Longitudinal analysis of bronchodilator response in asthmatics and effect modification of age-related trends by genotype
Joanne E Sordillo, Michael McGeachie, Sharon M Lutz, Jessica Lasky-Su, Kelan Tantisira, Ching Hui Tsai, Amber Dahlin, Rachel Kelly, Ann Chen Wu, Joanne E Sordillo, Michael McGeachie, Sharon M Lutz, Jessica Lasky-Su, Kelan Tantisira, Ching Hui Tsai, Amber Dahlin, Rachel Kelly, Ann Chen Wu
Abstract
Background and objectives: Genome Wide Association Studies (GWAS) have identified genetic polymorphisms associated with bronchodilator response (BDR), but it is unknown how these associations change across life stages. We examined the impact of genetic variants on BDR from childhood to adulthood in asthmatics to uncover potential effect modification by age.
Methods: We searched the National Human Genome Research Institute (NHGRI) catalog of published GWAS to obtain a list of genetic associations with BDR, and tested them for effect modification by age in 604 subjects from the Childhood Asthma Management Program (CAMP), a clinical trial with longitudinal measures of BDR (age range 5-30 years). We performed longitudinal analyses using linear mixed models and visualized longitudinal changes in BDR using generalized additive models with repeated measures, adjusting for treatment group, sex, and main effects of age and additive genotype.
Results: Increasing age was associated with decreased BDR (-0.24% per year). Polymorphisms rs295137 (T allele) near SPATS2L and rs2626393 (C allele) near ASB3 demonstrated their strongest associations with BDR in early childhood through adolescence, with a large decrease in their magnitude of effect from adolescence onward. The effect estimate for % BDR associated with rs295137 genotype (Beta = 1.3; 95%CI 0.6-2.1) was diminished by age (interaction term = -0.06, P = 0.004). The effect estimate for rs2626393 (Beta = -0.92 (95%CI -1.7 to -0.2) was also modified by age (interaction term = 0.05, P = 0.0004).
Conclusions: Polymorphisms associated with BDR in childhood may not be relevant for predicting adolescent and adult BDR, which could reflect age-related changes in asthma phenotypes.
Trial registration: ClinicalTrials.gov NCT00000575.
Keywords: age; asthma; bronchodilator response.
Conflict of interest statement
Conflict of Interest Statement: The authors have no conflicts of interest.
© 2018 Wiley Periodicals, Inc.
Figures
Figure 2.
Longitudinal BDR response by SPATS2L…
Figure 2.
Longitudinal BDR response by SPATS2L (rs295137) genotype. (a-c) Centered smooths adjusted for age,…
Figure 3.
Longitudinal BDR response by ASB3…
Figure 3.
Longitudinal BDR response by ASB3 (rs2626393) genotype. (a-c) Centered smooths for longitudinal BDR…
- Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene.Himes BE, Jiang X, Hu R, Wu AC, Lasky-Su JA, Klanderman BJ, Ziniti J, Senter-Sylvia J, Lima JJ, Irvin CG, Peters SP, Meyers DA, Bleecker ER, Kubo M, Tamari M, Nakamura Y, Szefler SJ, Lemanske RF Jr, Zeiger RS, Strunk RC, Martinez FD, Hanrahan JP, Koppelman GH, Postma DS, Nieuwenhuis MA, Vonk JM, Panettieri RA Jr, Markezich A, Israel E, Carey VJ, Tantisira KG, Litonjua AA, Lu Q, Weiss ST. Himes BE, et al. PLoS Genet. 2012 Jul;8(7):e1002824. doi: 10.1371/journal.pgen.1002824. Epub 2012 Jul 5. PLoS Genet. 2012. PMID: 22792082 Free PMC article.
- A genome-wide association study of bronchodilator response in Latinos implicates rare variants.Drake KA, Torgerson DG, Gignoux CR, Galanter JM, Roth LA, Huntsman S, Eng C, Oh SS, Yee SW, Lin L, Bustamante CD, Moreno-Estrada A, Sandoval K, Davis A, Borrell LN, Farber HJ, Kumar R, Avila PC, Brigino-Buenaventura E, Chapela R, Ford JG, Lenoir MA, Lurmann F, Meade K, Serebrisky D, Thyne S, Rodríguez-Cintrón W, Sen S, Rodríguez-Santana JR, Hernandez RD, Giacomini KM, Burchard EG. Drake KA, et al. J Allergy Clin Immunol. 2014 Feb;133(2):370-8. doi: 10.1016/j.jaci.2013.06.043. Epub 2013 Aug 29. J Allergy Clin Immunol. 2014. PMID: 23992748 Free PMC article.
- Stress and Bronchodilator Response in Children with Asthma.Brehm JM, Ramratnam SK, Tse SM, Croteau-Chonka DC, Pino-Yanes M, Rosas-Salazar C, Litonjua AA, Raby BA, Boutaoui N, Han YY, Chen W, Forno E, Marsland AL, Nugent NR, Eng C, Colón-Semidey A, Alvarez M, Acosta-Pérez E, Spear ML, Martinez FD, Avila L, Weiss ST, Soto-Quiros M, Ober C, Nicolae DL, Barnes KC, Lemanske RF Jr, Strunk RC, Liu A, London SJ, Gilliland F, Sleiman P, March M, Hakonarson H, Duan QL, Kolls JK, Fritz GK, Hu D, Fani N, Stevens JS, Almli LM, Burchard EG, Shin J, McQuaid EL, Ressler K, Canino G, Celedón JC. Brehm JM, et al. Am J Respir Crit Care Med. 2015 Jul 1;192(1):47-56. doi: 10.1164/rccm.201501-0037OC. Am J Respir Crit Care Med. 2015. PMID: 25918834 Free PMC article.
- A genome-wide association study of bronchodilator response in asthmatics.Duan QL, Lasky-Su J, Himes BE, Qiu W, Litonjua AA, Damask A, Lazarus R, Klanderman B, Irvin CG, Peters SP, Hanrahan JP, Lima JJ, Martinez FD, Mauger D, Chinchilli VM, Soto-Quiros M, Avila L, Celedón JC, Lange C, Weiss ST, Tantisira KG. Duan QL, et al. Pharmacogenomics J. 2014 Feb;14(1):41-7. doi: 10.1038/tpj.2013.5. Epub 2013 Mar 19. Pharmacogenomics J. 2014. PMID: 23508266 Free PMC article.
- Genome-wide association study of short-acting β2-agonists. A novel genome-wide significant locus on chromosome 2 near ASB3.Israel E, Lasky-Su J, Markezich A, Damask A, Szefler SJ, Schuemann B, Klanderman B, Sylvia J, Kazani S, Wu R, Martinez F, Boushey HA, Chinchilli VM, Mauger D, Weiss ST, Tantisira KG; SHARP Investigators. Israel E, et al. Am J Respir Crit Care Med. 2015 Mar 1;191(5):530-7. doi: 10.1164/rccm.201408-1426OC. Am J Respir Crit Care Med. 2015. PMID: 25562107 Free PMC article.
- Pharmacogenetics of Bronchodilator Response: Future Directions.Sordillo JE, Kelly RS, Lutz SM, Lasky-Su J, Wu AC. Sordillo JE, et al. Curr Allergy Asthma Rep. 2021 Dec 27;21(12):47. doi: 10.1007/s11882-021-01023-w. Curr Allergy Asthma Rep. 2021. PMID: 34958416 Free PMC article. Review.
- Pharmaco-Metabolomics of Inhaled Corticosteroid Response in Individuals with Asthma.Kachroo P, Sordillo JE, Lutz SM, Weiss ST, Kelly RS, McGeachie MJ, Wu AC, Lasky-Su JA. Kachroo P, et al. J Pers Med. 2021 Nov 4;11(11):1148. doi: 10.3390/jpm11111148. J Pers Med. 2021. PMID: 34834499 Free PMC article.
- Genetic Determinants of Poor Response to Treatment in Severe Asthma.Figueiredo RG, Costa RS, Figueiredo CA, Cruz AA. Figueiredo RG, et al. Int J Mol Sci. 2021 Apr 20;22(8):4251. doi: 10.3390/ijms22084251. Int J Mol Sci. 2021. PMID: 33923891 Free PMC article. Review.
- Single Nucleotide Polymorphisms (SNPs) in PRKG1 & SPATA13-AS1 are associated with bronchodilator response: a pilot study during acute asthma exacerbations in African American children.Fishe JN, Labilloy G, Higley R, Casey D, Ginn A, Baskovich B, Blake KV. Fishe JN, et al. Pharmacogenet Genomics. 2021 Sep 1;31(7):146-154. doi: 10.1097/FPC.0000000000000434. Pharmacogenet Genomics. 2021. PMID: 33851947 Free PMC article. Review.
- The Role of SNP Interactions when Determining Independence of Novel Signals in Genetic Association Studies-An Application to ARG1 and Bronchodilator Response.Walsh R, Voorhies K, McDonald ML, McGeachie M, Sordillo JE, Lange C, Wu AC, Lutz SM. Walsh R, et al. J Pers Med. 2021 Feb 19;11(2):145. doi: 10.3390/jpm11020145. J Pers Med. 2021. PMID: 33669563 Free PMC article.
- Randomized Controlled Trial
- Adolescent
- Adult
- Aging / genetics
- Asthma / drug therapy*
- Asthma / epidemiology
- Asthma / genetics*
- Bronchodilator Agents / therapeutic use*
- Child
- Child, Preschool
- Effect Modifier, Epidemiologic
- Female
- Genome-Wide Association Study
- Genotype
- Humans
- Male
- Treatment Outcome
- Young Adult
- Bronchodilator Agents
- ClinicalTrials.gov/NCT00000575
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Figure 3.
Longitudinal BDR response by ASB3…
Figure 3.
Longitudinal BDR response by ASB3 (rs2626393) genotype. (a-c) Centered smooths for longitudinal BDR…
- Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene.Himes BE, Jiang X, Hu R, Wu AC, Lasky-Su JA, Klanderman BJ, Ziniti J, Senter-Sylvia J, Lima JJ, Irvin CG, Peters SP, Meyers DA, Bleecker ER, Kubo M, Tamari M, Nakamura Y, Szefler SJ, Lemanske RF Jr, Zeiger RS, Strunk RC, Martinez FD, Hanrahan JP, Koppelman GH, Postma DS, Nieuwenhuis MA, Vonk JM, Panettieri RA Jr, Markezich A, Israel E, Carey VJ, Tantisira KG, Litonjua AA, Lu Q, Weiss ST. Himes BE, et al. PLoS Genet. 2012 Jul;8(7):e1002824. doi: 10.1371/journal.pgen.1002824. Epub 2012 Jul 5. PLoS Genet. 2012. PMID: 22792082 Free PMC article.
- A genome-wide association study of bronchodilator response in Latinos implicates rare variants.Drake KA, Torgerson DG, Gignoux CR, Galanter JM, Roth LA, Huntsman S, Eng C, Oh SS, Yee SW, Lin L, Bustamante CD, Moreno-Estrada A, Sandoval K, Davis A, Borrell LN, Farber HJ, Kumar R, Avila PC, Brigino-Buenaventura E, Chapela R, Ford JG, Lenoir MA, Lurmann F, Meade K, Serebrisky D, Thyne S, Rodríguez-Cintrón W, Sen S, Rodríguez-Santana JR, Hernandez RD, Giacomini KM, Burchard EG. Drake KA, et al. J Allergy Clin Immunol. 2014 Feb;133(2):370-8. doi: 10.1016/j.jaci.2013.06.043. Epub 2013 Aug 29. J Allergy Clin Immunol. 2014. PMID: 23992748 Free PMC article.
- Stress and Bronchodilator Response in Children with Asthma.Brehm JM, Ramratnam SK, Tse SM, Croteau-Chonka DC, Pino-Yanes M, Rosas-Salazar C, Litonjua AA, Raby BA, Boutaoui N, Han YY, Chen W, Forno E, Marsland AL, Nugent NR, Eng C, Colón-Semidey A, Alvarez M, Acosta-Pérez E, Spear ML, Martinez FD, Avila L, Weiss ST, Soto-Quiros M, Ober C, Nicolae DL, Barnes KC, Lemanske RF Jr, Strunk RC, Liu A, London SJ, Gilliland F, Sleiman P, March M, Hakonarson H, Duan QL, Kolls JK, Fritz GK, Hu D, Fani N, Stevens JS, Almli LM, Burchard EG, Shin J, McQuaid EL, Ressler K, Canino G, Celedón JC. Brehm JM, et al. Am J Respir Crit Care Med. 2015 Jul 1;192(1):47-56. doi: 10.1164/rccm.201501-0037OC. Am J Respir Crit Care Med. 2015. PMID: 25918834 Free PMC article.
- A genome-wide association study of bronchodilator response in asthmatics.Duan QL, Lasky-Su J, Himes BE, Qiu W, Litonjua AA, Damask A, Lazarus R, Klanderman B, Irvin CG, Peters SP, Hanrahan JP, Lima JJ, Martinez FD, Mauger D, Chinchilli VM, Soto-Quiros M, Avila L, Celedón JC, Lange C, Weiss ST, Tantisira KG. Duan QL, et al. Pharmacogenomics J. 2014 Feb;14(1):41-7. doi: 10.1038/tpj.2013.5. Epub 2013 Mar 19. Pharmacogenomics J. 2014. PMID: 23508266 Free PMC article.
- Genome-wide association study of short-acting β2-agonists. A novel genome-wide significant locus on chromosome 2 near ASB3.Israel E, Lasky-Su J, Markezich A, Damask A, Szefler SJ, Schuemann B, Klanderman B, Sylvia J, Kazani S, Wu R, Martinez F, Boushey HA, Chinchilli VM, Mauger D, Weiss ST, Tantisira KG; SHARP Investigators. Israel E, et al. Am J Respir Crit Care Med. 2015 Mar 1;191(5):530-7. doi: 10.1164/rccm.201408-1426OC. Am J Respir Crit Care Med. 2015. PMID: 25562107 Free PMC article.
- Pharmacogenetics of Bronchodilator Response: Future Directions.Sordillo JE, Kelly RS, Lutz SM, Lasky-Su J, Wu AC. Sordillo JE, et al. Curr Allergy Asthma Rep. 2021 Dec 27;21(12):47. doi: 10.1007/s11882-021-01023-w. Curr Allergy Asthma Rep. 2021. PMID: 34958416 Free PMC article. Review.
- Pharmaco-Metabolomics of Inhaled Corticosteroid Response in Individuals with Asthma.Kachroo P, Sordillo JE, Lutz SM, Weiss ST, Kelly RS, McGeachie MJ, Wu AC, Lasky-Su JA. Kachroo P, et al. J Pers Med. 2021 Nov 4;11(11):1148. doi: 10.3390/jpm11111148. J Pers Med. 2021. PMID: 34834499 Free PMC article.
- Genetic Determinants of Poor Response to Treatment in Severe Asthma.Figueiredo RG, Costa RS, Figueiredo CA, Cruz AA. Figueiredo RG, et al. Int J Mol Sci. 2021 Apr 20;22(8):4251. doi: 10.3390/ijms22084251. Int J Mol Sci. 2021. PMID: 33923891 Free PMC article. Review.
- Single Nucleotide Polymorphisms (SNPs) in PRKG1 & SPATA13-AS1 are associated with bronchodilator response: a pilot study during acute asthma exacerbations in African American children.Fishe JN, Labilloy G, Higley R, Casey D, Ginn A, Baskovich B, Blake KV. Fishe JN, et al. Pharmacogenet Genomics. 2021 Sep 1;31(7):146-154. doi: 10.1097/FPC.0000000000000434. Pharmacogenet Genomics. 2021. PMID: 33851947 Free PMC article. Review.
- The Role of SNP Interactions when Determining Independence of Novel Signals in Genetic Association Studies-An Application to ARG1 and Bronchodilator Response.Walsh R, Voorhies K, McDonald ML, McGeachie M, Sordillo JE, Lange C, Wu AC, Lutz SM. Walsh R, et al. J Pers Med. 2021 Feb 19;11(2):145. doi: 10.3390/jpm11020145. J Pers Med. 2021. PMID: 33669563 Free PMC article.
- Randomized Controlled Trial
- Adolescent
- Adult
- Aging / genetics
- Asthma / drug therapy*
- Asthma / epidemiology
- Asthma / genetics*
- Bronchodilator Agents / therapeutic use*
- Child
- Child, Preschool
- Effect Modifier, Epidemiologic
- Female
- Genome-Wide Association Study
- Genotype
- Humans
- Male
- Treatment Outcome
- Young Adult
- Bronchodilator Agents
- ClinicalTrials.gov/NCT00000575
Source: PubMed