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15. Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age

Author

Merid, S. K. (Simon Kebede), Novoloaca, A. (Alexei), Sharp, G. C. (Gemma C.), Kupers, L. K. (Leanne K.), Kho, A. T. (Alvin T.), Roy, R. (Ritu), Gao, L. (Lu), Annesi-Maesano, I. (Isabella), Jain, P. (Pooja), Plusquin, M. (Michelle), Kogevinas, M. (Manolis), Allard, C. (Catherine), Vehmeijer, F. O. (Florianne O.), Kazmi, N. (Nabila), Salas, L. A. (Lucas A.), Rezwan, F. I. (Faisal I.), Zhang, H. (Hongmei), Sebert, S. (Sylvain), Czamara, D. (Darina), Rifas-Shiman, S. L. (Sheryl L.), Melton, P. E. (Phillip E.), Lawlor, D. A. (Debbie A.), Pershagen, G. (Goran), Breton, C. V. (Carrie V.), Huen, K. (Karen), Baiz, N. (Nour), Gagliardi, L. (Luigi), Nawrot, T. S. (Tim S.), Corpeleijn, E. (Eva), Perron, P. (Patrice), Duijts, L. (Liesbeth), Nohr, E. A. (Ellen Aagaard), Bustamante, M. (Mariona), Ewart, S. L. (Susan L.), Karmaus, W. (Wilfried), Zhao, S. (Shanshan), Page, C. M. (Christian M.), Herceg, Z. (Zdenko), Jarvelin, M.-R. (Marjo-Riitta), Lahti, J. (Jari), Baccarelli, A. A. (Andrea A.), Anderson, D. (Denise), Kachroo, P. (Priyadarshini), Relton, C. L. (Caroline L.), Bergstrom, A. (Anna), Eskenazi, B. (Brenda), Soomro, M. H. (Munawar Hussain), Vineis, P. (Paolo), Snieder, H. (Harold), Bouchard, L. (Luigi), Jaddoe, V. W. (Vincent W.), Sorensen, T. I. (Thorkild I. A.), Vrijheid, M. (Martine), Arshad, S. H. (S. Hasan), Holloway, J. W. (John W.), Haberg, S. E. (Siri E.), Magnus, P. (Per), Dwyer, T. (Terence), Binder, E. B. (Elisabeth B.), DeMeo, D. L. (Dawn L.), Vonk, J. M. (Judith M.), Newnham, J. (John), Tantisira, K. G. (Kelan G.), Kull, I. (Inger), Wiemels, J. L. (Joseph L.), Heude, B. (Barbara), Sunyer, J. (Jordi), Nystad, W. (Wenche), Munthe-Kaas, M. C. (Monica C.), Raikkonen, K. (Katri), Oken, E. (Emily), Huang, R.-C. (Rae-Chi), Weiss, S. T. (Scott T.), Anto, J. M. (Josep Maria), Bousquet, J. (Jean), Kumar, A. (Ashish), Soderhall, C. (Cilla), Almqvist, C. (Catarina), Cardenas, A. (Andres), Gruzieva, O. (Olena), Xu, C.-J. (Cheng-Jian), Reese, S. E. (Sarah E.), Kere, J. (Juha), Brodin, P. (Petter), Solomon, O. (Olivia), Wielscher, M. (Matthias), Holland, N. (Nina), Ghantous, A. (Akram), Hivert, M.-F. (Marie-France), Felix, J. F. (Janine F.), Koppelman, G. H. (Gerard H.), London, S. J. (Stephanie J.), Melen, E. (Erik), Merid, S. K. (Simon Kebede), Novoloaca, A. (Alexei), Sharp, G. C. (Gemma C.), Kupers, L. K. (Leanne K.), Kho, A. T. (Alvin T.), Roy, R. (Ritu), Gao, L. (Lu), Annesi-Maesano, I. (Isabella), Jain, P. (Pooja), Plusquin, M. (Michelle), Kogevinas, M. (Manolis), Allard, C. (Catherine), Vehmeijer, F. O. (Florianne O.), Kazmi, N. (Nabila), Salas, L. A. (Lucas A.), Rezwan, F. I. (Faisal I.), Zhang, H. (Hongmei), Sebert, S. (Sylvain), Czamara, D. (Darina), Rifas-Shiman, S. L. (Sheryl L.), Melton, P. E. (Phillip E.), Lawlor, D. A. (Debbie A.), Pershagen, G. (Goran), Breton, C. V. (Carrie V.), Huen, K. (Karen), Baiz, N. (Nour), Gagliardi, L. (Luigi), Nawrot, T. S. (Tim S.), Corpeleijn, E. (Eva), Perron, P. (Patrice), Duijts, L. (Liesbeth), Nohr, E. A. (Ellen Aagaard), Bustamante, M. (Mariona), Ewart, S. L. (Susan L.), Karmaus, W. (Wilfried), Zhao, S. (Shanshan), Page, C. M. (Christian M.), Herceg, Z. (Zdenko), Jarvelin, M.-R. (Marjo-Riitta), Lahti, J. (Jari), Baccarelli, A. A. (Andrea A.), Anderson, D. (Denise), Kachroo, P. (Priyadarshini), Relton, C. L. (Caroline L.), Bergstrom, A. (Anna), Eskenazi, B. (Brenda), Soomro, M. H. (Munawar Hussain), Vineis, P. (Paolo), Snieder, H. (Harold), Bouchard, L. (Luigi), Jaddoe, V. W. (Vincent W.), Sorensen, T. I. (Thorkild I. A.), Vrijheid, M. (Martine), Arshad, S. H. (S. Hasan), Holloway, J. W. (John W.), Haberg, S. E. (Siri E.), Magnus, P. (Per), Dwyer, T. (Terence), Binder, E. B. (Elisabeth B.), DeMeo, D. L. (Dawn L.), Vonk, J. M. (Judith M.), Newnham, J. (John), Tantisira, K. G. (Kelan G.), Kull, I. (Inger), Wiemels, J. L. (Joseph L.), Heude, B. (Barbara), Sunyer, J. (Jordi), Nystad, W. (Wenche), Munthe-Kaas, M. C. (Monica C.), Raikkonen, K. (Katri), Oken, E. (Emily), Huang, R.-C. (Rae-Chi), Weiss, S. T. (Scott T.), Anto, J. M. (Josep Maria), Bousquet, J. (Jean), Kumar, A. (Ashish), Soderhall, C. (Cilla), Almqvist, C. (Catarina), Cardenas, A. (Andres), Gruzieva, O. (Olena), Xu, C.-J. (Cheng-Jian), Reese, S. E. (Sarah E.), Kere, J. (Juha), Brodin, P. (Petter), Solomon, O. (Olivia), Wielscher, M. (Matthias), Holland, N. (Nina), Ghantous, A. (Akram), Hivert, M.-F. (Marie-France), Felix, J. F. (Janine F.), Koppelman, G. H. (Gerard H.), London, S. J. (Stephanie J.), and Melen, E. (Erik)

Abstract

Background: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods: We performed meta-analysis of Illumina’s HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4–18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27–42 weeks), at Bonferroni significance, P < 1.06 × 10⁻⁷, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.

Published
2020

19. HLA-DQ strikes again: Genome-wide association study further confirms HLA-DQ in the diagnosis of asthma among adults

Author

Lasky-Su, J., Himes, B. E., Raby, B. A., Klanderman, B. J., Sylvia, Senter J., Lange, C., Melen, E., Martinez, F. D., Israel, E., Gauderman, J., Gilliland, F., Sleiman, P., Hakonarson, H., Celedón, J. C., Soto-Quiros, M., Avila, L., Lima, J. J., Irvin, C. G., Peters, S. P., Boushey, H., Chinchilli, V. M., Mauger, D., Tantisira, K., and Weiss, S. T.

Published
2012
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24. 17q21 variant increases the risk of exacerbations in asthmatic children despite inhaled corticosteroids use

Author

Farzan, N, Vijverberg, S J, Hernandez-Pacheco, N, Bel, E H D, Berce, V, Bønnelykke, K, Bisgaard, H, Burchard, E G, Canino, G, Celedón, J C, Chew, F T, Chiang, W C, Cloutier, M M, Forno, E, Francis, B, Hawcutt, D B, Herrera-Luis, E, Kabesch, M, Karimi, L, Melén, E, Mukhopadhyay, S, Merid, S K, Palmer, C N, Pino-Yanes, M, Pirmohamed, M, Potočnik, U, Repnik, K, Schieck, M, Sevelsted, A, Sio, Y Y, Smyth, R L, Soares, P, Söderhäll, C, Tantisira, K G, Tavendale, R, Tse, S M, Turner, S, Verhamme, K M, Maitland-van der Zee, A-H, Afd Pharmacoepi & Clinical Pharmacology, and Pharmacoepidemiology and Clinical Pharmacology

Published
2018

25. [Letter to the Editor] 17q21 variant increases the risk of exacerbations in asthmatic children despite inhaled corticosteroids use

Author

Farzan, N, Vijverberg, S J, Hernandez‐Pacheco, N, Bel, E H D, Berce, V, Bønnelykke, K, Bisgaard, H, Burchard, E G, Canino, G, Celedón, J C, Chew, F T, Chiang, W C, Cloutier, M M, Forno, E, Francis, B, Hawcutt, D B, Herrera‐Luis, E, Kabesch, M, Karimi, L, Melén, E, Mukhopadhyay, S, Merid, S K, Palmer, C N, Pirmohamed, M, Potočnik, U, Repnik, K, Schieck, M, Sevelsted, A, Yie Sio, Y, Smyth, R L, Soares, P, Söderhäll, C, Tantisira, K, Tavendale, R, Man Tse, S, Turner, S, Verhamme, K.M, and Maitland‐van der Zee, A-K

Subjects
RJ
Published
2018

26. A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis

Author

Dahlin, A., Lu, Q., Himes, B.E., Randell, S.H., Israel, E., Kan, M., Weiss, S.T., Sun, M., Wu, A.C., Tantisira, K., Panganiban, R.A., Shore, S., Iribarren, C., Park, H.-R., Park, J.-A., Jorgenson, E., and Mitchel, J.A.

Abstract

Background: Genetic variants in the chromosomal region 17q21 are consistently associated with asthma. However, mechanistic studies have not yet linked any of the associated variants to a function that could influence asthma, and as a result, the identity of the asthma gene(s) remains elusive. Objectives: We sought to identify and characterize functional variants in the 17q21 locus. Methods: We used the Exome Aggregation Consortium browser to identify coding (amino acid–changing) variants in the 17q21 locus. We obtained asthma association measures for these variants in both the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort (16,274 cases and 38,269 matched controls) and the EVE Consortium study (5,303 asthma cases and 12,560 individuals). Gene expression and protein localization were determined by quantitative RT-PCR and fluorescence immunostaining, respectively. Molecular and cellular studies were performed to determine the functional effects of coding variants. Results: Two coding variants (rs2305480 and rs11078928) of the gasdermin B (GSDMB) gene in the 17q21 locus were associated with lower asthma risk in both GERA (odds ratio, 0.92; P = 1.01 × 10−6) and EVE (odds ratio, 0.85; joint PEVE = 1.31 × 10−13). In GERA, rs11078928 had a minor allele frequency (MAF) of 0.45 in unaffected (nonasthmatic) controls and 0.43 in asthma cases. For European Americans in EVE, the MAF of rs2305480 was 0.45 for controls and 0.39 for cases; for all EVE subjects, the MAF was 0.32 for controls and 0.27 for cases. GSDMB is highly expressed in differentiated airway epithelial cells, including the ciliated cells. We found that, when the GSDMB protein is cleaved by inflammatory caspase-1 to release its N-terminal fragment, potent pyroptotic cell death is induced. The splice variant rs11078928 deletes the entire exon 6, which encodes 13 amino acids in the critical N-terminus, and abolishes the pyroptotic activity of the GSDMB protein. Conclusions: Our study identified a functional asthma variant in the GSDMB gene of the 17q21 locus and implicates GSDMB-mediated epithelial cell pyroptosis in pathogenesis.

Published
2018
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27. 17q21 variant increases the risk of exacerbations in asthmatic children despite inhaled corticosteroids use

Author

Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Farzan, N, Vijverberg, S J, Hernandez-Pacheco, N, Bel, E H D, Berce, V, Bønnelykke, K, Bisgaard, H, Burchard, E G, Canino, G, Celedón, J C, Chew, F T, Chiang, W C, Cloutier, M M, Forno, E, Francis, B, Hawcutt, D B, Herrera-Luis, E, Kabesch, M, Karimi, L, Melén, E, Mukhopadhyay, S, Merid, S K, Palmer, C N, Pino-Yanes, M, Pirmohamed, M, Potočnik, U, Repnik, K, Schieck, M, Sevelsted, A, Sio, Y Y, Smyth, R L, Soares, P, Söderhäll, C, Tantisira, K G, Tavendale, R, Tse, S M, Turner, S, Verhamme, K M, Maitland-van der Zee, A-H, Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Farzan, N, Vijverberg, S J, Hernandez-Pacheco, N, Bel, E H D, Berce, V, Bønnelykke, K, Bisgaard, H, Burchard, E G, Canino, G, Celedón, J C, Chew, F T, Chiang, W C, Cloutier, M M, Forno, E, Francis, B, Hawcutt, D B, Herrera-Luis, E, Kabesch, M, Karimi, L, Melén, E, Mukhopadhyay, S, Merid, S K, Palmer, C N, Pino-Yanes, M, Pirmohamed, M, Potočnik, U, Repnik, K, Schieck, M, Sevelsted, A, Sio, Y Y, Smyth, R L, Soares, P, Söderhäll, C, Tantisira, K G, Tavendale, R, Tse, S M, Turner, S, Verhamme, K M, and Maitland-van der Zee, A-H

Published
2018

28. 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

29. 17q21 variant increases the risk of exacerbations in asthmatic children despite inhaled corticosteroids use

Author

Farzan, N., primary, Vijverberg, S. J., additional, Hernandez‐Pacheco, N., additional, Bel, E. H. D., additional, Berce, V., additional, Bønnelykke, K., additional, Bisgaard, H., additional, Burchard, E. G., additional, Canino, G., additional, Celedón, J. C., additional, Chew, F. T., additional, Chiang, W. C., additional, Cloutier, M. M., additional, Forno, E., additional, Francis, B., additional, Hawcutt, D. B., additional, Herrera‐Luis, E., additional, Kabesch, M., additional, Karimi, L., additional, Melén, E., additional, Mukhopadhyay, S., additional, Merid, S. K., additional, Palmer, C. N., additional, Pino‐Yanes, M., additional, Pirmohamed, M., additional, Potočnik, U., additional, Repnik, K., additional, Schieck, M., additional, Sevelsted, A., additional, Sio, Y. Y., additional, Smyth, R. L., additional, Soares, P., additional, Söderhäll, C., additional, Tantisira, K. G., additional, Tavendale, R., additional, Tse, S. M., additional, Turner, S., additional, Verhamme, K. M., additional, and Maitland‐van der Zee, A.‐H., additional

Published
2018
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31. ST13 polymorphisms and their effect on exacerbations in steroid-treated asthmatic children and young adults

Author

Sub Pharmacoepidemiology, UIPS - Utrecht Institute for Pharmaceutical Sciences, Pharmacoepidemiology and Clinical Pharmacology, Vijverberg, S. J H, Koster, E. S., Tavendale, R., Leusink, M., Koenderman, L., Raaijmakers, J. A M, Postma, D. S., Koppelman, G. H., Turner, S. W., Mukhopadhyay, S., Tse, S. M., Tantisira, K. G., Hawcutt, D. B., Francis, B., Pirmohamed, M., Pino-Yanes, M., Eng, C., Burchard, E. G., Palmer, C. N A, Maitland-van der Zee, Anke Hilse, Sub Pharmacoepidemiology, UIPS - Utrecht Institute for Pharmaceutical Sciences, Pharmacoepidemiology and Clinical Pharmacology, Vijverberg, S. J H, Koster, E. S., Tavendale, R., Leusink, M., Koenderman, L., Raaijmakers, J. A M, Postma, D. S., Koppelman, G. H., Turner, S. W., Mukhopadhyay, S., Tse, S. M., Tantisira, K. G., Hawcutt, D. B., Francis, B., Pirmohamed, M., Pino-Yanes, M., Eng, C., Burchard, E. G., Palmer, C. N A, and Maitland-van der Zee, Anke Hilse

Published
2015

32. ST13 polymorphisms and their effect on exacerbations in steroid-treated asthmatic children and young adults

Author

Experimentele Afdeling Longziekten, Cancer, Infection & Immunity, Vijverberg, S. J. H., Koster, E. S., Tavendale, R., Leusink, M., Koenderman, L., Raaijmakers, J. A. M., Postma, D. S., Koppelman, G. H., Turner, S. W., Mukhopadhyay, S., Tse, S. M., Tantisira, K. G., Hawcutt, D. B., Francis, B., Pirmohamed, M., Pino-Yanes, M., Eng, C., Burchard, E. G., Palmer, C. N. A., Maitland-van der Zee, A. H., Experimentele Afdeling Longziekten, Cancer, Infection & Immunity, Vijverberg, S. J. H., Koster, E. S., Tavendale, R., Leusink, M., Koenderman, L., Raaijmakers, J. A. M., Postma, D. S., Koppelman, G. H., Turner, S. W., Mukhopadhyay, S., Tse, S. M., Tantisira, K. G., Hawcutt, D. B., Francis, B., Pirmohamed, M., Pino-Yanes, M., Eng, C., Burchard, E. G., Palmer, C. N. A., and Maitland-van der Zee, A. H.

Published
2015

34. ST13polymorphisms and their effect on exacerbations in steroid-treated asthmatic children and young adults

Author

Vijverberg, S. J. H., primary, Koster, E. S., additional, Tavendale, R., additional, Leusink, M., additional, Koenderman, L., additional, Raaijmakers, J. A. M., additional, Postma, D. S., additional, Koppelman, G. H., additional, Turner, S. W., additional, Mukhopadhyay, S., additional, Tse, S. M., additional, Tantisira, K. G., additional, Hawcutt, D. B., additional, Francis, B., additional, Pirmohamed, M., additional, Pino-Yanes, M., additional, Eng, C., additional, Burchard, E. G., additional, Palmer, C. N. A., additional, and Maitland-van der Zee, A. H., additional

Published
2015
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35. A genome-wide association study of bronchodilator response in asthmatics

Author

Duan, Q L, primary, Lasky-Su, J, additional, Himes, B E, additional, Qiu, W, additional, Litonjua, A A, additional, Damask, A, additional, Lazarus, R, additional, Klanderman, B, additional, Irvin, C G, additional, Peters, S P, additional, Hanrahan, J P, additional, Lima, J J, additional, Martinez, F D, additional, Mauger, D, additional, Chinchilli, V M, additional, Soto-Quiros, M, additional, Avila, L, additional, Celedón, J C, additional, Lange, C, additional, Weiss, S T, additional, and Tantisira, K G, additional

Published
2013
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45. Effect of vitamin D and inhaled corticosteroid treatment on lung function in children.

Author

Wu AC, Tantisira K, Li L, Fuhlbrigge AL, Weiss ST, Litonjua A, Childhood Asthma Management Program Research Group, Wu, Ann Chen, Tantisira, Kelan, Li, Lingling, Fuhlbrigge, Anne L, Weiss, Scott T, and Litonjua, Augusto

Abstract

Rationale: Low vitamin D levels are associated with asthma and decreased airway responsiveness. Treatment with inhaled corticosteroids improves airway responsiveness and asthma control.Objectives: To assess the effect of vitamin D levels on prebronchodilator FEV(1), bronchodilator response, and responsiveness to methacholine (PC(20), provocative concentration of methacholine producing a 20% decline in FEV(1)) in patients with asthma treated with inhaled corticosteroids.Methods: We measured 25-hydroxyvitamin D levels in the serum of children with persistent asthma at the time of enrollment in the Childhood Asthma Management Program. We divided subjects into the vitamin D sufficiency (>30 ng/ml), insufficiency (20-30 ng/ml), and deficiency (<20 ng/ml) groups. Covariates included age, treatment, sex, body mass index, race, history of emergency department visits, hospitalizations, and season that vitamin D specimen was drawn. Our main outcome measures were change in prebronchodilator FEV(1), bronchodilator response, and PC(20) from enrollment to 8-12 months.Measurements and Main Results: Of the 1,024 subjects, 663 (65%) were vitamin D sufficient, 260 (25%) were insufficient, and 101 (10%) were deficient. Vitamin D-deficient subjects were more likely to be older, African American, and have a higher body mass index compared with the vitamin D-sufficient and insufficient subjects. In the inhaled corticosteroid treatment group, prebronchodilator FEV(1) increased from randomization to 12 months by 140 ml in the vitamin D-deficient group and prebronchodilator FEV(1) increased by 330 ml in the vitamin D insufficiency group and by 290 ml in the vitamin D sufficiency group (P = 0.0072), in adjusted models.Conclusions: In children with asthma treated with inhaled corticosteroids, vitamin D deficiency is associated with poorer lung function than in children with vitamin D insufficiency or sufficiency. [ABSTRACT FROM AUTHOR]

Published
2012

46. A role for Wnt signaling genes in the pathogenesis of impaired lung function in asthma.

Author

Sharma S, Tantisira K, Carey V, Murphy AJ, Lasky-Su J, Celedón JC, Lazarus R, Klanderman B, Rogers A, Soto-Quirós M, Avila L, Mariani T, Gaedigk R, Leeder S, Torday J, Warburton D, Raby B, Weiss ST, Sharma, Sunita, and Tantisira, Kelan

Abstract

Rationale: Animal models demonstrate that aberrant gene expression in utero can result in abnormal pulmonary phenotypes.Objectives: We sought to identify genes that are differentially expressed during in utero airway development and test the hypothesis that variants in these genes influence lung function in patients with asthma.Methods: Stage 1 (Gene Expression): Differential gene expression analysis across the pseudoglandular (n = 27) and canalicular (n = 9) stages of human lung development was performed using regularized t tests with multiple comparison adjustments. Stage 2 (Genetic Association): Genetic association analyses of lung function (FEV(1), FVC, and FEV(1)/FVC) for variants in five differentially expressed genes were conducted in 403 parent-child trios from the Childhood Asthma Management Program (CAMP). Associations were replicated in 583 parent-child trios from the Genetics of Asthma in Costa Rica study.Measurements and Main Results: Of the 1,776 differentially expressed genes between the pseudoglandular (gestational age: 7-16 wk) and the canalicular (gestational age: 17-26 wk) stages, we selected 5 genes in the Wnt pathway for association testing. Thirteen single nucleotide polymorphisms in three genes demonstrated association with lung function in CAMP (P < 0.05), and associations for two of these genes were replicated in the Costa Ricans: Wnt1-inducible signaling pathway protein 1 with FEV(1) (combined P = 0.0005) and FVC (combined P = 0.0004), and Wnt inhibitory factor 1 with FVC (combined P = 0.003) and FEV(1)/FVC (combined P = 0.003).Conclusions: Wnt signaling genes are associated with impaired lung function in two childhood asthma cohorts. Furthermore, gene expression profiling of human fetal lung development can be used to identify genes implicated in the pathogenesis of lung function impairment in individuals with asthma. [ABSTRACT FROM AUTHOR]

Published
2010
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47. Sequence, haplotype, and association analysis of ADRbeta2 in a multiethnic asthma case-control study.

Author

Hawkins GA, Tantisira K, Meyers DA, Ampleford EJ, Moore WC, Klanderman B, Liggett SB, Peters SP, Weiss ST, Bleecker ER, Hawkins, Gregory A, Tantisira, Kelan, Meyers, Deborah A, Ampleford, Elizabeth J, Moore, Wendy C, Klanderman, Barbara, Liggett, Stephen B, Peters, Stephen P, Weiss, Scott T, and Bleecker, Eugene R

Abstract

Rationale: The comprehensive evaluation of gene variation, haplotype structure, and linkage disequilibrium is important in understanding the function of beta2-adrenergic receptor gene (ADRbeta2) on disease susceptibility, pulmonary function, and therapeutic responses in different ethnic groups with asthma.Objectives: To identify ADRbeta2 polymorphisms and haplotype structure in white and African American subjects and to test for genotype and haplotype association with asthma phenotypes.Methods: A 5.3-kb region of ADRbeta2 was resequenced in 669 individuals from 429 whites and 240 African Americans. A total of 12 polymorphisms, representing an optimal haplotype tagging set, were genotyped in whites (338 patients and 326 control subjects) and African Americans (222 patients and 299 control subjects).Results: A total of 49 polymorphisms were identified, 21 of which are novel; 31 polymorphisms (frequency > 0.03) were used to identify 24 haplotypes (frequency > 0.01) and assess linkage disequilibrium. Association with ratio (FEV1/FVC)2 for single-nucleotide polymorphism +79 (p < 0.05) was observed in African Americans. Significant haplotype association for (FEV1/FVC)2 was also observed in African Americans.Conclusions: There are additional genetic variants besides +46 (Gly16Arg) that are important in determining asthma phenotypes. These data suggest that the length of a poly-C repeat (+1269) in the 3' untranslated region of ADRbeta2 may influence lung function, and may be important in delineating variation in beta-agonist responses, especially in African Americans. [ABSTRACT FROM AUTHOR]

Published
2006
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48. T-bet polymorphisms are associated with asthma and airway hyperresponsiveness.

Author

Raby BA, Hwang E, Van Steen K, Tantisira K, Peng S, Litonjua A, Lazarus R, Giallourakis C, Rioux JD, Sparrow D, Silverman EK, Glimcher LH, Weiss ST, Raby, Benjamin A, Hwang, Eun-Sook, Van Steen, Kristel, Tantisira, Kelan, Peng, Stanford, Litonjua, Augusto, and Lazarus, Ross

Abstract

Rationale: T-bet (TBX21 or T-box 21) is a critical regulator of T-helper 1 lineage commitment and IFN-gamma production. Knockout mice lacking T-bet develop airway hyperresponsiveness (AHR) to methacholine, peribronchial eosinophilic and lymphocytic inflammation, and increased type III collagen deposition below the bronchial epithelium basement membrane, reminiscent of both acute and chronic asthma histopathology. Little is known regarding the role of genetic variation surrounding T-bet in the development of human AHR.Objectives: To assess the relationship between T-bet polymorphisms and asthma-related phenotypes using family-based association.Methods: Single nucleotide polymorphism discovery was performed by resequencing the T-bet genomic locus in 30 individuals (including 22 patients with asthma). Sixteen variants were genotyped in 580 nuclear families ascertained through offspring with asthma from the Childhood Asthma Management Program clinical trial. Haplotype patterns were determined from this genotype data. Family-based tests of association were performed with asthma, AHR, lung function, total serum immunoglobulin E, and blood eosinophil levels.Main Results: We identified 24 variants. Evidence of association was observed between c.-7947 and asthma in white families using both additive (p = 0.02) or dominant models (p = 0.006). c.-7947 and three other variants were also associated with AHR (log-methacholine PC(20), p = 0.02-0.04). Haplotype analysis suggested that an AHR locus is in linkage disequilibrium with variants in the 3'UTR. Evidence of association of AHR with c.-7947, but not with other 3'UTR SNPs, was replicated in an independent cohort of adult males with AHR.Conclusions: These data suggest that T-bet variation contributes to airway responsiveness in asthma. [ABSTRACT FROM AUTHOR]

Published
2006
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49. Mechanical forces induce an asthma gene signature in healthy airway epithelial cells

Author

Drazen, J.M., Kho, A.T., Fredberg, J.J., Randell, S.H., Kılıç, A., Park, J.-A., Cheng, F., Tantisira, K., De Marzio, M., Mitchel, J.A., Weiss, S.T., Santolini, M., McGill, M., Sharma, A., Ameli, A., and O'Sullivan, M.J.

Subjects
3. Good health
Abstract

Bronchospasm compresses the bronchial epithelium, and this compressive stress has been implicated in asthma pathogenesis. However, the molecular mechanisms by which this compressive stress alters pathways relevant to disease are not well understood. Using air-liquid interface cultures of primary human bronchial epithelial cells derived from non-asthmatic donors and asthmatic donors, we applied a compressive stress and then used a network approach to map resulting changes in the molecular interactome. In cells from non-asthmatic donors, compression by itself was sufficient to induce inflammatory, late repair, and fibrotic pathways. Remarkably, this molecular profile of non-asthmatic cells after compression recapitulated the profile of asthmatic cells before compression. Together, these results show that even in the absence of any inflammatory stimulus, mechanical compression alone is sufficient to induce an asthma-like molecular signature.

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