer, Matthias, Gerlic, Motti, and Masters, Seth L.
- Abstract
NLRP1 is an innate immune sensor that can form cytoplasmic inflammasome complexes. Polymorphisms in NLRP1 are linked to asthma; however, there is currently no functional or mechanistic explanation for this. We sought to clarify the role of NLRP1 in asthma pathogenesis. Results from the GALA II cohort study were used to identify a link between NLRP1 and asthma in Mexican Americans. In vitro and in vivo models for NLRP1 activation were applied to investigate the role of this inflammasome in asthma at the molecular level. We document the association of an NLRP1 haplotype with asthma for which the single nucleotide polymorphism rs11651270 (M1184V) individually is the most significant. Surprisingly, M1184V increases NLRP1 activation in the context of N-terminal destabilization, but decreases NLRP1 activation on dipeptidyl peptidase 9 inhibition. In vitro studies demonstrate that M1184V increases binding to dipeptidyl peptidase 9, which can account for its inhibitory role in this context. In addition, in vivo data from a mouse model of airway inflammation reveal a protective role for NLRP1 inflammasome activation reducing eosinophilia in this setting. Linking our in vitro and in vivo results, we found that the NLRP1 variant M1184V reduces inflammasome activation in the context of dipeptidyl peptidase 9 inhibition and could thereby increase asthma severity. Our studies may have implications for the treatment of asthma in patients carrying this variant of NLRP1. [Display omitted] [ABSTRACT FROM AUTHOR]
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- 2021
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19. A deoxyribonuclease 1–like 3 genetic variant associates with asthma exacerbations.
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Herrera-Luis, Esther, Lorenzo-Diaz, Fabian, Samedy-Bates, Lesly-Anne, Eng, Celeste, Villar, Jesús, Rodriguez-Santana, Jose R., Burchard, Esteban G., and Pino-Yanes, Maria
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- 2021
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20. Childhood asthma exacerbations and the Arg16 β2-receptor polymorphism: A meta-analysis stratified by treatment.
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Turner, Steve, Francis, Ben, Vijverberg, Susanne, Pino-Yanes, Maria, Maitland-van der Zee, Anke H., Basu, Kaninika, Bignell, Lauren, Mukhopadhyay, Somnath, Tavendale, Roger, Palmer, Colin, Hawcutt, Daniel, Pirmohamed, Munir, Burchard, Esteban G., and Lipworth, Brian
- Abstract
Background The Gly-to-Arg substitution at the 16 position (rs1042713) in the β 2 -adrenoceptor gene (ADRB2) is associated with enhanced downregulation and uncoupling of β 2 -receptors. Objectives We sought to undertake a meta-analysis to test the hypothesis that there is an interaction between the A allele of rs1042713 (Arg16 amino acid) and long-acting β-agonist (LABA) exposure for asthma exacerbations in children. Methods Children with diagnosed asthma were recruited in 5 populations (BREATHE, Genes-Environments and Admixture in Latino Americans II, PACMAN, the Paediatric Asthma Gene Environment Study, and the Pharmacogenetics of Adrenal Suppression with Inhaled Steroid Study). A history of recent exacerbation and asthma treatment was determined from questionnaire data. DNA was extracted, and the Gly16Arg genotype was determined. Results Data from 4226 children of white Northern European and Latino origin were analyzed, and the odds ratio for exacerbation increased by 1.52 (95% CI, 1.17-1.99; P = .0021) for each copy of the A allele among the 637 children treated with inhaled corticosteroids (ICSs) plus LABAs but not for treatment with ICSs alone (n = 1758) or ICSs plus leukotriene receptor antagonist (LTRAs; n = 354) or ICSs plus LABAs plus LTRAs (n = 569). Conclusions The use of a LABA but not an LTRA as an “add-on controller” is associated with increased risk of asthma exacerbation in children carrying 1 or 2 A alleles at rs1042713. Prospective genotype-stratified clinical trials are now required to explore the potential role of rs1042713 genotyping for personalized asthma therapy in children. [ABSTRACT FROM AUTHOR]
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- 2016
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21. Sensitization to mouse and cockroach allergens and asthma morbidity in urban minority youth: Genes-environments and Admixture in Latino American (GALA-II) and Study of African-Americans, Asthma, Genes, and Environments (SAGE-II).
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Fishbein, Anna B., Lee, Todd A., Cai, Miao, Oh, Sam S., Eng, Celeste, Hu, Donglei, Huntsman, Scott, Farber, Harold J., Serebrisky, Denise, Silverberg, Jonathan, Williams, L. Keoki, Seibold, Max A., Sen, Saunak, Borrell, Luisa N., Avila, Pedro, Rodriguez-Cintron, William, Rodriguez-Santana, Jose R., Burchard, Esteban G., and Kumar, Rajesh
- Published
- 2016
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22. Assessing differences in inhaled corticosteroid response by self-reported race-ethnicity and genetic ancestry among asthmatic subjects.
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Wells, Karen E., Cajigal, Sonia, Peterson, Edward L., Ahmedani, Brian K., Kumar, Rajesh, Lanfear, David E., Burchard, Esteban G., and Williams, L. Keoki
- Abstract
Background Inhaled corticosteroids (ICSs) are the preferred treatment for achieving asthma control. However, little is known regarding the factors contributing to treatment response and whether treatment response differs by population group. Objective We sought to assess behavioral, sociodemographic, and genetic factors related to ICS response among African American and European American subjects with asthma. Methods Study participants were part of the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). The analytic sample included asthmatic subjects aged 12 to 56 years with greater than 12% bronchodilator reversibility and percent predicted FEV 1 of between 40% and 90%. Participants received 6 weeks of inhaled beclomethasone dipropionate. The primary measure of ICS response was a change in Asthma Control Test (ACT) score; the secondary measure was a change in prebronchodilator FEV 1 . Adherence was measured with electronic monitors. Genetic ancestry was estimated for African American participants by using genome-wide genotype data. Results There were 339 study participants; 242 self-identified as African American and 97 as European American. Baseline ACT score, percent predicted FEV 1 , degree of bronchodilator response, and ICS adherence were significantly associated with ICS response. A baseline ACT score of 19 or less was useful in identifying those who would respond, as evidenced by the significant dose-response relationship with ICS adherence. Neither self-reported race-ethnicity among all participants nor proportion of African ancestry among African American participants was associated with ICS responsiveness. Conclusions Our findings suggest that baseline lung function measures and self-reported asthma control predict ICS response, whereas self-reported race-ethnicity and genetic ancestry do not. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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23. Fine mapping of the myosin light chain kinase (MYLK) gene replicates the association with asthma in populations of Spanish descent.
- Author
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Acosta-Herrera, Marialbert, Pino-Yanes, Maria, Ma, Shwu-Fan, Barreto-Luis, Amalia, Corrales, Almudena, Cumplido, José, Pérez-Rodríguez, Eva, Campo, Paloma, Eng, Celeste, García-Robaina, José Carlos, Quintela, Inés, Villar, Jesús, Blanca, Miguel, Carracedo, Ángel, Carrillo, Teresa, Garcia, Joe G.N., Torgerson, Dara G., Burchard, Esteban G., and Flores, Carlos
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- 2015
- Full Text
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24. Dissecting childhood asthma with nasal transcriptomics distinguishes subphenotypes of disease.
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Poole, Alex, Urbanek, Cydney, Eng, Celeste, Schageman, Jeoffrey, Jacobson, Sean, O'Connor, Brian P., Galanter, Joshua M., Gignoux, Christopher R., Roth, Lindsey A., Kumar, Rajesh, Lutz, Sharon, Liu, Andrew H., Fingerlin, Tasha E., Setterquist, Robert A., Burchard, Esteban G., Rodriguez-Santana, Jose, and Seibold, Max A.
- Abstract
Background: Bronchial airway expression profiling has identified inflammatory subphenotypes of asthma, but the invasiveness of this technique has limited its application to childhood asthma. Objectives: We sought to determine whether the nasal transcriptome can proxy expression changes in the lung airway transcriptome in asthmatic patients. We also sought to determine whether the nasal transcriptome can distinguish subphenotypes of asthma. Methods: Whole-transcriptome RNA sequencing was performed on nasal airway brushings from 10 control subjects and 10 asthmatic subjects, which were compared with established bronchial and small-airway transcriptomes. Targeted RNA sequencing nasal expression analysis was used to profile 105 genes in 50 asthmatic subjects and 50 control subjects for differential expression and clustering analyses. Results: We found 90.2% overlap in expressed genes and strong correlation in gene expression (ρ = .87) between the nasal and bronchial transcriptomes. Previously observed asthmatic bronchial differential expression was strongly correlated with asthmatic nasal differential expression (ρ = 0.77, P = 5.6 × 10
−9 ). Clustering analysis identified TH 2-high and TH 2-low subjects differentiated by expression of 70 genes, including IL13, IL5, periostin (POSTN), calcium-activated chloride channel regulator 1 (CLCA1), and serpin peptidase inhibitor, clade B (SERPINB2). TH 2-high subjects were more likely to have atopy (odds ratio, 10.3; P = 3.5 × 10−6 ), atopic asthma (odds ratio, 32.6; P = 6.9 × 10−7 ), high blood eosinophil counts (odds ratio, 9.1; P = 2.6 × 10−6 ), and rhinitis (odds ratio, 8.3; P = 4.1 × 10−6 ) compared with TH 2-low subjects. Nasal IL13 expression levels were 3.9-fold higher in asthmatic participants who experienced an asthma exacerbation in the past year (P = .01). Several differentially expressed nasal genes were specific to asthma and independent of atopic status. Conclusion: Nasal airway gene expression profiles largely recapitulate expression profiles in the lung airways. Nasal expression profiling can be used to identify subjects with IL13-driven asthma and a TH 2-skewed systemic immune response. [Copyright &y& Elsevier]- Published
- 2014
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25. Genetic variation in B cell–activating factor of the TNF family (BAFF) and asthma exacerbations among African American subjects.
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Kumar, Rajesh, Williams, L. Keoki, Kato, Atsushi, Peterson, Edward L., Favoreto, Silvio, Hulse, Katie, Wang, Deli, Beckman, Kenneth, Thyne, Shannon, LeNoir, Michael, Meade, Kelley, Lanfear, David E., Levin, Albert M., Favro, David, Yang, James J., Weiss, Kevin, Boushey, Homer A., Grammer, Leslie, Avila, Pedro C., and Burchard, Esteban G.
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- 2012
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26. Case-control admixture mapping in Latino populations enriches for known asthma-associated genes.
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Torgerson, Dara G., Gignoux, Christopher R., Galanter, Joshua M., Drake, Katherine A., Roth, Lindsey A., Eng, Celeste, Huntsman, Scott, Torres, Raul, Avila, Pedro C., Chapela, Rocio, Ford, Jean G., Rodríguez-Santana, José R., Rodríguez-Cintrón, William, Hernandez, Ryan D., and Burchard, Esteban G.
- Subjects
ASTHMA ,GENETIC polymorphisms ,DISEASE susceptibility ,HISPANIC Americans ,HERITABILITY ,CASE-control method ,HUMAN genetic variation ,LINKAGE disequilibrium - Abstract
Background: Polymorphisms in more than 100 genes have been associated with asthma susceptibility, yet much of the heritability remains to be explained. Asthma disproportionately affects different racial and ethnic groups in the United States, suggesting that admixture mapping is a useful strategy to identify novel asthma-associated loci. Objective: We sought to identify novel asthma-associated loci in Latino populations using case-control admixture mapping. Methods: We performed genome-wide admixture mapping by comparing levels of local Native American, European, and African ancestry between children with asthma and nonasthmatic control subjects in Puerto Rican and Mexican populations. Within candidate peaks, we performed allelic tests of association, controlling for differences in local ancestry. Results: Between the 2 populations, we identified a total of 62 admixture mapping peaks at a P value of less than 10
−3 that were significantly enriched for previously identified asthma-associated genes (P = .0051). One of the peaks was statistically significant based on 100 permutations in the Mexican sample (6q15); however, it was not significant in Puerto Rican subjects. Another peak was identified at nominal significance in both populations (8q12); however, the association was observed with different ancestries. Conclusion: Case-control admixture mapping is a promising strategy for identifying novel asthma-associated loci in Latino populations and implicates genetic variation at 6q15 and 8q12 regions with asthma susceptibility. This approach might be useful for identifying regions that contribute to both shared and population-specific differences in asthma susceptibility. [ABSTRACT FROM AUTHOR]- Published
- 2012
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- View/download PDF
27. Quantifying the proportion of severe asthma exacerbations attributable to inhaled corticosteroid nonadherence.
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Williams, L. Keoki, Peterson, Edward L., Wells, Karen, Ahmedani, Brian K., Kumar, Rajesh, Burchard, Esteban G., Chowdhry, Vimal K., Favro, David, Lanfear, David E., and Pladevall, Manel
- Subjects
ASTHMA ,CORTICOSTEROIDS ,PHARMACOGENOMICS ,PATIENT compliance ,PROPORTIONAL hazards models - Abstract
Background Asthma is an inflammatory condition often punctuated by episodic symptomatic worsening, and accordingly, patients with asthma might have waxing and waning adherence to controller therapy. Objective We sought to measure changes in inhaled corticosteroid (ICS) adherence over time and to estimate the effect of this changing pattern of use on asthma exacerbations. Methods ICS adherence was estimated from electronic prescription and fill information for 298 participants in the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity. For each patient, we calculated a moving average of ICS adherence for each day of follow-up. Asthma exacerbations were defined as the need for oral corticosteroids, an asthma-related emergency department visit, or an asthma-related hospitalization. Proportional hazard models were used to assess the relationship between ICS medication adherence and asthma exacerbations. Results Adherence to ICS medications began to increase before the first asthma exacerbation and continued afterward. Adherence was associated with a reduction in exacerbations but was only statistically significant among patients whose adherence was greater than 75% of the prescribed dose (hazard ratio, 0.61; 95% CI, 0.41-0.90) when compared with patients whose adherence was 25% or less. This pattern was largely confined to patients whose asthma was not well controlled initially. An estimated 24% of asthma exacerbations were attributable to ICS medication nonadherence. Conclusions ICS adherence varies in the time period leading up to and after an asthma exacerbation, and nonadherence likely contributes to a large number of these exacerbations. High levels of adherence are likely required to prevent these events. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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28. Cosmopolitan and ethnic-specific replication of genetic risk factors for asthma in 2 Latino populations.
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Galanter, Joshua M., Torgerson, Dara, Gignoux, Christopher R., Sen, Saunak, Roth, Lindsey A., Via, Marc, Aldrich, Melinda C., Eng, Celeste, Huntsman, Scott, Rodriguez-Santana, Jose, Rodriguez-Cintrón, William, Chapela, Rocio, Ford, Jean G., and Burchard, Esteban G.
- Subjects
DISEASE risk factors ,GENETICS of asthma ,DISEASE prevalence ,HISPANIC Americans ,NUCLEOTIDES ,CLINICAL immunology ,MEXICANS ,PUERTO Ricans ,DISEASES - Abstract
Background: Although Mexicans and Puerto Ricans are jointly classified as “Hispanic/Latino,” there are significant differences in asthma prevalence, severity, and mortality between the 2 groups. We sought to examine the possibility that population-specific genetic risks contribute to this disparity. Objectives: More than 100 candidate genes have been associated with asthma and replicated in an independent population, and 7 genome-wide association studies in asthma have been performed. We compared the pattern of replication of these associations in Puerto Ricans and Mexicans. Methods: We genotyped Mexican and Puerto Rican trios using an Affymetrix 6.0 GeneChip and used a family-based analysis to test for genetic associations in 124 genes previously associated with asthma. Results: We identified 32 single nucleotide polymorphisms (SNPs) in 17 genes associated with asthma in at least 1 of the 2 populations. Twenty-two of these SNPs in 11 genes were significantly associated with asthma in the combined population and showed no significant heterogeneity of association, whereas 5 SNPs were associated in only 1 population and showed statistically significant heterogeneity. In a gene-based approach 2 additional genes were associated with asthma in the combined population, and 3 additional genes displayed ethnic-specific associations with heterogeneity. Conclusions: Our results show that only a minority of genetic association studies replicate in our population of Mexican and Puerto Rican asthmatic subjects. Among SNPs that were successfully replicated, most showed no significant heterogeneity across populations. However, we identified several population-specific genetic associations. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
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