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1. An epistatic interaction between pre-natal smoke exposure and socioeconomic status has a significant impact on bronchodilator drug response in African American youth with asthma

Author

Magaña, J, Contreras, MG, Keys, KL, Risse-Adams, O, Goddard, PC, Zeiger, AM, Mak, ACY, Elhawary, JR, Samedy-Bates, LA, Lee, E, Thakur, N, Hu, D, Eng, C, Salazar, S, Huntsman, S, Hu, T, Burchard, EG, and White, MJ

Subjects
Data Management and Data Science, Information and Computing Sciences, Biological Sciences, Bioinformatics and Computational Biology, Asthma, Lung, Health Disparities, Pediatric, Social Determinants of Health, Minority Health, 2.1 Biological and endogenous factors, Respiratory, Good Health and Well Being, Epistatic interactions, Non-parametric methods, Asthma drug response, Health disparities, Pediatric asthma, Epistatic interactions, Non-parametric methods, Asthma drug response, Health disparities, Pediatric asthma, Artificial Intelligence and Image Processing, Medical Biochemistry and Metabolomics, Specialist Studies in Education, Bioinformatics and computational biology, Data management and data science
Abstract

BackgroundAsthma is one of the leading chronic illnesses among children in the United States. Asthma prevalence is higher among African Americans (11.2%) compared to European Americans (7.7%). Bronchodilator medications are part of the first-line therapy, and the rescue medication, for acute asthma symptoms. Bronchodilator drug response (BDR) varies substantially among different racial/ethnic groups. Asthma prevalence in African Americans is only 3.5% higher than that of European Americans, however, asthma mortality among African Americans is four times that of European Americans; variation in BDR may play an important role in explaining this health disparity. To improve our understanding of disparate health outcomes in complex phenotypes such as BDR, it is important to consider interactions between environmental and biological variables.ResultsWe evaluated the impact of pairwise and three-variable interactions between environmental, social, and biological variables on BDR in 233 African American youth with asthma using Visualization of Statistical Epistasis Networks (ViSEN). ViSEN is a non-parametric entropy-based approach able to quantify interaction effects using an information-theory metric known as Information Gain (IG). We performed analyses in the full dataset and in sex-stratified subsets. Our analyses identified several interaction models significantly, and suggestively, associated with BDR. The strongest interaction significantly associated with BDR was a pairwise interaction between pre-natal smoke exposure and socioeconomic status (full dataset IG: 2.78%, p = 0.001; female IG: 7.27%, p = 0.004)). Sex-stratified analyses yielded divergent results for females and males, indicating the presence of sex-specific effects.ConclusionsOur study identified novel interaction effects significantly, and suggestively, associated with BDR in African American children with asthma. Notably, we found that all of the interactions identified by ViSEN were "pure" interaction effects, in that they were not the result of strong main effects on BDR, highlighting the complexity of the network of biological and environmental factors impacting this phenotype. Several associations uncovered by ViSEN would not have been detected using regression-based methods, thus emphasizing the importance of employing statistical methods optimized to detect both additive and non-additive interaction effects when studying complex phenotypes such as BDR. The information gained in this study increases our understanding and appreciation of the complex nature of the interactions between environmental and health-related factors that influence BDR and will be invaluable to biomedical researchers designing future studies.

Published
2020

2. The genetic diversity of multiple sclerosis risk among Hispanic and African American populations living in the United States.

Author

Beecham, AH, Amezcua, L, Chinea, A, Manrique, CP, Rubi, C, Isobe, N, Lund, BT, Santaniello, A, Beecham, GW, Burchard, EG, Comabella, M, Patsopoulos, N, Fitzgerald, K, Calabresi, PA, De Jager, P, Conti, DV, Delgado, SR, Oksenberg, JR, and McCauley, JL

Subjects
Humans, Multiple Sclerosis, Polymorphism, Single Nucleotide, Alleles, United States, Genetic Variation, Hispanic or Latino, Black or African American, Multiple sclerosis, admixture, allelic heterogeneity, genetics, locus heterogeneity, multi-ethnic, pathway analysis, risk score, Genetics, Neurodegenerative, Human Genome, Brain Disorders, Clinical Research, Autoimmune Disease, Genetic Testing, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Clinical Sciences, Neurology & Neurosurgery
Abstract

BackgroundSubstantial progress has been made toward unraveling the genetic architecture of multiple sclerosis (MS) within populations of European ancestry, but few genetic studies have focused on Hispanic and African American populations within the United States.ObjectiveWe sought to test the relevance of common European MS risk variants outside of the major histocompatibility complex (n = 200) within these populations.MethodsGenotype data were available on 2652 Hispanics (1298 with MS, 1354 controls) and 2435 African Americans (1298 with MS, 1137 controls). We conducted single variant, pathway, and cumulative genetic risk score analyses.ResultsWe found less replication than statistical power suggested, particularly among African Americans. This could be due to limited correlation between the tested and causal variants within the sample or alternatively could indicate allelic and locus heterogeneity. Differences were observed between pathways enriched among the replicating versus all 200 variants. Although these differences should be examined in larger samples, a potential role exists for gene-environment or gene-gene interactions which alter phenotype differentially across racial and ethnic groups. Cumulative genetic risk scores were associated with MS within each study sample but showed limited diagnostic capability.ConclusionThese findings provide a framework for fine-mapping efforts in multi-ethnic populations of MS.

Published
2020

3. PAI‐1 gain‐of‐function genotype, factors increasing PAI‐1 levels, and airway obstruction: The GALA II Cohort

Author

Sherenian, MG, Cho, SH, Levin, A, Min, J‐Y, Oh, SS, Hu, D, Galanter, J, Sen, S, Huntsman, S, Eng, C, Rodriguez‐Santana, JR, Serebrisky, D, Avila, PC, Kalhan, R, Smith, LJ, Borrell, LN, Seibold, MA, Williams, L Keoki, Burchard, EG, and Kumar, R

Subjects
Biomedical and Clinical Sciences, Immunology, Lung, Genetics, Prevention, Clinical Research, Asthma, Aetiology, 2.1 Biological and endogenous factors, Respiratory, Adolescent, Adult, Airway Obstruction, Alleles, Asthma, Occupational, Child, Cohort Studies, Ethnicity, Female, Gain of Function Mutation, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Male, Odds Ratio, Plasminogen Activator Inhibitor 1, Polymorphism, Single Nucleotide, Respiratory Function Tests, Young Adult, asthma, epidemiology, PAI-1, pediatrics, Nutrition and Dietetics, Public Health and Health Services, Allergy
Abstract

BackgroundPAI-1 gain-of-function variants promote airway fibrosis and are associated with asthma and with worse lung function in subjects with asthma.ObjectiveWe sought to determine whether the association of a gain-of-function polymorphism in plasminogen activator inhibitor-1 (PAI-1) with airway obstruction is modified by asthma status, and whether any genotype effect persists after accounting for common exposures that increase PAI-1 level.MethodsWe studied 2070 Latino children (8-21y) with genotypic and pulmonary function data from the GALA II cohort. We estimated the relationship of the PAI-1 risk allele with FEV1/FVC by multivariate linear regression, stratified by asthma status. We examined the association of the polymorphism with asthma and airway obstruction within asthmatics via multivariate logistic regression. We replicated associations in the SAPPHIRE cohort of African Americans (n=1056). Secondary analysis included the effect of the at-risk polymorphism on postbronchodilator lung function.ResultsThere was an interaction between asthma status and the PAI-1 polymorphism on FEV1 /FVC (P=.03). The gain-of-function variants, genotypes (AA/AG), were associated with lower FEV1 /FVC in subjects with asthma (β=-1.25, CI: -2.14,-0.35, P=.006), but not in controls. Subjects with asthma and the AA/AG genotypes had a 5% decrease in FEV1 /FVC (P

Published
2017

4. Maternal age and asthma in Latino populations

Author

Abid, Z, Oh, SS, Hu, D, Sen, S, Huntsman, S, Eng, C, Farber, HJ, Rodriguez‐Cintron, W, Rodriguez‐Santana, JR, Serebrisky, D, Avila, PC, Thyne, SM, Kim, K‐Y A, Borrell, LN, Williams, LK, Seibold, MA, Burchard, EG, and Kumar, R

Subjects
Biomedical and Clinical Sciences, Immunology, Pediatric, Clinical Research, Lung, Asthma, Reproductive health and childbirth, Adolescent, Case-Control Studies, Child, Female, Hispanic or Latino, Humans, Male, Maternal Age, Population Surveillance, Risk Factors, United States, Young Adult, prenatal exposures, asthma, Nutrition and Dietetics, Public Health and Health Services, Allergy
Abstract

BackgroundYounger maternal age at birth is associated with increased risk of asthma in offspring in European descent populations, but has not been studied in Latino populations.ObjectivesWe sought to examine the relationship between maternal age at birth and prevalence of asthma in a nationwide study of Latino children.MethodsWe included 3473 Latino children aged 8-21 years (1696 subjects with physician-diagnosed asthma and 1777 healthy controls) from five US centres and Puerto Rico recruited from July 2008 through November 2011. We used multiple logistic regression models to examine the effect of maternal age at birth on asthma in offspring overall and in analyses stratified by ethnic subgroup (Mexican American, Puerto Rican and other Latino). Secondary analyses evaluated the effects of siblings, acculturation and income on this relationship.ResultsMaternal age < 20 years was significantly associated with decreased odds of asthma in offspring, independent of other risk factors (OR = 0.73, 95% CI: 0.57-0.93). In subgroup analyses, the protective effect of younger maternal age was observed only in Mexican Americans (OR = 0.53, 95% CI: 0.36, 0.79). In Puerto Ricans, older maternal age was associated with decreased odds of asthma (OR = 0.65, 95% CI: 0.44-0.97). In further stratified models, the protective effect of younger maternal age in Mexican Americans was seen only in children without older siblings (OR = 0.44, 95% CI: 0.23-0.81).Conclusion and clinical relevanceIn contrast to European descent populations, younger maternal age was associated with decreased odds of asthma in offspring in Mexican American women. Asthma is common in urban minority populations but the factors underlying the varying prevalence among different Latino ethnicities in the United States is not well understood. Maternal age represents one factor that may help to explain this variability.

Published
2016

5. Novel genetic risk factors for asthma in African American children: Precision Medicine and the SAGE II Study

Author

White, Marquitta J, Risse-Adams, O, Goddard, P, Contreras, MG, Adams, J, Hu, D, Eng, C, Oh, SS, Davis, A, Meade, K, Brigino-Buenaventura, E, LeNoir, MA, Bibbins-Domingo, K, Pino-Yanes, M, and Burchard, EG

Subjects
Biomedical and Clinical Sciences, Immunology, Prevention, Clinical Research, Obesity, Genetics, Pediatric, Lung, Asthma, 2.1 Biological and endogenous factors, Aetiology, Respiratory, Good Health and Well Being, Adolescent, Adult, Black or African American, Case-Control Studies, Child, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Polymorphism, Single Nucleotide, Precision Medicine, Risk Factors, San Francisco, White People, Young Adult, Health disparities, Children, GWAS
Abstract

Asthma, an inflammatory disorder of the airways, is the most common chronic disease of children worldwide. There are significant racial/ethnic disparities in asthma prevalence, morbidity, and mortality among US children. This trend is mirrored in obesity, which may share genetic and environmental risk factors with asthma. The majority of asthma biomedical research has been performed in populations of European decent. We sought to identify genetic risk factors for asthma in African American children. We also assessed the generalizability of genetic variants associated with asthma in European and Asian populations to African American children. Our study population consisted of 1227 (812 asthma cases, 415 controls) African American children with genome-wide single nucleotide polymorphism (SNP) data. Logistic regression was used to identify associations between SNP genotype and asthma status. We identified a novel variant in the PTCHD3 gene that is significantly associated with asthma (rs660498, p = 2.2 × 10(-7)) independent of obesity status. Approximately 5 % of previously reported asthma genetic associations identified in European populations replicated in African Americans. Our identification of novel variants associated with asthma in African American children, coupled with our inability to replicate the majority of findings reported in European Americans, underscores the necessity for including diverse populations in biomedical studies of asthma.

Published
2016

7. ST13 polymorphisms and their effect on exacerbations in steroid‐treated asthmatic children and young adults

Author

Vijverberg, SJH, Koster, ES, Tavendale, R, Leusink, M, Koenderman, L, Raaijmakers, JAM, Postma, DS, Koppelman, GH, Turner, SW, Mukhopadhyay, S, Tse, SM, Tantisira, KG, Hawcutt, DB, Francis, B, Pirmohamed, M, Pino-Yanes, M, Eng, C, Burchard, EG, Palmer, CNA, and Maitland-van der Zee, AH

Subjects
Biomedical and Clinical Sciences, Immunology, Clinical Research, Lung, Pediatric, Asthma, Genetics, Aetiology, 2.1 Biological and endogenous factors, Respiratory, Adolescent, Adrenal Cortex Hormones, Anti-Asthmatic Agents, Carrier Proteins, Child, Child, Preschool, Cohort Studies, Disease Progression, Female, Humans, Male, Odds Ratio, Polymorphism, Single Nucleotide, Treatment Outcome, Tumor Suppressor Proteins, Young Adult, childhood asthma, corticosteroids, exacerbations, pharmacogenomics, ST13, Nutrition and Dietetics, Public Health and Health Services, Allergy
Abstract

BackgroundThe clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS.MethodsWe performed a meta-analysis of three cohort studies: Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory effects (n = 357, age: 4-12 years, the Netherlands), BREATHE (n = 820, age: 3-22 years, UK) and Paediatric Asthma Gene Environment Study (n = 391, age: 2-16 years, UK). Seventeen genes were selected based on a role in the glucocorticoid signalling pathway or a reported association with asthma. Two outcome parameters were used to reflect exacerbations: hospital visits and oral corticosteroid (OCS) use in the previous year. The most significant associations were tested in three independent validation cohorts; the Childhood Asthma Management Programme (clinical trial, n = 172, age: 5-12 years, USA), the Genes- environment and Mixture in Latino Americans II- study (n = 745, age: 8-21, USA) and the Pharmacogenetics of adrenal suppression cohort (n = 391, age: 5-18, UK) to test the robustness of the findings. Finally, all results were meta-analysed.ResultsTwo SNPs in ST13 (rs138335 and rs138337), but not in the other genes, were associated at a nominal level with an increased risk of exacerbations in asthmatics using ICS in the three cohorts studied. In a meta-analysis of all six studies, ST13 rs138335 remained associated with an increased risk of asthma-related hospital visits and OCS use in the previous year; OR = 1.22 (P = 0.013) and OR = 1.22 (P = 0.0017), respectively.Conclusion and clinical relevanceA novel susceptibility gene, ST13, coding for a cochaperone of the glucocorticoid receptor, is associated with exacerbations in asthmatic children and young adults despite their ICS use. Genetic variation in the glucocorticoid signalling pathway may contribute to the interindividual variability in clinical response to ICS treatment in children and young adults.

Published
2015

8. CRISPR-Cas9-mediated gene knockout in primary human airway epithelial cells reveals a proinflammatory role for MUC18

Author

Burchard, Esteban, Chu, HW, Rios, C, Huang, C, Wesolowska-Andersen, A, Burchard, EG, O'Connor, BP, Fingerlin, TE, Nichols, D, Reynolds, SD, and Seibold, MA

Abstract

© 2015 Macmillan Publishers Limited All rights reserved.Targeted knockout of genes in primary human cells using CRISPR-Cas9-mediated genome-editing represents a powerful approach to study gene function and to discern molecular mechanisms underlying complex

Published
2015

9. Adapt-Mix: Learning local genetic correlation structure improves summary statistics-based analyses

Author

Burchard, Esteban, Zaitlen, Noah, Park, DS, Brown, B, Eng, C, Huntsman, S, Hu, D, Torgerson, DG, and Burchard, EG

Abstract

© The Author 2015. Published by Oxford University Press.Motivation: Approaches to identifying new risk loci, training risk prediction models, imputing untyped variants and fine-mapping causal variants from summary statistics of genome-wide association stud

Published
2015

10. Gene-based association identifies SPATA13-AS1 as a pharmacogenomic predictor of inhaled short-acting beta-agonist response in multiple population groups

Author

Burchard, Esteban, Kwok, Pui-Yan, Padhukasahasram, B, Yang, JJ, Levin, AM, Yang, M, Burchard, EG, Kumar, R, Kwok, PY, Seibold, MA, Lanfear, DE, and Williams, LK

Abstract

Inhaled short-acting beta-agonist (SABA) medication is commonly used in asthma patients to rapidly reverse airway obstruction and improve acute symptoms. We performed a genome-wide association study of SABA medication response using gene-based association

Published
2014

11. Genome-wide association analysis identifies six new loci associated with forced vital capacity

Author

Loth, DW, Artigas, MS, Gharib, SA, Wain, LV, Franceschini, N, Koch, B, Pottinger, TD, Smith, AV, Duan, Q, Oldmeadow, C, Lee, MK, Strachan, DP, James, AL, Huffman, JE, Vitart, V, Ramasamy, A, Wareham, NJ, Kaprio, J, Wang, XQ, Trochet, H, Kähönen, M, Flexeder, C, Albrecht, E, Lopez, LM, De Jong, K, Thyagarajan, B, Alves, AC, Enroth, S, Omenaas, E, Joshi, PK, Fall, T, Viñuela, A, Launer, LJ, Loehr, LR, Fornage, M, Li, G, Wilk, JB, Tang, W, Manichaikul, A, Lahousse, L, Harris, TB, North, KE, Rudnicka, AR, Hui, J, Gu, X, Lumley, T, Wright, AF, Hastie, ND, Campbell, S, Kumar, R, Pin, I, Scott, RA, Pietiläinen, KH, Surakka, I, Liu, Y, Holliday, EG, Schulz, H, Heinrich, J, Davies, G, Vonk, JM, Wojczynski, M, Pouta, A, Johansson, A, Wild, SH, Ingelsson, E, Rivadeneira, F, Völzke, H, Hysi, PG, Eiriksdottir, G, Morrison, AC, Rotter, JI, Gao, W, Postma, DS, White, WB, Rich, SS, Hofman, A, Aspelund, T, Couper, D, Smith, LJ, Psaty, BM, Lohman, K, Burchard, EG, Uitterlinden, AG, Garcia, M, Joubert, BR, McArdle, WL, Musk, AB, Hansel, N, Heckbert, SR, Zgaga, L, Van Meurs, JBJ, Navarro, P, Rudan, I, Oh, YM, Redline, S, Jarvis, DL, Zhao, JH, Rantanen, T, O'Connor, GT, and Ripatti, S

Subjects
Developmental Biology, Medical and Health Sciences, Biological Sciences
Abstract

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10-8) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.© 2014 Nature America, Inc. All rights reserved.

Published
2014

12. Association of bronchial steroid inducible methylation quantitative trait loci with asthma and chronic obstructive pulmonary disease treatment response.

Author

Slob, EMA, Faiz, A, van Nijnatten, J, Vijverberg, SJH, Longo, C, Kutlu, M, Chew, FT, Sio, YY, Herrera-Luis, E, Espuela-Ortiz, A, Perez-Garcia, J, Pino-Yanes, M, Burchard, EG, Potočnik, U, Gorenjak, M, Palmer, C, Maroteau, C, Turner, S, Verhamme, K, Karimi, L, Mukhopadhyay, S, Timens, W, Hiemstra, PS, Pijnenburg, MW, Neighbors, M, Grimbaldeston, MA, Tew, GW, Brandsma, CA, Berce, V, Aliee, H, Theis, F, Sin, DD, Li, X, van den Berge, M, Maitland-van der Zee, AH, Koppelman, GH, Slob, EMA, Faiz, A, van Nijnatten, J, Vijverberg, SJH, Longo, C, Kutlu, M, Chew, FT, Sio, YY, Herrera-Luis, E, Espuela-Ortiz, A, Perez-Garcia, J, Pino-Yanes, M, Burchard, EG, Potočnik, U, Gorenjak, M, Palmer, C, Maroteau, C, Turner, S, Verhamme, K, Karimi, L, Mukhopadhyay, S, Timens, W, Hiemstra, PS, Pijnenburg, MW, Neighbors, M, Grimbaldeston, MA, Tew, GW, Brandsma, CA, Berce, V, Aliee, H, Theis, F, Sin, DD, Li, X, van den Berge, M, Maitland-van der Zee, AH, and Koppelman, GH

Published
2022

13. NLRP1 variant M1184V decreases inflammasome activation in the context of DPP9 inhibition and asthma severity

Author

Moecking, J, Laohamonthonkul, P, Chalker, K, White, MJ, Harapas, CR, Yu, C-H, Davidson, S, Hrovat-Schaale, K, Hu, D, Eng, C, Huntsman, S, Calleja, DJ, Horvat, JC, Hansbro, PM, O'Donoghue, RJJ, Ting, JP, Burchard, EG, Geyer, M, Gerlic, M, Masters, SL, Moecking, J, Laohamonthonkul, P, Chalker, K, White, MJ, Harapas, CR, Yu, C-H, Davidson, S, Hrovat-Schaale, K, Hu, D, Eng, C, Huntsman, S, Calleja, DJ, Horvat, JC, Hansbro, PM, O'Donoghue, RJJ, Ting, JP, Burchard, EG, Geyer, M, Gerlic, M, and Masters, SL

Abstract

BACKGROUND: 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. OBJECTIVE: We sought to clarify the role of NLRP1 in asthma pathogenesis. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Published
2021

14. IL1RL1 gene variations are associated with asthma exacerbations in children and adolescents using inhaled corticosteroids

Author

Dijk, FN, Vijverberg, SJ, Hernandez-Pacheco, N, Repnik, K, Karimi Gazafroudi, Leila, Mitratza, M, Farzan, N, Nawijn, MC, Burchard, EG, Engelkes, Marjolein, Verhamme, Katia, Poto?nik, U, Pino-Yanes, M, Postma, DS, Zee, AHMVD, Koppelman, GH, Dijk, FN, Vijverberg, SJ, Hernandez-Pacheco, N, Repnik, K, Karimi Gazafroudi, Leila, Mitratza, M, Farzan, N, Nawijn, MC, Burchard, EG, Engelkes, Marjolein, Verhamme, Katia, Poto?nik, U, Pino-Yanes, M, Postma, DS, Zee, AHMVD, and Koppelman, GH

Published
2020

15. NLRP1 variant M1184V decreases inflammasome activation in the context of DPP9 inhibition and asthma severity.

Author

Moecking J, Laohamonthonkul P, Chalker K, White MJ, Harapas CR, Yu C-H, Davidson S, Hrovat-Schaale K, Hu D, Eng C, Huntsman S, Calleja DJ, Horvat JC, Hansbro PM, O'Donoghue RJJ, Ting JP, Burchard EG, Geyer M, Gerlic M, Masters SL, Moecking J, Laohamonthonkul P, Chalker K, White MJ, Harapas CR, Yu C-H, Davidson S, Hrovat-Schaale K, Hu D, Eng C, Huntsman S, Calleja DJ, Horvat JC, Hansbro PM, O'Donoghue RJJ, Ting JP, Burchard EG, Geyer M, Gerlic M, and Masters SL

Abstract

Background

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.

Objective

We sought to clarify the role of NLRP1 in asthma pathogenesis.

Methods

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.

Results

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.

Conclusions

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.

Published
2020

16. Pairwise and Higher-Order Epistatic Interactions Have a Significant Impact on Bronchodilator Drug Response in African American Youth with Asthma

Author

Magaña, J, primary, Contreras, MG, additional, Keys, KL, additional, Risse-Adams, O, additional, Goddard, PC, additional, Zeiger, AM, additional, Mak, ACY, additional, Elhawary, JR, additional, Samedy-Bates, LA, additional, Lee, E, additional, Thakur, N, additional, Hu, D, additional, Eng, C, additional, Salazar, S, additional, Huntsman, S, additional, Hu, T, additional, Burchard, EG, additional, and White, MJ, additional

Published
2020
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17. Author Correction: Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Author

Waage, J, Standl, M, Curtin, JA, Jessen, LE, Thorsen, J, Tian, C, Schoettler, N, 23andMe Research Team, AAGC collaborators, Flores, C, Abdellaoui, A, Ahluwalia, TS, Alves, AC, Amaral, AFS, Antó, JM, Arnold, A, Barreto-Luis, A, Baurecht, H, van Beijsterveldt, CEM, Bleecker, ER, Bonàs-Guarch, S, Boomsma, DI, Brix, S, Bunyavanich, S, Burchard, EG, Chen, Z, Curjuric, I, Custovic, A, den Dekker, HT, Dharmage, SC, Dmitrieva, J, Duijts, L, Ege, MJ, Gauderman, WJ, Georges, M, Gieger, C, Gilliland, F, Granell, R, Gui, H, Hansen, T, Heinrich, J, Henderson, J, Hernandez-Pacheco, N, Holt, P, Imboden, M, Jaddoe, VWV, Jarvelin, M-R, Jarvis, DL, Jensen, KK, Jónsdóttir, I, Kabesch, M, Kaprio, J, Kumar, A, Lee, Y-A, Levin, AM, Li, X, Lorenzo-Diaz, F, Melén, E, Mercader, JM, Meyers, DA, Myers, R, Nicolae, DL, Nohr, EA, Palviainen, T, Paternoster, L, Pennell, CE, Pershagen, G, Pino-Yanes, M, Probst-Hensch, NM, Rüschendorf, F, Simpson, A, Stefansson, K, Sunyer, J, Sveinbjornsson, G, Thiering, E, Thompson, PJ, Torrent, M, Torrents, D, Tung, JY, Wang, CA, Weidinger, S, Weiss, S, Willemsen, G, Williams, LK, Ober, C, Hinds, DA, Ferreira, MA, Bisgaard, H, Strachan, DP, and Bønnelykke, K

Subjects
ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION, ComputingMethodologies_COMPUTERGRAPHICS
Abstract

In the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.

Published
2018

18. Cohort Profile: Pregnancy And Childhood Epigenetics (PACE) Consortium

Author

Felix, JF, Joubert, BR, Baccarelli, AA, Sharp, GC, Almqvist, C, Annesi-Maesano, I, Arshad, H, Baïz, N, Bakermans-Kranenburg, MJ, Bakulski, KM, Binder, EB, Bouchard, L, Breton, CV, Brunekreef, B, Brunst, KJ, Burchard, EG, Bustamante, M, Chatzi, L, Munthe-Kaas, M, Corpeleijn, E, Czamara, D, Dabelea, D, Smith, G, De Boever, P, Duijts, L, Dwyer, T, Eng, C, Eskenazi, B, Everson, TM, Falahi, F, Fallin, MD, Farchi, S, Fernandez, MF, Gao, L, Gaunt, TR, Ghantous, A, Gillman, MW, Gonseth, S, Grote, V, Gruzieva, O, Håberg, SE, Herceg, Z, Hivert, M-F, Holland, N, Holloway, JW, Hoyo, C, Hu, D, Huang, R-C, Huen, K, Järvelin, M-R, Jima, DD, Just, AC, Karagas, MR, Karlsson, R, Karmaus, W, Kechris, KJ, Kere, J, Kogevinas, M, Koletzko, B, Koppelman, GH, Küpers, LK, Ladd-Acosta, C, Lahti, J, Lambrechts, N, Langie, SAS, Lie, RT, Liu, AH, Magnus, MC, Magnus, P, Maguire, RL, Marsit, CJ, McArdle, W, Melén, E, Melton, P, Murphy, SK, Nawrot, TS, Nisticò, L, Nohr, EA, Nordlund, B, Nystad, W, Oh, SS, Oken, E, Page, CM, Perron, P, Pershagen, G, Pizzi, C, Plusquin, M, Raikkonen, K, Reese, SE, Reischl, E, Richiardi, L, Ring, S, Roy, RP, Rzehak, P, Schoeters, G, Schwartz, DA, Sebert, S, Snieder, H, Sørensen, TIA, Starling, AP, Sunyer, J, Taylor, JA, Tiemeier, H, Ullemar, V, Vafeiadi, M, Van Ijzendoorn, MH, Vonk, JM, Vriens, A, Vrijheid, M, Wang, P, Wiemels, JL, Wilcox, AJ, Wright, RJ, Xu, C-J, Xu, Z, Yang, IV, Yousefi, P, Zhang, H, Zhang, W, Zhao, S, Agha, G, Relton, CL, Jaddoe, VWV, London, SJ, Epidemiology, Erasmus MC other, Pediatrics, Child and Adolescent Psychiatry / Psychology, Psychiatry, Research Methods and Techniques, dIRAS RA-2, One Health Chemisch, Reproductive Origins of Adult Health and Disease (ROAHD), Lifestyle Medicine (LM), Groningen Research Institute for Asthma and COPD (GRIAC), Life Course Epidemiology (LCE), Department of Psychology and Logopedics, Helsinki Collegium for Advanced Studies, Medicum, University of Helsinki, and Developmental Psychology Research Group

Subjects
DNA Methylation/physiology, Epidemiology, Maternal Health, education, Embaràs, DISEASE, Environmental Pollution/analysis, Epigenesis, Genetic, Cohort Studies, Prenatal Exposure Delayed Effects/epidemiology, Folic Acid, Pregnancy, Journal Article, Humans, MATERNAL SMOKING, CORD BLOOD, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Cohort Profiles, METAANALYSIS, PRENATAL EXPOSURE, Maternal Exposure/adverse effects, EPIGENOME-WIDE ASSOCIATION, 0104 Statistics, Child Health, Infant, Newborn, DNA METHYLATION DATA, DNA Methylation, Epigenètica, BIRTH-WEIGHT, 3142 Public health care science, environmental and occupational health, Folic Acid/blood, 1117 Public Health And Health Services, Maternal Exposure, Prenatal Exposure Delayed Effects, MENDELIAN RANDOMIZATION, Epigenetics, Female, Human medicine, Environmental Pollution
Abstract

UK Medical Research Council; Wellcome Trust [102215/2/13/2, WT088806, 084762MA]; UK Biotechnology and Biological Sciences Research Council [BB/I025751/1, BB/I025263/1]; UK Medical Research Council Integrative Epidemiology Unit; University of Bristol [MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5, MC_UU_12013_8]; United States National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK10324]; Swedish Research Council; Swedish Heart-Lung Foundation; Freemason Child House Foundation in Stockholm; MeDALL (Mechanisms of the Development of ALLergy), within the European Union [261357]; Stockholm County Council (ALF); Swedish Foundation for Strategic Research (SSF) [RBc08-0027]; Strategic Research Programme (SFO) in Epidemiology at Karolinska Institutet; Swedish Research Council Formas; Swedish Environment Protection Agency; Center for Integrative Research on Childhood Leukemia and the Environment [P01ES018172]; NIH [P50ES018172, R01ES09137, 5P30CA082103, P01 ES009605, R01 ES021369, R01ES023067, K01ES017801, R01ES022216, P30ES007048, R01ES014447, P01ES009581, R826708-01, RD831861-01, P50ES026086, R01DK068001, R01 DK100340, R01 DK076648, R01ES022934, R01HL111108, R01NR013945, R37 HD034568, UL1 TR001082, P30 DK56350]; EPA [RD83451101, RD83615901, RD 82670901, RD 83451301, 83615801-0]; UCSF Comprehensive Cancer Center Support grant [P30 CA82103]; Swiss Science National Foundation [P2LAP3_158674]; Sutter-Stottner Foundation; Commission of the European Community, specific RTD Programme 'Quality of Life and Management of Living Resources' within the 5th Framework Programme [QLRT-2001-00389, QLK1-CT-2002-30582]; 6th Framework Programme [007036]; European Union's Seventh Framework Programme (FP7), project EarlyNutrition [289346]; European Research Council Advanced grant ERC-AdG [322605 META-GROWTH]; Autism Speaks grant [260377]; Funds for Research in Respiratory Health; French Ministry of Research: IFR program; INSERM Nutrition Research Program; French Ministry of Health: Perinatality Program; French National Institute for Population Health Surveillance (INVS); Paris-Sud University; French National Institute for Health Education (INPES); Nestle; Mutuelle Generale de l'Education Nationale (MGEN); French-speaking association for the study of diabetes and metabolism (Alfediam) [2012/51290-6]; EU; European Research Council [ERC-2012-StG.310898, 268479-BREATHE]; Flemish Scientific Research Council (FWO) [N1516112 / G.0.873.11N.10]; European Community's Seventh Framework Programme FP7 project EXPOsOMICS [308610]; People Program (Marie Curie Actions) of the European Union's Seventh Framework Program FP7 under REA grant [628858]; Bijzonder Onderzoeksfonds (BOF) Hasselt University; Ministry of the Flemish Community (Department of Economics, Science and Innovation); Ministry of the Flemish Community (Department of Environment, Nature and Energy); CEFIC LRI award by the Research Foundation-Flanders (FWO); CEFIC LRI award by the Research Foundation-Flanders (FWO) [12L5216N]; Flemish Institute for Technological Research (VITO) [12L5216N]; Bill AMP; Melinda Gates Foundation Grand Challenges Exploration grant [OPP119403]; Sandler Family Foundation; American Asthma Foundation; National Institutes of Health; National Heart, Lung and Blood Institute [HL117004]; National Institute of Environmental Health Sciences [ES24844]; National Institute on Minority Health and Health Disparities [MD006902, MD009523]; National Institute of General Medical Sciences [GM007546]; Tobacco-Related Disease Research Program [24RT-0025]; Hutchison Whampoa Ltd, Hong Kong; University of Groningen; Well Baby Clinic Foundation Icare; Noordlease; Youth Health Care Drenthe; Biobanking and Biomolecular Research Infrastructure Netherlands [CP2011-19]; Erasmus Medical Center, Rotterdam; Erasmus University Rotterdam; Netherlands Organization for Health Research and Development; Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO); Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; Genetic Laboratory of the Department of Internal Medicine, Erasmus MC; European Union's Horizon research and innovation programme [733206, 633595]; National Institute of Child and Human Development [R01HD068437]; Netherlands Organization for Health Research and Development [VIDI 016.136.361]; Consolidator grant from the European Research Council [ERC-2014-CoG-648916]; Netherlands' Organization for Scientific Research (NWO VICI); European Research Council ERC; Netherlands' Organization for Scientific Research (NWO Spinoza Award); Gravitation program of the Dutch Ministry of Education, Culture, and Science; Netherlands Organization for Scientific Research (NWO) [024.001.003]; Lung Foundation Netherlands [3.2.12.089]; Fonds de Recherche du Quebec en Sante (FRQ-S) [20697]; Canadian Institute of Health Reseach (CIHR) [MOP 115071]; Diabete Quebec grant; Canadian Diabetes Association operating grant [OG-3-08-2622]; American Diabetes Association Pathways Accelerator Early Investigator Award [1-15-ACE-26]; MRC Integrative Epidemiology Unit - Medical Research Council [MC_UU_12013/1-9]; National Institute of Environmental Health Sciences, National Institutes of Health [K99ES025817]; Instituto de Salud Carlos III [Red INMA G03/176, CB06/02/0041]; Spanish Ministry of Health [FIS-PI04/1436, FIS-PI08/1151]; Spanish Ministry of Health (FEDER funds) [FIS-PI11/00610, FIS-FEDER-PI06/0867, FIS-FEDER-PI03-1615]; Generalitat de Catalunya [CIRIT 1999SGR 00241]; Fundacio La Marato de TV3 [090430]; EU Commission [261357-MeDALL]; National Institute of Allergy and Infectious Diseases [N01-AI90052]; National Institutes of Health USA [R01 HL082925, R01 HL132321]; Asthma UK [364]; NIAID/NIH [R01AI091905, R01AI121226]; National Institute of Health [R01AI121226, R01 AI091905, R01HL132321]; NIH/NIEHS [N01-ES75558]; NIH/NINDS [1 UO1 NS 047537-01, 2 UO1 NS 047537-06A1]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01-ES-49019, Z01 ES044005, ES049033, ES049032]; Norwegian Research Council/BIOBANK [221097]; Oslo University Hospital; Unger-Vetlesens foundation; Norwegian American Womens Club; INCA/Plan Cancer-EVA-INSERM, France; International Childhood Cancer Cohort Consortium (I4C); INCA/Plan Cancer-EVA-INSERM (France); IARC Postdoctoral Fellowship; EC FP7 Marie Curie Actions-People-Co-funding of regional, national and international programmes (COFUND); NIEHS [R21ES014947, R01ES016772]; NIDDK [R01DK085173]; National Institute of Environmental Health Science [P30 ES025128]; University of Oulu grant [65354]; Oulu University Hospital [2/97, 8/97]; Ministry of Health and Social Affairs [23/251/97, 160/97, 190/97]; National Institute for Health and Welfare, Helsinki [54121]; Regional Institute of Occupational Health, Oulu, Finland [50621, 54231]; EU [QLG1-CT-2000-01643, E51560]; NorFA grant [731, 20056, 30167]; Academy of Finland; NIH-NIEHS [P01 ES022832]; US EPA [RD83544201]; NIH-NIGMS [P20GM104416]; NCI [R25CA134286]; Netherlands Organization for Scientific Research and Development; Netherlands Asthma Fund; Netherlands Ministry of Spatial Planning, Housing, and the Environment; Netherlands Ministry of Health, Welfare, and Sport; MeDALL; European Union under the Health Cooperation Work Program of the 7th Framework program [261357]; Italian National Centre for Disease Prevention and Control (CCM grant); Italian Ministry of Health (art 12); Italian Ministry of Health (12bis Dl.gs.vo) [502/92]; EraNet; EVO; University of Helsinki Research Funds; Signe and Ane Gyllenberg foundation; Emil Aaltonen Foundation; Finnish Medical Foundation; Jane and Aatos Erkko Foundation; Novo Nordisk Foundation; Paivikki and Sakari Sohlberg Foundation; Sigrid Juselius Foundation; University of Helsinki; University of Western Australia (UWA); Curtin University; Raine Medical Research Foundation; UWA Faculty of Medicine, Dentistry and Health Sciences; Telethon Kids Institute; Women's and Infant's Research Foundation (KEMH); Edith Cowan University; National Health and Medical Research Council [1059711]; National Health and Medical Research Council (NHMRC) fellowship [1053384]; Australian National Health and Medical Research Council; United States National Institute of Health; Greek Ministry of Health (programme of prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece); Greek Ministry of Health ('Rhea Plus': Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health); European Union (EU) [EU FP6-2003-Food-3-NewGeneris, EU FP7 ENV.2007.1.2.2.2, 211250 ESCAPE, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7 ENV.2008.1.2.1.6, 226285 ENRIECO]; National Institutes of Health [NIH-NIMH R01MH094609, NIH-NIEHS R01ES022223, NIH-NIEHS R01ES025145]; Centers for Disease Control and Prevention [U10DD000180, U10DD000181, U10DD000182, U10DD000183, U10DD000184, U10DD000498]; Autism Speaks [7659]; Swedish Research Council through the Swedish Initiative for research on Microdata in the Social And Medical Sciences (SIMSAM) [340-2013-5867]; Stockholm County Council (ALF projects); Strategic Research Program in Epidemiology at Karolinska Institutet; Swedish Asthma and Allergy Association's Research Foundation; Stiftelsen Frimurare Barnahuset Stockholm; Norwegian Ministry of Health and Care Services; Ministry of the Flemish Community (Flemish Agency for Care and Health); University of Bristol; Ministry of Education and Research; European Union (EU) (EU FP7-HEALTH-single stage CHICOS); European Union (EU) (EU-FP7-HEALTH) [308333 HELIX]; European Union (EU) (EU FP6. STREP HiWATE); UK Medical Research Council; Wellcome Trust [102215/2/13/2, WT088806, 084762MA]; UK Biotechnology and Biological Sciences Research Council [BB/I025751/1, BB/I025263/1]; UK Medical Research Council Integrative Epidemiology Unit; University of Bristol [MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5, MC_UU_12013_8]; United States National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK10324]; Swedish Research Council; Swedish Heart-Lung Foundation; Freemason Child House Foundation in Stockholm; MeDALL (Mechanisms of the Development of ALLergy), within the European Union [261357]; Stockholm County Council (ALF); Swedish Foundation for Strategic Research (SSF) [RBc08-0027]; Strategic Research Programme (SFO) in Epidemiology at Karolinska Institutet; Swedish Research Council Formas; Swedish Environment Protection Agency; Center for Integrative Research on Childhood Leukemia and the Environment [P01ES018172]; NIH [P50ES018172, R01ES09137, 5P30CA082103, P01 ES009605, R01 ES021369, R01ES023067, K01ES017801, R01ES022216, P30ES007048, R01ES014447, P01ES009581, R826708-01, RD831861-01, P50ES026086, R01DK068001, R01 DK100340, R01 DK076648, R01ES022934, R01HL111108, R01NR013945, R37 HD034568, UL1 TR001082, P30 DK56350]; EPA [RD83451101, RD83615901, RD 82670901, RD 83451301, 83615801-0]; UCSF Comprehensive Cancer Center Support grant [P30 CA82103]; Swiss Science National Foundation [P2LAP3_158674]; Sutter-Stottner Foundation; Commission of the European Community, specific RTD Programme 'Quality of Life and Management of Living Resources' within the 5th Framework Programme [QLRT-2001-00389, QLK1-CT-2002-30582]; 6th Framework Programme [007036]; European Union's Seventh Framework Programme (FP7), project EarlyNutrition [289346]; European Research Council Advanced grant ERC-AdG [322605 META-GROWTH]; Autism Speaks grant [260377]; Funds for Research in Respiratory Health; French Ministry of Research: IFR program; INSERM Nutrition Research Program; French Ministry of Health: Perinatality Program; French National Institute for Population Health Surveillance (INVS); Paris-Sud University; French National Institute for Health Education (INPES); Nestle; Mutuelle Generale de l'Education Nationale (MGEN); French-speaking association for the study of diabetes and metabolism (Alfediam) [2012/51290-6]; EU; European Research Council [ERC-2012-StG.310898, 268479-BREATHE]; Flemish Scientific Research Council (FWO) [N1516112 / G.0.873.11N.10]; European Community's Seventh Framework Programme FP7 project EXPOsOMICS [308610]; People Program (Marie Curie Actions) of the European Union's Seventh Framework Program FP7 under REA grant [628858]; Bijzonder Onderzoeksfonds (BOF) Hasselt University; Ministry of the Flemish Community (Department of Economics, Science and Innovation); Ministry of the Flemish Community (Department of Environment, Nature and Energy); CEFIC LRI award by the Research Foundation-Flanders (FWO); CEFIC LRI award by the Research Foundation-Flanders (FWO) [12L5216N]; Flemish Institute for Technological Research (VITO) [12L5216N]; Bill AMP; Melinda Gates Foundation Grand Challenges Exploration grant [OPP119403]; Sandler Family Foundation; American Asthma Foundation; National Institutes of Health; National Heart, Lung and Blood Institute [HL117004]; National Institute of Environmental Health Sciences [ES24844]; National Institute on Minority Health and Health Disparities [MD006902, MD009523]; National Institute of General Medical Sciences [GM007546]; Tobacco-Related Disease Research Program [24RT-0025]; Hutchison Whampoa Ltd, Hong Kong; University of Groningen; Well Baby Clinic Foundation Icare; Noordlease; Youth Health Care Drenthe; Biobanking and Biomolecular Research Infrastructure Netherlands [CP2011-19]; Erasmus Medical Center, Rotterdam; Erasmus University Rotterdam; Netherlands Organization for Health Research and Development; Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO); Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; Genetic Laboratory of the Department of Internal Medicine, Erasmus MC; European Union's Horizon research and innovation programme [733206, 633595]; National Institute of Child and Human Development [R01HD068437]; Netherlands Organization for Health Research and Development [VIDI 016.136.361]; Consolidator grant from the European Research Council [ERC-2014-CoG-648916]; Netherlands' Organization for Scientific Research (NWO VICI); European Research Council ERC; Netherlands' Organization for Scientific Research (NWO Spinoza Award); Gravitation program of the Dutch Ministry of Education, Culture, and Science; Netherlands Organization for Scientific Research (NWO) [024.001.003]; Lung Foundation Netherlands [3.2.12.089]; Fonds de Recherche du Quebec en Sante (FRQ-S) [20697]; Canadian Institute of Health Reseach (CIHR) [MOP 115071]; Diabete Quebec grant; Canadian Diabetes Association operating grant [OG-3-08-2622]; American Diabetes Association Pathways Accelerator Early Investigator Award [1-15-ACE-26]; MRC Integrative Epidemiology Unit - Medical Research Council [MC_UU_12013/1-9]; National Institute of Environmental Health Sciences, National Institutes of Health [K99ES025817]; Instituto de Salud Carlos III [Red INMA G03/176, CB06/02/0041]; Spanish Ministry of Health [FIS-PI04/1436, FIS-PI08/1151]; Spanish Ministry of Health (FEDER funds) [FIS-PI11/00610, FIS-FEDER-PI06/0867, FIS-FEDER-PI03-1615]; Generalitat de Catalunya [CIRIT 1999SGR 00241]; Fundacio La Marato de TV3 [090430]; EU Commission [261357-MeDALL]; National Institute of Allergy and Infectious Diseases [N01-AI90052]; National Institutes of Health USA [R01 HL082925, R01 HL132321]; Asthma UK [364]; NIAID/NIH [R01AI091905, R01AI121226]; National Institute of Health [R01AI121226, R01 AI091905, R01HL132321]; NIH/NIEHS [N01-ES75558]; NIH/NINDS [1 UO1 NS 047537-01, 2 UO1 NS 047537-06A1]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01-ES-49019, Z01 ES044005, ES049033, ES049032]; Norwegian Research Council/BIOBANK [221097]; Oslo University Hospital; Unger-Vetlesens foundation; Norwegian American Womens Club; INCA/Plan Cancer-EVA-INSERM, France; International Childhood Cancer Cohort Consortium (I4C); INCA/Plan Cancer-EVA-INSERM (France); IARC Postdoctoral Fellowship; EC FP7 Marie Curie Actions-People-Co-funding of regional, national and international programmes (COFUND); NIEHS [R21ES014947, R01ES016772]; NIDDK [R01DK085173]; National Institute of Environmental Health Science [P30 ES025128]; University of Oulu grant [65354]; Oulu University Hospital [2/97, 8/97]; Ministry of Health and Social Affairs [23/251/97, 160/97, 190/97]; National Institute for Health and Welfare, Helsinki [54121]; Regional Institute of Occupational Health, Oulu, Finland [50621, 54231]; EU [QLG1-CT-2000-01643, E51560]; NorFA grant [731, 20056, 30167]; Academy of Finland; NIH-NIEHS [P01 ES022832]; US EPA [RD83544201]; NIH-NIGMS [P20GM104416]; NCI [R25CA134286]; Netherlands Organization for Scientific Research and Development; Netherlands Asthma Fund; Netherlands Ministry of Spatial Planning, Housing, and the Environment; Netherlands Ministry of Health, Welfare, and Sport; MeDALL; European Union under the Health Cooperation Work Program of the 7th Framework program [261357]; Italian National Centre for Disease Prevention and Control (CCM grant); Italian Ministry of Health (art 12); Italian Ministry of Health (12bis Dl.gs.vo) [502/92]; EraNet; EVO; University of Helsinki Research Funds; Signe and Ane Gyllenberg foundation; Emil Aaltonen Foundation; Finnish Medical Foundation; Jane and Aatos Erkko Foundation; Novo Nordisk Foundation; Paivikki and Sakari Sohlberg Foundation; Sigrid Juselius Foundation; University of Helsinki; University of Western Australia (UWA); Curtin University; Raine Medical Research Foundation; UWA Faculty of Medicine, Dentistry and Health Sciences; Telethon Kids Institute; Women's and Infant's Research Foundation (KEMH); Edith Cowan University; National Health and Medical Research Council [1059711]; National Health and Medical Research Council (NHMRC) fellowship [1053384]; Australian National Health and Medical Research Council; United States National Institute of Health; Greek Ministry of Health (programme of prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece); Greek Ministry of Health ('Rhea Plus': Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health); European Union (EU) [EU FP6-2003-Food-3-NewGeneris, EU FP7 ENV.2007.1.2.2.2, 211250 ESCAPE, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7 ENV.2008.1.2.1.6, 226285 ENRIECO]; National Institutes of Health [NIH-NIMH R01MH094609, NIH-NIEHS R01ES022223, NIH-NIEHS R01ES025145]; Centers for Disease Control and Prevention [U10DD000180, U10DD000181, U10DD000182, U10DD000183, U10DD000184, U10DD000498]; Autism Speaks [7659]; Swedish Research Council through the Swedish Initiative for research on Microdata in the Social And Medical Sciences (SIMSAM) [340-2013-5867]; Stockholm County Council (ALF projects); Strategic Research Program in Epidemiology at Karolinska Institutet; Swedish Asthma and Allergy Association's Research Foundation; Stiftelsen Frimurare Barnahuset Stockholm; Norwegian Ministry of Health and Care Services; Ministry of the Flemish Community (Flemish Agency for Care and Health); University of Bristol; Ministry of Education and Research; European Union (EU) (EU FP7-HEALTH-single stage CHICOS); European Union (EU) (EU-FP7-HEALTH) [308333 HELIX]; European Union (EU) (EU FP6. STREP HiWATE); [R01ES017646]; [R01ES01900]; [R01ES16443]; [USA / NIHH 2000 G DF682]; [50945]; [R01 HL095606]; [R01 HL1143396]

Published
2018

19. The genetic diversity of multiple sclerosis risk among Hispanic and African American populations living in the United States

Author

Beecham, AH, primary, Amezcua, L, additional, Chinea, A, additional, Manrique, CP, additional, Rubi, C, additional, Isobe, N, additional, Lund, BT, additional, Santaniello, A, additional, Beecham, GW, additional, Burchard, EG, additional, Comabella, M, additional, Patsopoulos, N, additional, Fitzgerald, K, additional, Calabresi, PA, additional, De Jager, P, additional, Conti, DV, additional, Delgado, SR, additional, Oksenberg, JR, additional, and McCauley, JL, additional

Published
2019
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20. Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Author

Wyss, AB, Sofer, T, Lee, MK, Terzikhan, N, Nguyen, JN, Lahousse, L, Latourelle, JC, Smith, AV, Bartz, TM, Feitosa, MF, Gao, W, Ahluwalia, TS, Tang, W, Oldmeadow, C, Duan, Q, de Jong, K, Wojczynski, MK, Wang, X-Q, Noordam, R, Hartwig, FP, Jackson, VE, Wang, T, Obeidat, M, Hobbs, BD, Huan, T, Gui, H, Parker, MM, Hu, D, Mogil, LS, Kichaev, G, Jin, J, Graff, M, Harris, TB, Kalhan, R, Heckbert, SR, Paternoster, L, Burkart, KM, Liu, Y, Holliday, EG, Wilson, JG, Vonk, JM, Sanders, JL, Barr, RG, de Mutsert, R, Baptista Menezes, AM, Adams, HHH, van den Berge, M, Joehanes, R, Levin, AM, Liberto, J, Launer, LJ, Morrison, AC, Sitlani, CM, Celedon, JC, Kritchevsky, SB, Scott, RJ, Christensen, K, Rotter, JI, Bonten, TN, Wehrmeister, FC, Bosse, Y, Xiao, S, Oh, S, Franceschini, N, Brody, JA, Kaplan, RC, Lohman, K, McEvoy, M, Province, MA, Rosendaal, FR, Taylor, KD, Nickle, DC, Williams, LK, Burchard, EG, Wheeler, HE, Sin, DD, Gudnason, V, North, KE, Fornage, M, Psaty, BM, Myers, RH, O'Connor, G, Hansen, T, Laurie, CC, Cassano, PA, Sung, J, Kim, WJ, Attia, JR, Lange, L, Boezen, HM, Thyagarajan, B, Rich, SS, Mook-Kanamori, DO, Horta, BL, Uitterlinden, AG, Im, HK, Cho, MH, Brusselle, GG, Gharib, SA, Dupuis, J, Manichaikul, A, London, SJ, Wyss, AB, Sofer, T, Lee, MK, Terzikhan, N, Nguyen, JN, Lahousse, L, Latourelle, JC, Smith, AV, Bartz, TM, Feitosa, MF, Gao, W, Ahluwalia, TS, Tang, W, Oldmeadow, C, Duan, Q, de Jong, K, Wojczynski, MK, Wang, X-Q, Noordam, R, Hartwig, FP, Jackson, VE, Wang, T, Obeidat, M, Hobbs, BD, Huan, T, Gui, H, Parker, MM, Hu, D, Mogil, LS, Kichaev, G, Jin, J, Graff, M, Harris, TB, Kalhan, R, Heckbert, SR, Paternoster, L, Burkart, KM, Liu, Y, Holliday, EG, Wilson, JG, Vonk, JM, Sanders, JL, Barr, RG, de Mutsert, R, Baptista Menezes, AM, Adams, HHH, van den Berge, M, Joehanes, R, Levin, AM, Liberto, J, Launer, LJ, Morrison, AC, Sitlani, CM, Celedon, JC, Kritchevsky, SB, Scott, RJ, Christensen, K, Rotter, JI, Bonten, TN, Wehrmeister, FC, Bosse, Y, Xiao, S, Oh, S, Franceschini, N, Brody, JA, Kaplan, RC, Lohman, K, McEvoy, M, Province, MA, Rosendaal, FR, Taylor, KD, Nickle, DC, Williams, LK, Burchard, EG, Wheeler, HE, Sin, DD, Gudnason, V, North, KE, Fornage, M, Psaty, BM, Myers, RH, O'Connor, G, Hansen, T, Laurie, CC, Cassano, PA, Sung, J, Kim, WJ, Attia, JR, Lange, L, Boezen, HM, Thyagarajan, B, Rich, SS, Mook-Kanamori, DO, Horta, BL, Uitterlinden, AG, Im, HK, Cho, MH, Brusselle, GG, Gharib, SA, Dupuis, J, Manichaikul, A, and London, SJ

Abstract

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

Published
2018

21. 17q21 variant increases the risk of exacerbations in asthmatic children despite inhaled corticosteroids use

Author

Farzan, N, Vijverberg, SJ, Hernandez-Pacheco, N, Bel, EHD, Berce, V, Bonnelykke, K, Bisgaard, H, Burchard, EG, Canino, G, Celedon, JC, Chew, FT, Chiang, WC, Cloutier, MM, Forno, E, Francis, B, Hawcutt, DB, Herrera-Luis, E, Kabesch, M, Karimi Gazafroudi, Leila, Melen, E, Mukhopadhyay, S, Merid, SK, Palmer, CN, Pino-Yanes, M, Pirmohamed, M, Potocnik, U, Repnik, K, Schieck, M, Sevelsted, A, Sio, YY, Smyth, RL, Soares, P, Soderhall, C, Tantisira, KG, Tavendale, R, Tse, SM, Turner, S, Verhamme, Katia, Zee, AH, Farzan, N, Vijverberg, SJ, Hernandez-Pacheco, N, Bel, EHD, Berce, V, Bonnelykke, K, Bisgaard, H, Burchard, EG, Canino, G, Celedon, JC, Chew, FT, Chiang, WC, Cloutier, MM, Forno, E, Francis, B, Hawcutt, DB, Herrera-Luis, E, Kabesch, M, Karimi Gazafroudi, Leila, Melen, E, Mukhopadhyay, S, Merid, SK, Palmer, CN, Pino-Yanes, M, Pirmohamed, M, Potocnik, U, Repnik, K, Schieck, M, Sevelsted, A, Sio, YY, Smyth, RL, Soares, P, Soderhall, C, Tantisira, KG, Tavendale, R, Tse, SM, Turner, S, Verhamme, Katia, and Zee, AH

Published
2018

22. Cohort Profile: Pregnancy And Childhood Epigenetics (PACE) Consortium

Author

Felix, Janine, Joubert, BR, Baccarelli, AA, Sharp, GC, Almqvist, C, Annesi-Maesano, I, Arshad, H, Baiz, N, Bakermans-Kranenburg, MJ, Bakulski, KM, Binder, EB, Bouchard, L, Breton, CV, Brunekreef, B, Brunst, KJ, Burchard, EG, Bustamante, M, Chatzi, L, Munthe-Kaas, MC, Corpeleijn, E, Czamara, D, Dabelea, D, Smith, GD, De Boever, P, Duijts, Liesbeth, Dwyer, T, Eng, C, Eskenazi, B, Everson, TM, Falahi, F, Fallin, MD, Farchi, S, Fernandez, MF, Gao, L, Gaunt, TR, Ghantous, A, Gillman, MW, Gonseth, S, Grote, V, Gruzieva, O, Haberg, SE, Herceg, Z, Hivert, MF, Holland, N, Holloway, JW, Hoyo, C, Hu, DL, Huang, RC, Huen, K, Jarvelin, MR, Jima, DD, Just, AC, Karagas, MR, Karlsson, R, Karmaus, W, Kechris, KJ, Kere, J, Kogevinas, M, Koletzko, B, Koppelman, GH, Kupers, LK, Ladd-Acosta, C, Lahti, J, Lambrechts, N, Langie, SAS, Lie, RT, Liu, AH, Magnus, MC, Magnus, P, Maguire, RL, Marsit, CJ, McArdle, W, Melen, E, Melton, P, Murphy, SK, Nawrot, TS, Nistico, L, Nohr, EA, Nordlund, B, Nystad, W, Oh, SS, Oken, E, Page, CM, Perron, P, Pershagen, G, Pizzi, C, Plusquin, M, Raikkonen, K, Reese, SE, Reischl, E, Richiardi, L, Ring, S, Roy, RP, Rzehak, P, Schoeters, G, Schwartz, DA, Sebert, S, Snieder, H, Sorensen, TIA, Starling, AP, Sunyer, J, Ataylor, J, Tiemeier, Henning, Ullemar, V, Vafeiadi, M, van IJzendoorn, Marinus, Vonk, JM, Vriens, A, Vrijheid, M, Wang, P, Wiemels, JL, Wilcox, AJ, Wright, RJ, Xu, CJ, Xu, ZL, Yang, IV, Yousefi, P, Zhang, HM, Zhang, WM, Zhao, SS, Agha, G, Relton, CL, Jaddoe, Vincent, London, SJ, Felix, Janine, Joubert, BR, Baccarelli, AA, Sharp, GC, Almqvist, C, Annesi-Maesano, I, Arshad, H, Baiz, N, Bakermans-Kranenburg, MJ, Bakulski, KM, Binder, EB, Bouchard, L, Breton, CV, Brunekreef, B, Brunst, KJ, Burchard, EG, Bustamante, M, Chatzi, L, Munthe-Kaas, MC, Corpeleijn, E, Czamara, D, Dabelea, D, Smith, GD, De Boever, P, Duijts, Liesbeth, Dwyer, T, Eng, C, Eskenazi, B, Everson, TM, Falahi, F, Fallin, MD, Farchi, S, Fernandez, MF, Gao, L, Gaunt, TR, Ghantous, A, Gillman, MW, Gonseth, S, Grote, V, Gruzieva, O, Haberg, SE, Herceg, Z, Hivert, MF, Holland, N, Holloway, JW, Hoyo, C, Hu, DL, Huang, RC, Huen, K, Jarvelin, MR, Jima, DD, Just, AC, Karagas, MR, Karlsson, R, Karmaus, W, Kechris, KJ, Kere, J, Kogevinas, M, Koletzko, B, Koppelman, GH, Kupers, LK, Ladd-Acosta, C, Lahti, J, Lambrechts, N, Langie, SAS, Lie, RT, Liu, AH, Magnus, MC, Magnus, P, Maguire, RL, Marsit, CJ, McArdle, W, Melen, E, Melton, P, Murphy, SK, Nawrot, TS, Nistico, L, Nohr, EA, Nordlund, B, Nystad, W, Oh, SS, Oken, E, Page, CM, Perron, P, Pershagen, G, Pizzi, C, Plusquin, M, Raikkonen, K, Reese, SE, Reischl, E, Richiardi, L, Ring, S, Roy, RP, Rzehak, P, Schoeters, G, Schwartz, DA, Sebert, S, Snieder, H, Sorensen, TIA, Starling, AP, Sunyer, J, Ataylor, J, Tiemeier, Henning, Ullemar, V, Vafeiadi, M, van IJzendoorn, Marinus, Vonk, JM, Vriens, A, Vrijheid, M, Wang, P, Wiemels, JL, Wilcox, AJ, Wright, RJ, Xu, CJ, Xu, ZL, Yang, IV, Yousefi, P, Zhang, HM, Zhang, WM, Zhao, SS, Agha, G, Relton, CL, Jaddoe, Vincent, and London, SJ

Published
2018

23. 17q21 gene variation increases the risk of exacerbations in asthmatic children treated with inhaled corticosteroids: A meta-analysis in the multi-ethnic pica consortium

Author

Farzan, N, Vijverberg, SJ, Hernandez-Pacheco, N, Berce, V, Burchard, EG, Canino, G, Celedon, JC, Cloutier, MM, Forno, E, Francis, B, Hawcutt, DB, Kabesch, M, Karimi, L, Melen, E, Mukhopadhyay, S, Nilsson, S, Palmer, CN, Pino-Yanes, M, Pirmohamed, M, Potocnik, U, Raaijmakers, JA, Repnik, K, Schieck, M, Smyth, RL, Tantisira, KG, Tavendale, R, Tse, SM, Turner, S, Verhamme, KM, and Maitland-Van der Zee, AH

Published
2017

24. 17q21 Gene Variance Increases The Risk Of Exacerbations In Asthmatic Children Treated With Inhaled Corticosteroids: A Meta-Analysis In The Pica Consortium

Author

Farzan, N, Vijverberg, S, Hernandez-Pacheco, N, Berce, V, Burchard, EG, Canino, G, Celedon, JC, Cloutier, MM, Forno, E, Francis, B, Hawcutt, D, Kabesch, M, Karimi, L, Melen, E, Mukhopadhyay, S, Nilsson, S, Palmer, C, Pino-Yanes, M, Pirmohamed, M, Potocnik, U, Raaijmakers, J, Repnik, K, Schieck, M, Smyth, R, Tantisira, K, Turner, S, Verhamme, K, and Maitland-van Der Zee, A-H

Published
2017

25. Apolipoprotein E epsilon 4 (APOE-epsilon 4) genotype is associated with decreased 6-month verbal memory performance after mild traumatic brain injury

Author

Yue, JK, Robinson, CK, Burke, JF, Winkler, EA, Deng, HS, Cnossen, MC, Lingsma, Hester, Ferguson, AR, McAllister, TW, Rosand, J, Burchard, EG, Sorani, MD, Sharma, S, Nielson, JL, Satris, GG, Talbott, JF, Tarapore, PE, Korley, FK, Wang, KKW, Yuh, EL, Mukherjee, P, Diaz-Arrastia, R, Valadka, AB, Okonkwo, DO, Manley, GT, Yue, JK, Robinson, CK, Burke, JF, Winkler, EA, Deng, HS, Cnossen, MC, Lingsma, Hester, Ferguson, AR, McAllister, TW, Rosand, J, Burchard, EG, Sorani, MD, Sharma, S, Nielson, JL, Satris, GG, Talbott, JF, Tarapore, PE, Korley, FK, Wang, KKW, Yuh, EL, Mukherjee, P, Diaz-Arrastia, R, Valadka, AB, Okonkwo, DO, and Manley, GT

Published
2017

26. COMT Val158Met polymorphism is associated with post-traumatic stress disorder and functional outcome following mild traumatic brain injury

Author

Winkler, EA, Yue, JK, Ferguson, AR, Temkin, NR, Stein, MB, Barber, J, Yuh, EL, Sharma, S, Satris, GG, McAllister, TW, Rosand, J, Sorani, MD, Lingsma, Hester, Tarapore, PE, Burchard, EG, Hui, DL, Eng, C, Wang, KKW, Mukherjee, P, Okonkwo, DO, Diaz-Arrastia, R, Manley, GT, and Public Health

Subjects
Adult, Male, Polymorphism, Genetic, Substance-Related Disorders, Glasgow Outcome Scale, Valine, Middle Aged, Catechol O-Methyltransferase, behavioral disciplines and activities, Polymorphism, Single Nucleotide, Article, Stress Disorders, Post-Traumatic, Methionine, mental disorders, Brain Injuries, Traumatic, Ethnicity, Humans, Female, Glasgow Coma Scale, Prospective Studies, Alleles, Aged
Abstract

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 Val158Met 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 Met158 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 Val158Met 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.

Published
2016

27. Pacifiplex: an ancestry-informative SNP panel centred on Australia and the Pacific region

Author

Santos C, Phillips C, Fondevila M, Daniel R, van Oorschot RA, Burchard EG, Schanfield MS, Souto L, Uacyisrael J, Via M, Carracedo Á, and Lareu MV

Subjects
Ancestry informative, Australia, Forensic assay, Pacific region, Single nucleotide polymorphisms
Abstract

The analysis of human population variation is an area of considerable interest in the forensic, medical genetics and anthropological fields. Several forensic single nucleotide polymorphism (SNP) assays provide ancestry-informative genotypes in sensitive tests designed to work with limited DNA samples, including a 34-SNP multiplex differentiating African, European and East Asian ancestries. Although assays capable of differentiating Oceanian ancestry at a global scale have become available, this study describes markers compiled specifically for differentiation of Oceanian populations. A sensitive multiplex assay, termed Pacifiplex, was developed and optimized in a small-scale test applicable to forensic analyses. The Pacifiplex assay comprises 29 ancestry-informative marker SNPs (AIM-SNPs) selected to complement the 34-plex test, that in a combined set distinguish Africans, Europeans, East Asians and Oceanians. Nine Pacific region study populations were genotyped with both SNP assays, then compared to four reference population groups from the HGDP-CEPH human diversity panel. STRUCTURE analyses estimated population cluster membership proportions that aligned with the patterns of variation suggested for each study population's currently inferred demographic histories. Aboriginal Taiwanese and Philippine samples indicated high East Asian ancestry components, Papua New Guinean and Aboriginal Australians samples were predominantly Oceanian, while other populations displayed cluster patterns explained by the distribution of divergence amongst Melanesians, Polynesians and Micronesians. Genotype data from Pacifiplex and 34-plex tests is particularly well suited to analysis of Australian Aboriginal populations and when combined with Y and mitochondrial DNA variation will provide a powerful set of markers for ancestry inference applied to modern Australian demographic profiles. On a broader geographic scale, Pacifiplex adds highly informative data for inferring the ancestry of individuals from Oceanian populations. The sensitivity of Pacifiplex enabled successful genotyping of population samples from 50-year-old serum samples obtained from several Oceanian regions that would otherwise be unlikely to produce useful population data. This indicates tests primarily developed for forensic ancestry analysis also provide an important contribution to studies of populations where useful samples are in limited supply.

Published
2016

28. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

Author

Paternoster, L, Standl, M, Waage, J, Baurecht, H, Hotze, M, Strachan, DP, Curtin, JA, Bonnelykke, K, Tian, C, Takahashi, A, Esparza-Gordillo, J, Alves, AC, Thyssen, JP, den Dekker, HT, Ferreira, MA, Altmaier, E, Sleiman, PMA, Xiao, FL, Gonzalez, JR, Marenholz, I, Kalb, B, Pino-Yanes, M, Xu, C-J, Carstensen, L, Groen-Blokhuis, MM, Venturini, C, Pennell, CE, Barton, SJ, Levin, AM, Curjuric, I, Bustamante, M, Kreiner-Moller, E, Lockett, GA, Bacelis, J, Bunyavanich, S, Myers, RA, Matanovic, A, Kumar, A, Tung, JY, Hirota, T, Kubo, M, McArdle, WL, Henderson, AJ, Kemp, JP, Zheng, J, Smith, GD, Rueschendorf, F, Bauerfeind, A, Lee-Kirsch, MA, Arnold, A, Homuth, G, Schmidt, CO, Mangold, E, Cichon, S, Keil, T, Rodriguez, E, Peters, A, Franke, A, Lieb, W, Novak, N, Foelster-Holst, R, Horikoshi, M, Pekkanen, J, Sebert, S, Husemoen, LL, Grarup, N, De Jongste, JC, Rivadeneira, F, Hofman, A, Jaddoe, VWV, Pasmans, SGMA, Elbert, NJ, Uitterlinden, AG, Marks, GB, Thompson, PJ, Matheson, MC, Robertson, CF, Ried, JS, Li, J, Zuo, XB, Zheng, XD, Yin, XY, Sun, LD, McAleer, MA, O'Regan, GM, Fahy, CMR, Campbell, LE, Macek, M, Kurek, M, Hu, D, Eng, C, Postma, DS, Feenstra, B, Geller, F, Hottenga, JJ, Middeldorp, CM, Hysi, P, Bataille, V, Spector, T, Tiesler, CMT, Thiering, E, Pahukasahasram, B, Yang, JJ, Imboden, M, Huntsman, S, Vilor-Tejedor, N, Relton, CL, Myhre, R, Nystad, W, Custovic, A, Weiss, ST, Meyers, DA, Soederhaell, C, Melen, E, Ober, C, Raby, BA, Simpson, A, Jacobsson, B, Holloway, JW, Bisgaard, H, Sunyer, J, Probst-Hensch, NM, Williams, LK, Godfrey, KM, Wang, CA, Boomsma, DI, Melbye, M, Koppelman, GH, Jarvis, D, McLean, WHI, Irvine, AD, Zhang, XJ, Hakonarson, H, Gieger-, C, Burchard, EG, Martin, NG, Duijts, L, Linneberg, A, Jarvelin, M-R, Noethen, MM, Lau, S, Huebner, N, Lee, Y-A, Tamari, M, Hinds, DA, Glass, D, Brown, SJ, Heinrich, J, Evans, DM, Weidinger, S, AAGC, AAGC, and Epidemio, EGL

Abstract

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.

Published
2015

29. Human genetics. The genetics of Mexico recapitulates Native American substructure and affects biomedical traits

Author

Moreno-Estrada A, Gignoux CR, Fernández-López JC, Zakharia F, Sikora M, Contreras AV, Acuña-Alonzo V, Sandoval K, Eng C, Romero-Hidalgo S, Ortiz-Tello P, Robles V, Kenny EE, Nuño-Arana I, Barquera-Lozano R, Macín-Pérez G, Granados-Arriola J, Huntsman S, Galanter JM, Via M, Ford JG, Chapela R, Rodriguez-Cintron W, Rodríguez-Santana JR, Romieu I, Sienra-Monge JJ, del Rio Navarro B, London SJ, Ruiz-Linares A, Garcia-Herrera R, Estrada K, Hidalgo-Miranda A, Jimenez-Sanchez G, Carnevale A, Soberón X, Canizales-Quinteros S, Rangel-Villalobos H, Silva-Zolezzi I, Burchard EG, and Bustamante CD

Subjects
Genome, Human, Mexican Americans, Population, Indians, North American, Black People, Genetic Variation, Humans, Mexico, White People
Abstract

Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-wide variation from this region remain largely uncharacterized. We studied genomic variation within Mexico from over 1000 individuals representing 20 indigenous and 11 mestizo populations. We found striking genetic stratification among indigenous populations within Mexico at varying degrees of geographic isolation. Some groups were as differentiated as Europeans are from East Asians. Pre-Columbian genetic substructure is recapitulated in the indigenous ancestry of admixed mestizo individuals across the country. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican Americans showed a significant association between subcontinental ancestry and lung function. Thus, accounting for fine-scale ancestry patterns is critical for medical and population genetic studies within Mexico, in Mexican-descent populations, and likely in many other populations worldwide.

Published
2014

30. An integrated map of genetic variation from 1,092 human genomes

Author

Altshuler, DM, Durbin, RM, Abecasis, GR, Bentley, DR, Chakravarti, A, Clark, AG, Donnelly, P, Eichler, EE, Flicek, P, Gabriel, SB, Gibbs, RA, Green, ED, Hurles, ME, Knoppers, BM, Korbel, JO, Lander, ES, Lee, C, Lehrach, H, Mardis, ER, Marth, GT, McVean, GA, Nickerson, DA, Schmidt, JP, Sherry, ST, Wang, J, Wilson, RK, Dinh, H, Kovar, C, Lee, S, Lewis, L, Muzny, D, Reid, J, Wang, M, Fang, X, Guo, X, Jian, M, Jiang, H, Jin, X, Li, G, Li, J, Li, Y, Li, Z, Liu, X, Lu, Y, Ma, X, Su, Z, Tai, S, Tang, M, Wang, B, Wang, G, Wu, H, Wu, R, Yin, Y, Zhang, W, Zhao, J, Zhao, M, Zheng, X, Zhou, Y, Gupta, N, Clarke, L, Leinonen, R, Smith, RE, Zheng-Bradley, X, Grocock, R, Humphray, S, James, T, Kingsbury, Z, Sudbrak, R, Albrecht, MW, Amstislavskiy, VS, Borodina, TA, Lienhard, M, Mertes, F, Sultan, M, Timmermann, B, Yaspo, M-L, Fulton, L, Fulton, R, Weinstock, GM, Balasubramaniam, S, Burton, J, Danecek, P, Keane, TM, Kolb-Kokocinski, A, McCarthy, S, Stalker, J, Quail, M, Davies, CJ, Gollub, J, Webster, T, Wong, B, Zhan, Y, Auton, A, Yu, F, Bainbridge, M, Challis, D, Evani, US, Lu, J, Nagaswamy, U, Sabo, A, Wang, Y, Yu, J, Coin, LJM, Fang, L, Li, Q, Lin, H, Liu, B, Luo, R, Qin, N, Shao, H, Xie, Y, Ye, C, Yu, C, Zhang, F, Zheng, H, Zhu, H, Garrison, EP, Kural, D, Lee, W-P, Leong, WF, Ward, AN, Wu, J, Zhang, M, Griffin, L, Hsieh, C-H, Mills, RE, Shi, X, Von Grotthuss, M, Zhang, C, Daly, MJ, DePristo, MA, Banks, E, Bhatia, G, Carneiro, MO, Del Angel, G, Genovese, G, Handsaker, RE, Hartl, C, McCarroll, SA, Nemesh, JC, Poplin, RE, Schaffner, SF, Shakir, K, Yoon, SC, Lihm, J, Makarov, V, Jin, H, Kim, W, Kim, KC, Rausch, T, Beal, K, Cunningham, F, Herrero, J, McLaren, WM, Ritchie, GRS, Gottipati, S, Keinan, A, Rodriguez-Flores, JL, Sabeti, PC, Grossman, SR, Tabrizi, S, Tariyal, R, Cooper, DN, Ball, EV, Stenson, PD, Barnes, B, Bauer, M, Cheetham, RK, Cox, T, Eberle, M, Kahn, S, Murray, L, Peden, J, Shaw, R, Ye, K, Batzer, MA, Konkel, MK, Walker, JA, MacArthur, DG, Lek, M, Herwig, R, Shriver, MD, Bustamante, CD, Byrnes, JK, De la Vega, FM, Gravel, S, Kenny, EE, Kidd, JM, Lacroute, P, Maples, BK, Moreno-Estrada, A, Zakharia, F, Halperin, E, Baran, Y, Craig, DW, Christoforides, A, Homer, N, Izatt, T, Kurdoglu, AA, Sinari, SA, Squire, K, Xiao, C, Sebat, J, Bafna, V, Burchard, EG, Hernandez, RD, Gignoux, CR, Haussler, D, Katzman, SJ, Kent, WJ, Howie, B, Ruiz-Linares, A, Dermitzakis, ET, Lappalainen, T, Devine, SE, Maroo, A, Tallon, LJ, Rosenfeld, JA, Michelson, LP, Kang, HM, Anderson, P, Angius, A, Bigham, A, Blackwell, T, Busonero, F, Cucca, F, Fuchsberger, C, Jones, C, Jun, G, Lyons, R, Maschio, A, Porcu, E, Reinier, F, Sanna, S, Schlessinger, D, Sidore, C, Tan, A, Trost, MK, Awadalla, P, Hodgkinson, A, Lunter, G, Marchini, JL, Myers, S, Churchhouse, C, Delaneau, O, Gupta-Hinch, A, Iqbal, Z, Mathieson, I, Rimmer, A, Xifara, DK, Oleksyk, TK, Fu, Y, Xiong, M, Jorde, L, Witherspoon, D, Xing, J, Browning, BL, Alkan, C, Hajirasouliha, I, Hormozdiari, F, Ko, A, Sudmant, PH, Chen, K, Chinwalla, A, Ding, L, Dooling, D, Koboldt, DC, McLellan, MD, Wallis, JW, Wendl, MC, Zhang, Q, Tyler-Smith, C, Albers, CA, Ayub, Q, Chen, Y, Coffey, AJ, Colonna, V, Huang, N, Jostins, L, Li, H, Scally, A, Walter, K, Xue, Y, Zhang, Y, Gerstein, MB, Abyzov, A, Balasubramanian, S, Chen, J, Clarke, D, Habegger, L, Harmanci, AO, Jin, M, Khurana, E, Mu, XJ, Sisu, C, Degenhardt, J, Stuetz, AM, Church, D, Michaelson, JJ, Ben, B, Lindsay, SJ, Ning, Z, Frankish, A, Harrow, J, Fowler, G, Hale, W, Kalra, D, Barker, J, Kelman, G, Kulesha, E, Radhakrishnan, R, Roa, A, Smirnov, D, Streeter, I, Toneva, I, Vaughan, B, Ananiev, V, Belaia, Z, Beloslyudtsev, D, Bouk, N, Chen, C, Cohen, R, Cook, C, Garner, J, Hefferon, T, Kimelman, M, Liu, C, Lopez, J, Meric, P, O'Sullivan, C, Ostapchuk, Y, Phan, L, Ponomarov, S, Schneider, V, Shekhtman, E, Sirotkin, K, Slotta, D, Zhang, H, Barnes, KC, Beiswanger, C, Cai, H, Cao, H, Gharani, N, Henn, B, Jones, D, Kaye, JS, Kent, A, Kerasidou, A, Mathias, R, Ossorio, PN, Parker, M, Reich, D, Rotimi, CN, Royal, CD, Sandoval, K, Su, Y, Tian, Z, Tishkoff, S, Toji, LH, Via, M, Yang, H, Yang, L, Zhu, J, Bodmer, W, Bedoya, G, Ming, CZ, Yang, G, You, CJ, Peltonen, L, Garcia-Montero, A, Orfao, A, Dutil, J, Martinez-Cruzado, JC, Brooks, LD, Felsenfeld, AL, McEwen, JE, Clemm, NC, Duncanson, A, Dunn, M, Guyer, MS, Peterson, JL, 1000 Genomes Project Consortium, Dermitzakis, Emmanouil, Universitat de Barcelona, Massachusetts Institute of Technology. Department of Biology, Altshuler, David, and Lander, Eric S.

Subjects
Natural selection, LOCI, Genome-wide association study, Evolutionary biology, Continental Population Groups/genetics, Human genetic variation, VARIANTS, Genoma humà, Binding Sites/genetics, 0302 clinical medicine, RARE, Sequence Deletion/genetics, WIDE ASSOCIATION, ddc:576.5, Copy-number variation, MUTATION, Exome sequencing, transcription factor, Conserved Sequence, Human evolution, Sequence Deletion, Genetics, RISK, 0303 health sciences, Multidisciplinary, Continental Population Groups, 1000 Genomes Project Consortium, Genetic analysis, Genomics, Polymorphism, Single Nucleotide/genetics, Research Highlight, 3. Good health, Algorithm, Multidisciplinary Sciences, Genetic Variation/genetics, Map, Science & Technology - Other Topics, Conserved Sequence/genetics, Integrated approach, General Science & Technology, Genetics, Medical, Haplotypes/genetics, Biology, Polymorphism, Single Nucleotide, Evolution, Molecular, 03 medical and health sciences, Genetic variation, Humans, Transcription Factors/metabolism, POPULATION-STRUCTURE, 1000 Genomes Project, Polymorphism, Nucleotide Motifs, Alleles, 030304 developmental biology, COPY NUMBER VARIATION, Science & Technology, Binding Sites, Human genome, Genome, Human, Racial Groups, Genetic Variation, Genetics, Population, Haplotypes, Genome, Human/genetics, untranslated RNA, 030217 neurology & neurosurgery, Transcription Factors, Genome-Wide Association Study
Abstract

By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million single nucleotide polymorphisms, 1.4 million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations., National Institutes of Health (U.S.) (Grant RC2HL102925), National Institutes of Health (U.S.) (Grant U54HG3067)

Published
2012

31. Admixture mapping identifies a locus on 6q25 associated with breast cancer risk in US Latinas

Author

Fejerman L, Chen GK, Eng C, Huntsman S, Hu D, Williams A, Pasaniuc B, John EM, Via M, Gignoux C, Ingles S, Monroe KR, Kolonel LN, Torres-Mejía G, Pérez-Stable EJ, Burchard EG, Henderson BE, Haiman CA, and Ziv E

Abstract

Among US Latinas and Mexican women, those with higher European ancestry have increased risk of breast cancer. We combined an admixture mapping and genome-wide association mapping approach to search for genomic regions that may explain this observation. Latina women with breast cancer (n= 1497) and Latina controls (n= 1272) were genotyped using Affymetrix and Illumina arrays. We inferred locus-specific genetic ancestry and compared the ancestry between cases and controls. We also performed single nucleotide polymorphism (SNP) association analyses in regions of interest. Correction for multiple-hypothesis testing was conducted using permutations (P(corrected)). We identified one region where genetic ancestry was significantly associated with breast cancer risk: 6q25 [odds ratio (OR) per Indigenous American chromosome 0.75, 95% confidence interval (CI): 0.65-0.85, P= 1.1 × 10(-5), P(corrected)= 0.02]. A second region on 11p15 showed a trend towards association (OR per Indigenous American chromosome 0.77, 95% CI: 0.68-0.87, P= 4.3 × 10(-5), P(corrected)= 0.08). In both regions, breast cancer risk decreased with higher Indigenous American ancestry in concordance with observations made on global ancestry. The peak of the 6q25 signal includes the estrogen receptor 1 (ESR1) gene and 5' region, a locus previously implicated in breast cancer. Genome-wide association analysis found that a multi-SNP model explained the admixture signal in both regions. Our results confirm that the association between genetic ancestry and breast cancer risk in US Latinas is partly due to genetic differences between populations of European and Indigenous Americans origin. Fine-mapping within the 6q25 and possibly the 11p15 loci will lead to the discovery of the biologically functional variant/s behind this association.

Published
2012

32. Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene

Author

Himes, BE, Sheppard, K, Berndt, A, Leme, AS, Myers, RA, Gignoux, CR, Levin, AM, Gauderman, WJ, Yang, JJ, Mathias, RA, Romieu, I, Torgerson, DG, Roth, LA, Huntsman, S, Eng, C, Klanderman, B, Ziniti, J, Senter-Sylvia, J, Szefler, SJ, Lemanske, RF, Zeiger, RS, Strunk, RC, Martinez, FD, Boushey, H, Chinchilli, VM, Israel, E, Mauger, D, Koppelman, GH, Postma, DS, Nieuwenhuis, MAE, Vonk, JM, Lima, JJ, Irvin, CG, Peters, SP, Kubo, M, Tamari, M, Nakamura, Y, Litonjua, AA, Tantisira, KG, Raby, BA, Bleecker, ER, Meyers, DA, London, SJ, Barnes, KC, Gilliland, FD, Williams, LK, Burchard, EG, Nicolae, DL, Ober, C, DeMeo, DL, Silverman, EK, Paigen, B, Churchill, G, Shapiro, SD, Weiss, ST, Himes, BE, Sheppard, K, Berndt, A, Leme, AS, Myers, RA, Gignoux, CR, Levin, AM, Gauderman, WJ, Yang, JJ, Mathias, RA, Romieu, I, Torgerson, DG, Roth, LA, Huntsman, S, Eng, C, Klanderman, B, Ziniti, J, Senter-Sylvia, J, Szefler, SJ, Lemanske, RF, Zeiger, RS, Strunk, RC, Martinez, FD, Boushey, H, Chinchilli, VM, Israel, E, Mauger, D, Koppelman, GH, Postma, DS, Nieuwenhuis, MAE, Vonk, JM, Lima, JJ, Irvin, CG, Peters, SP, Kubo, M, Tamari, M, Nakamura, Y, Litonjua, AA, Tantisira, KG, Raby, BA, Bleecker, ER, Meyers, DA, London, SJ, Barnes, KC, Gilliland, FD, Williams, LK, Burchard, EG, Nicolae, DL, Ober, C, DeMeo, DL, Silverman, EK, Paigen, B, Churchill, G, Shapiro, SD, and Weiss, ST

Abstract

Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data. © 2013 Himes et al.

Published
2013

33. Genetic ancestry-smoking interactions and lung function in African Americans: A cohort Study

Author

Aldrich, MC, Kumar, R, Colangelo, LA, Williams, LK, Sen, S, Kritchevsky, SB, Meibohm, B, Galanter, J, Hu, D, Gignoux, CR, Liu, Y, Harris, TB, Ziv, E, Zmuda, J, Garcia, M, Leak, TS, Foreman, MG, Smith, LJ, Fornage, M, Liu, K, Burchard, EG, Aldrich, MC, Kumar, R, Colangelo, LA, Williams, LK, Sen, S, Kritchevsky, SB, Meibohm, B, Galanter, J, Hu, D, Gignoux, CR, Liu, Y, Harris, TB, Ziv, E, Zmuda, J, Garcia, M, Leak, TS, Foreman, MG, Smith, LJ, Fornage, M, Liu, K, and Burchard, EG

Abstract

Background: Smoking tobacco reduces lung function. African Americans have both lower lung function and decreased metabolism of tobacco smoke compared to European Americans. African ancestry is also associated with lower pulmonary function in African Americans. We aimed to determine whether African ancestry modifies the association between smoking and lung function and its rate of decline in African Americans. Methodology/Principal Findings: We evaluated a prospective ongoing cohort of 1,281 African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study initiated in 1997. We also examined an ongoing prospective cohort initiated in 1985 of 1,223 African Americans in the Coronary Artery Disease in Young Adults (CARDIA) Study. Pulmonary function and tobacco smoking exposure were measured at baseline and repeatedly over the follow-up period. Individual genetic ancestry proportions were estimated using ancestry informative markers selected to distinguish European and West African ancestry. African Americans with a high proportion of African ancestry had lower baseline forced expiratory volume in one second (FEV1) per pack-year of smoking (-5.7 ml FEV1/ smoking pack-year) compared with smokers with lower African ancestry (-4.6 ml in FEV1/ smoking pack-year) (interaction P value = 0.17). Longitudinal analyses revealed a suggestive interaction between smoking, and African ancestry on the rate of FEV1 decline in Health ABC and independently replicated in CARDIA. Conclusions/Significance: African American individuals with a high proportion of African ancestry are at greater risk for losing lung function while smoking. © 2012 Aldrich et al.

Published
2012

36. Polymorphisms in the ORMDL3 Gene Are Associated with Early-Onset Asthma in African Americans.

Author

Galanter, JM, primary, Choudhry, S, additional, Eng, C, additional, Nazario, S, additional, Rodriguez-Santana, JR, additional, Casal, J, additional, Torres, A, additional, Salas, J, additional, Chapela, R, additional, Watson, HG, additional, Meade, K, additional, Lenoir, M, additional, Rodriguez-Cintron, W, additional, Avila, P, additional, and Burchard, EG, additional

Published
2009
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41. Birthplace and mortality among insured Latinos: the paradox revisited.

Author

Iribarren C, Darbinian JA, Fireman BH, Burchard EG, Iribarren, Carlos, Darbinian, Jeanne A, Fireman, Bruce H, and Burchard, Esteban González

Abstract

Objectives: We investigated the Latino paradox in a managed care setting and examined the role of birthplace.Methods: We evaluated 133,155 non-Latino Whites and 5,237 Latinos (36% born in the United States, 34% in Central and South America, 21% in Mexico, and 8% in the Caribbean Islands) who were enrolled in an integrated healthcare delivery system in northern California. Baseline data were from 1964-1973, and the median followup was 34 years. Main outcome measures were cause-specific and all-cause mortality.Results: In fully-adjusted analyses, and compared with non-Latino Whites, the risk of death from circulatory causes was significantly lower among US-born Latinos (hazard ratio [HR] .79, 95% confidence interval [CI] .66-.93), among Central and South America-born Latinos (HR .76, 95% CI .63-.91), and Caribbean-born Latinos (HR .66, 95% CI .47-0.93). Risk of death by malignant neoplasms was significantly lower among US-born Latinos (HR .68, 95% CI .56-.83). Risk of respiratory death was significantly lower among Central and South America-born Latinos (HR .50, 95% CI .32-.80). All-cause mortality risk was significantly decreased in US-born Latinos (HR .79, 95% CI .71-.87), Central and South America-born Latinos (HR .81, 95% CI .73-.90), and Caribbean-born Latinos (HR .76, 95% CI .63-.93) but not in Mexico-born Latinos.Conclusions: In our managed care setting, the Latino paradox phenomenon varied by birthplace; it was more evident among US-born Latinos. This subgroup experienced lower circulatory, cancer, and all-cause mortality than did non-Latino Whites, despite higher prevalences of current smoking, obesity, and asymptomatic hyperglycemia. [ABSTRACT FROM AUTHOR]

Published
2009

43. ORMDL3 gene is associated with asthma in three ethnically diverse populations.

Author

Galanter J, Choudhry S, Eng C, Nazario S, Rodríguez-Santana JR, Casal J, Torres-Palacios A, Salas J, Chapela R, Watson HG, Meade K, LeNoir M, Rodríguez-Cintrón W, Avila PC, Burchard EG, Galanter, Joshua, Choudhry, Shweta, Eng, Celeste, Nazario, Sylvette, and Rodríguez-Santana, José R

Abstract

Rationale: Independent replication of genetic associations in complex diseases, particularly in whole-genome association studies, is critical to confirm the association.Objectives: A whole-genome association study identified ORMDL3 as a promising candidate gene for asthma in white populations. Here, we attempted to confirm the role of ORMDL3 genetic variants in asthma in three ethnically diverse populations: Mexican, Puerto Rican, and African American.Methods: We used family-based analyses to test for association between seven candidate single-nucleotide polymorphisms (SNPs) in and around the ORMDL3 gene and asthma and related phenotypes in 701 Puerto Rican and Mexican parent-child trios. We also evaluated these seven SNPs and an additional ORMDL3 SNP in 264 African American subjects with asthma and 176 healthy control subjects.Measurements and Main Results: We found significant associations between two SNPs within ORMDL3 (rs4378650 and rs12603332) and asthma in Mexicans and African Americans (P = 0.028 and 0.001 for rs4378650 and P = 0.021 and 0.001 for rs12603332, respectively), and a trend toward association in Puerto Ricans (P = 0.076 and 0.080 for SNPs rs4378650 and rs12603332, respectively). These associations became stronger among Mexican and Puerto Rican subjects with asthma with IgE levels greater than 100 IU/ml. We did not find any association between ORMDL3 SNPs and baseline lung function or response to the bronchodilator albuterol.Conclusions: Our results confirm that the ORMDL3 locus is a risk factor for asthma in ethnically diverse populations. However, inconsistent SNP-level results suggest that further studies will be needed to determine the mechanism by which ORMDL3 predisposes to asthma. [ABSTRACT FROM AUTHOR]

Published
2008
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44. 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.

Author

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

Published
2008
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45. Ethnicity-specific gene-gene interaction between IL-13 and IL-4Ralpha among African Americans with asthma.

Author

Battle NC, Choudhry S, Tsai H, Eng C, Kumar G, Beckman KB, Naqvi M, Meade K, Watson HG, LeNoir M, Burchard EG, SAGE Investigators, Battle, Natalie C, Choudhry, Shweta, Tsai, Hui-Ju, Eng, Celeste, Kumar, Gunjan, Beckman, Kenneth B, Naqvi, Mariam, and Meade, Kelley

Abstract

Rationale: Genes in the interleukin (IL)-4/IL-13/IL-4Ralpha pathway have been shown to be associated with asthma and related phenotypes in some populations, but not in others. Furthermore, interaction between these genes has been shown to affect asthma in white and Chinese populations.Objectives: To determine whether there are IL-4/IL-13 and IL-4Ralpha gene-gene interactions that are associated with asthma in African Americans.Methods: Eighteen single-nucleotide polymorphisms (SNPs) in IL-4, IL-13, and IL-4Ralpha genes were genotyped in 264 African Americans with asthma and 176 healthy control subjects. We tested the SNPs for genetic associations and gene-gene interactions with asthma, baseline lung function, bronchodilator drug response, and total serum IgE levels.Measurements and Main Results: We identified 94 SNPs in IL-4, IL-13, and IL-4Ralpha genes by directly sequencing these genes in 24 African-American subjects with asthma. Seventeen SNPs were analyzed for association with asthma and related phenotypes. We found no evidence of association in the IL-4 gene. One SNP in the IL-13 gene (A-646G, rs2069743) and two SNPs in the IL-4Ralpha gene (A+4679G, rs1805010, and C+22656T, rs1805015) showed association with lung function (both baseline and post-bronchodilator). Although the association between individual SNPs and asthma-related phenotypes differed from previous studies performed in white and Chinese populations, significant gene-gene interaction was found between the IL-13 (A-646G) and IL-4Ralpha (A+4679G) SNPs for baseline lung function among African-American subjects with asthma.Conclusions: Gene-gene interaction between the IL-13 and IL-4Ralpha genes may play an important role in asthma among African Americans. [ABSTRACT FROM AUTHOR]

Published
2007
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46. Ancestry-environment interactions and asthma risk among Puerto Ricans.

Author

Choudhry S, Burchard EG, Borrell LN, Tang H, Gomez I, Naqvi M, Nazario S, Torres A, Casal J, Martinez-Cruzado JC, Ziv E, Avila PC, Rodriguez-Cintron W, Risch NJ, Choudhry, Shweta, Burchard, Esteban González, Borrell, Luisa N, Tang, Hua, Gomez, Ivan, and Naqvi, Mariam

Abstract

Background: Puerto Ricans, an admixed population of African, European, and Native American ancestries, have the highest asthma prevalence, morbidity, and mortality rates of any United States' population. Although socioeconomic status (SES) is negatively correlated with asthma incidence in most populations, no such relationship has been identified among Puerto Ricans. We hypothesized that, in this admixed population, the association between SES and asthma may interact with genetic ancestry.Methods: We analyzed 135 Puerto Rican subjects with asthma and 156 control subjects recruited from six different recruitment centers in Puerto Rico. Individual ancestry for each subject was estimated using 44 ancestry informative markers. SES was assigned using the census tracts' median family income. Analyses of SES were based on the SES of the clinic site from which the subjects were recruited and on a subset of individuals on whom home address-based SES was available.Results: In the two (independent) analyses, we found a significant interaction between SES, ancestry, and asthma disease status. At lower SES, European ancestry was associated with increased risk of asthma, whereas African ancestry was associated with decreased risk. The opposite was true for their higher SES counterparts.Conclusions: The observed interaction may help to explain the unique pattern of risk for asthma in Puerto Ricans and the lack of association with SES observed in previous studies when not accounting for varying proportions of ancestry. [ABSTRACT FROM AUTHOR]

Published
2006
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47. Race, genetics, and health disparities. Latino populations: a unique opportunity for the study of race, genetics, and social environment in epidemiological research.

Author

Burchard EG, Borrell LN, Choudhry S, Naqvi M, Tsai H, Rodriguez-Santana JR, Chapela R, Rogers SD, Mei R, Rodriguez-Cintron W, Arena JF, Kittles R, Perez-Stable EJ, Ziv E, and Risch N

Abstract

Latinos are the largest minority population in the United States. Although usually classified as a single ethnic group by researchers, Latinos are heterogeneous from cultural, socioeconomic, and genetic perspectives. From a cultural and social perspective, Latinos represent a wide variety of national origins and ethnic and cultural groups, with a full spectrum of social class. From a genetic perspective, Latinos are descended from indigenous American, European, and African populations. We review the historical events that led to the formation of contemporary Latino populations and use results from recent genetic and clinical studies to illustrate the unique opportunity Latino groups offer for studying the interaction between racial, genetic, and environmental contributions to disease occurrence and drug response. [ABSTRACT FROM AUTHOR]

Published
2005
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48. Lower bronchodilator responsiveness in Puerto Rican than in Mexican subjects with asthma.

Author

Burchard EG, Avila PC, Nazario S, Casal J, Torres A, Rodriguez-Santana JR, Toscano M, Sylvia JS, Alioto M, Salazar M, Gomez I, Fagan JK, Salas J, Lilly C, Matallana H, Ziv E, Castro R, Selman M, Chapela R, and Sheppard D

Abstract

In the United States, Puerto Ricans and Mexicans have the highest and lowest asthma prevalence, morbidity, and mortality, respectively. To determine whether ethnicity-specific differences in therapeutic response, clinical response, and/or genetic factors contribute to differences in asthma outcomes, we compared asthma-related clinical characteristics among 684 Mexican and Puerto Rican individuals with asthma recruited from San Francisco, New York City, Puerto Rico, and Mexico City. Puerto Ricans with asthma had reduced lung function, greater morbidity, and longer asthma duration than did Mexicans with asthma. Bronchodilator responsiveness, measured as percentage change from baseline FEV1, was significantly lower among Puerto Ricans with asthma than among Mexicans with asthma. Puerto Ricans with asthma had on average 7.3% (95% confidence interval [CI], 4.6 to 9.9; p < 0.001) lower bronchodilator reversibility in FEV1, higher risk of an emergency department visit in the previous year (odds ratio, 2.63; 95% CI, 1.6 to 4.3; p < 0.001), and of previous hospitalization for asthma (odds ratio, 1.94; 95% CI, 1.2 to 3.2; p = 0.009) than Mexicans. Subgroup analysis corroborated that Puerto Ricans with asthma had more severe disease than did Mexicans on the basis of lung function measurements, responsiveness to beta2-adrenergic agonists, and health care use. We conclude that Puerto Ricans with asthma respond less to albuterol than do Mexicans with asthma. These findings underscore the need for additional research on racial/ethnic differences in asthma morbidity and response to therapy. [ABSTRACT FROM AUTHOR]

Published
2004
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49. Implications of Race Adjustment in Lung-Function Equations.

Author

Diao JA, He Y, Khazanchi R, Nguemeni Tiako MJ, Witonsky JI, Pierson E, Rajpurkar P, Elhawary JR, Melas-Kyriazi L, Yen A, Martin AR, Levy S, Patel CJ, Farhat M, Borrell LN, Cho MH, Silverman EK, Burchard EG, and Manrai AK

Subjects
Adolescent, Adult, Aged, Child, Female, Humans, Male, Middle Aged, Young Adult, Lung Diseases diagnosis, Lung Diseases economics, Lung Diseases ethnology, Lung Diseases therapy, Lung Transplantation statistics & numerical data, Nutrition Surveys statistics & numerical data, Pulmonary Disease, Chronic Obstructive diagnosis, Pulmonary Disease, Chronic Obstructive economics, Pulmonary Disease, Chronic Obstructive ethnology, Pulmonary Disease, Chronic Obstructive therapy, Racial Groups, Spirometry, United States epidemiology, Black or African American statistics & numerical data, White statistics & numerical data, Disability Evaluation, Veterans Disability Claims classification, Veterans Disability Claims economics, Veterans Disability Claims statistics & numerical data, Disabled Persons classification, Disabled Persons statistics & numerical data, Occupational Diseases diagnosis, Occupational Diseases economics, Occupational Diseases ethnology, Financing, Government economics, Financing, Government statistics & numerical data, Respiratory Function Tests classification, Respiratory Function Tests economics, Respiratory Function Tests standards, Respiratory Insufficiency diagnosis, Respiratory Insufficiency economics, Respiratory Insufficiency ethnology, Respiratory Insufficiency therapy
Abstract

Background: Adjustment for race is discouraged in lung-function testing, but the implications of adopting race-neutral equations have not been comprehensively quantified., Methods: We obtained longitudinal data from 369,077 participants in the National Health and Nutrition Examination Survey, U.K. Biobank, the Multi-Ethnic Study of Atherosclerosis, and the Organ Procurement and Transplantation Network. Using these data, we compared the race-based 2012 Global Lung Function Initiative (GLI-2012) equations with race-neutral equations introduced in 2022 (GLI-Global). Evaluated outcomes included national projections of clinical, occupational, and financial reclassifications; individual lung-allocation scores for transplantation priority; and concordance statistics (C statistics) for clinical prediction tasks., Results: Among the 249 million persons in the United States between 6 and 79 years of age who are able to produce high-quality spirometric results, the use of GLI-Global equations may reclassify ventilatory impairment for 12.5 million persons, medical impairment ratings for 8.16 million, occupational eligibility for 2.28 million, grading of chronic obstructive pulmonary disease for 2.05 million, and military disability compensation for 413,000. These potential changes differed according to race; for example, classifications of nonobstructive ventilatory impairment may change dramatically, increasing 141% (95% confidence interval [CI], 113 to 169) among Black persons and decreasing 69% (95% CI, 63 to 74) among White persons. Annual disability payments may increase by more than $1 billion among Black veterans and decrease by $0.5 billion among White veterans. GLI-2012 and GLI-Global equations had similar discriminative accuracy with regard to respiratory symptoms, health care utilization, new-onset disease, death from any cause, death related to respiratory disease, and death among persons on a transplant waiting list, with differences in C statistics ranging from -0.008 to 0.011., Conclusions: The use of race-based and race-neutral equations generated similarly accurate predictions of respiratory outcomes but assigned different disease classifications, occupational eligibility, and disability compensation for millions of persons, with effects diverging according to race. (Funded by the National Heart Lung and Blood Institute and the National Institute of Environmental Health Sciences.)., (Copyright © 2024 Massachusetts Medical Society.)

Published
2024
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50. Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes.

Author

Keener R, Chhetri SB, Connelly CJ, Taub MA, Conomos MP, Weinstock J, Ni B, Strober B, Aslibekyan S, Auer PL, Barwick L, Becker LC, Blangero J, Bleecker ER, Brody JA, Cade BE, Celedon JC, Chang YC, Cupples LA, Custer B, Freedman BI, Gladwin MT, Heckbert SR, Hou L, Irvin MR, Isasi CR, Johnsen JM, Kenny EE, Kooperberg C, Minster RL, Naseri T, Viali S, Nekhai S, Pankratz N, Peyser PA, Taylor KD, Telen MJ, Wu B, Yanek LR, Yang IV, Albert C, Arnett DK, Ashley-Koch AE, Barnes KC, Bis JC, Blackwell TW, Boerwinkle E, Burchard EG, Carson AP, Chen Z, Chen YI, Darbar D, de Andrade M, Ellinor PT, Fornage M, Gelb BD, Gilliland FD, He J, Islam T, Kaab S, Kardia SLR, Kelly S, Konkle BA, Kumar R, Loos RJF, Martinez FD, McGarvey ST, Meyers DA, Mitchell BD, Montgomery CG, North KE, Palmer ND, Peralta JM, Raby BA, Redline S, Rich SS, Roden D, Rotter JI, Ruczinski I, Schwartz D, Sciurba F, Shoemaker MB, Silverman EK, Sinner MF, Smith NL, Smith AV, Tiwari HK, Vasan RS, Weiss ST, Williams LK, Zhang Y, Ziv E, Raffield LM, Reiner AP, Arvanitis M, Greider CW, Mathias RA, and Battle A

Subjects
Humans, K562 Cells, Polymorphism, Single Nucleotide, Gene Expression Regulation, CRISPR-Cas Systems, Genome-Wide Association Study, Telomere genetics, Telomere metabolism, Telomere Homeostasis genetics
Abstract

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation., (© 2024. The Author(s).)

Published
2024
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