Pharmacometabolomics of Bronchodilator Response in Asthma and the Role of Age-Metabolite Interactions
Abstract
:1. Introduction
2. Results
2.1. Study Population
2.2. Age*Metabolite Interactions
2.3. Sensitivity Analyses
3. Discussion
4. Materials and Methods
4.1. Study Population
4.1.1. Discovery Population
4.1.2. Replication Population
4.2. Spirometry
4.3. Metabolomic Profiling
4.4. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Baseline (n = 560) | Study End (n = 563) | Follow-up (n = 295) | |||||
---|---|---|---|---|---|---|---|
Characteristic | n | % | n | % | n | % | |
Sex | Male | 359 | 64.1% | 357 | 63.4% | 189 | 64.1% |
Female | 201 | 35.9% | 206 | 36.6% | 106 | 35.9% | |
Race | White | 395 | 70.5% | 399 | 70.9% | 213 | 72.2% |
Black | 82 | 14.6% | 81 | 14.4% | 35 | 11.9% | |
Hispanic | 56 | 10.0% | 56 | 9.9% | 21 | 7.1% | |
Other | 27 | 4.8% | 27 | 4.8% | 26 | 8.8% | |
Treatment Group | Budesonide | 151 | 27.0% | 156 | 27.7% | 78 | 26.4% |
Nedocromil | 171 | 30.5% | 169 | 30.0% | 83 | 28.1% | |
Placebo | 238 | 42.5% | 238 | 42.3% | 134 | 45.4% | |
Age at blood sample | mean (SD) [range] | 8.8 (2.1) | [5.1, 13.2] | 12.8 [2.2] | [9.1, 17.2] | 16.8 (2.9) | [12.2, 25.9] |
BDR at blood sample | mean (SD) [range] | 0.11 (0.10) | [−0.17,0.82] | 0.09 [0.08] | [−0.08, 0.59] | 0.08 (0.07) | [−0.14,0.49] |
Other available time-points | Baseline | - | - | 558 | 99.1% | 294 | 99.7% |
End | 558 | 99.6% | - | - | 295 | 100.0% | |
Follow-up | 294 | 52.5% | 295 | 52.4% | - | - |
Metabolite | Beta | Interaction p-Value | Interaction q-Value a |
---|---|---|---|
2-hydroxyglutarate | −0.004 | 1.77 × 10−4 | 0.089 |
adipate | −0.004 | 0.001 | 0.136 |
GABA | 0.004 | 0.004 | 0.468 |
2-O-methyladenosine | 0.002 | 0.005 | 0.468 |
3-methyladipate/pimelate | −0.002 | 0.005 | 0.468 |
C18:1 CE | 0.005 | 0.006 | 0.468 |
ectoine | −0.002 | 0.007 | 0.468 |
saccharin | 0.001 | 0.008 | 0.468 |
C18:3 CE | 0.004 | 0.010 | 0.468 |
sebacate | −0.002 | 0.011 | 0.468 |
suberate | −0.002 | 0.011 | 0.468 |
C36:1 DAG | −0.002 | 0.011 | 0.468 |
linoleoyl ethanolamide | 0.002 | 0.012 | 0.477 |
C18:0 CE | 0.004 | 0.014 | 0.489 |
C22:5 CE | 0.003 | 0.015 | 0.492 |
C16:0 CE | 0.005 | 0.021 | 0.576 |
cortisone | 0.002 | 0.022 | 0.576 |
C54:1 TAG | −0.002 | 0.022 | 0.576 |
C10:2 carnitine | −0.001 | 0.024 | 0.576 |
arginine | 0.004 | 0.024 | 0.576 |
C6 carnitine | 0.002 | 0.025 | 0.576 |
taurodeoxycholate/taurochenodeoxycholate | −0.002 | 0.026 | 0.576 |
C56:2 TAG | −0.003 | 0.027 | 0.576 |
C36:0 DAG | −0.004 | 0.028 | 0.576 |
C30:0 DAG | −0.001 | 0.029 | 0.589 |
C36:2 DAG or TAG fragment | −0.002 | 0.032 | 0.614 |
C58:10 TAG | 0.001 | 0.038 | 0.622 |
sphingosine | 0.002 | 0.039 | 0.622 |
C36:2 DAG | −0.002 | 0.041 | 0.622 |
C20:3 CE | 0.003 | 0.042 | 0.622 |
phenyllactate | −0.003 | 0.042 | 0.622 |
C20:4 CE | 0.003 | 0.043 | 0.622 |
C32:1 DAG | −0.002 | 0.043 | 0.622 |
C5 carnitine | 0.002 | 0.043 | 0.622 |
C54:2 TAG | −0.002 | 0.044 | 0.622 |
C16:1 CE | 0.003 | 0.045 | 0.622 |
ribothymidine | 0.002 | 0.046 | 0.622 |
taurocholate | −0.002 | 0.047 | 0.622 |
C3 carnitine | 0.002 | 0.050 | 0.641 |
Metabolite | CAMP | GACRS | ||||
---|---|---|---|---|---|---|
Beta | Interaction p-Value | Interaction q-Value a | Beta | Interaction p-Value | Interaction q-Value a | |
2-hydroxyglutarate * | −0.004 | 1.80 × 10−4 | 0.089 | −0.015 | 0.018 | 0.997 |
GABA. | 0.004 | 0.004 | 0.468 | 0.01 | 0.085 | 0.997 |
3-methyladipate/pimelate | −0.002 | 0.005 | 0.468 | −0.01 | 0.133 | 0.997 |
C18:1 CE * | 0.005 | 0.006 | 0.468 | 0.023 | 0.041 | 0.997 |
C18:3 CE | 0.004 | 0.01 | 0.468 | 0.009 | 0.203 | 0.997 |
C36:1 DAG | −0.002 | 0.011 | 0.468 | 0.001 | 0.823 | 0.997 |
linoleoyl ethanolamide | 0.002 | 0.012 | 0.477 | 0.001 | 0.807 | 0.997 |
C18:0 CE. | 0.004 | 0.014 | 0.489 | 0.012 | 0.101 | 0.997 |
C22:5 CE | 0.003 | 0.015 | 0.492 | 0.011 | 0.125 | 0.997 |
C16:0 CE. | 0.005 | 0.021 | 0.576 | 0.023 | 0.056 | 0.997 |
Cortisone | 0.002 | 0.022 | 0.576 | 0.001 | 0.812 | 0.997 |
C54:1 TAG | −0.002 | 0.022 | 0.576 | −0.001 | 0.760 | 0.997 |
C10:2 carnitine | −0.001 | 0.024 | 0.576 | −0.002 | 0.683 | 0.997 |
Arginine | 0.004 | 0.024 | 0.576 | −0.002 | 0.747 | 0.997 |
C6 carnitine | 0.002 | 0.025 | 0.576 | −0.001 | 0.841 | 0.997 |
taurodeoxycholate/taurochenodeoxycholate | −0.002 | 0.026 | 0.576 | −0.004 | 0.321 | 0.997 |
C56:2 TAG | −0.003 | 0.027 | 0.576 | −0.003 | 0.572 | 0.997 |
C30:0 DAG | −0.001 | 0.029 | 0.589 | 0.001 | 0.799 | 0.997 |
C58:10 TAG | 0.001 | 0.038 | 0.622 | −0.003 | 0.572 | 0.997 |
C36:2 DAG | −0.002 | 0.04 | 0.622 | 0.001 | 0.949 | 0.997 |
C20:3 CE | 0.003 | 0.042 | 0.622 | 0.01 | 0.189 | 0.997 |
C20:4 CE. | 0.003 | 0.043 | 0.622 | 0.017 | 0.076 | 0.997 |
C32:1 DAG | −0.002 | 0.043 | 0.622 | 0.001 | 0.832 | 0.997 |
C5 carnitine | 0.002 | 0.043 | 0.622 | −0.001 | 0.861 | 0.997 |
C54:2 TAG | −0.002 | 0.044 | 0.622 | −0.002 | 0.760 | 0.997 |
C16:1 CE | 0.003 | 0.045 | 0.622 | 0.01 | 0.195 | 0.997 |
Ribothymidine. | 0.002 | 0.046 | 0.622 | 0.01 | 0.088 | 0.997 |
Taurocholate | −0.002 | 0.047 | 0.622 | −0.005 | 0.166 | 0.997 |
C3 carnitine | 0.002 | 0.05 | 0.641 | 0.003 | 0.629 | 0.997 |
Metabolite | CAMP | Costa Rica | ||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Baseline | Study End | Follow-up | ||||||||||||||
Beta | 95% CI | p-Value | q-Value a | Beta | 95% CI | p-Value | q-Value a | Beta | 95% CI | p-Value | q-Value a | Beta | 95% CI | p-Value | q-Value a | |
2-hydroxy glutarate | −0.015 | (−0.034, 0.004) | 0.114 | 0.314 | −0.013 | (−0.029, 0.002) | 0.082 | 0.082 | 0.032 | (0.014, 0.05) | 0.001 * | 0.001 | −0.008 | (−0.038, 0.021) | 0.581 | 0.931 |
C18:1 CE | −0.008 | (−0.02, 0.003) | 0.159 | 0.314 | −0.017 | (−0.028, −0.007) | 0.001 * | 0.009 | −0.02 | (−0.032, −0.008) | 0.002 * | 0.002 | −0.005 | (−0.022, 0.011) | 0.52 | 0.931 |
C16:0 CE | 9.5 × 10−5 | (−0.01, 0.011) | 0.986 | 0.986 | −0.012 | (−0.022, −0.003) | 0.014 * | 0.016 | −0.009 | (−0.02, 0.002) | 0.108 * | 0.126 | −0.008 | (−0.024, 0.008) | 0.317 | 0.921 |
GABA | −0.012 | (−0.028, 0.004) | 0.132 | 0.314 | −0.019 | (−0.034, −0.004) | 0.012 * | 0.016 | −0.029 | (−0.046, −0.013) | 0.001 * | 0.001 | −0.008 | (−0.038, 0.021) | 0.581 | 0.931 |
C18:0 CE | 3.7 × 10−4 | (−0.014, 0.014) | 0.959 | 0.986 | −0.018 | (−0.031, −0.005) | 0.005 * | 0.012 | −0.036 | (−0.051, −0.02) | 7.7 × 10−6 * | 2.7 × 10−5 | 0.006 | (−0.017, 0.029) | 0.625 | 0.931 |
C20:4 CE | −0.009 | (−0.021, 0.004) | 0.18 | 0.314 | −0.018 | (−0.031, −0.006) | 0.005 * | 0.012 | −0.006 | (−0.021, 0.008) | 0.404 | 0.404 | −0.012 | (−0.032, 0.009) | 0.265 | 0.921 |
Ribo thymidine | −0.009 | (−0.025, 0.006) | 0.236 | 0.330 | −0.018 | (−0.031, −0.005) | 0.007 * | 0.012 | −0.062 | (−0.077, −0.047) | 6.2 × 10−15 * | 4.3 × 10−14 | 4.7 × 10−4 | (−0.031, 0.032) | 0.977 | 0.972 |
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Kelly, R.S.; Sordillo, J.E.; Lutz, S.M.; Avila, L.; Soto-Quiros, M.; Celedón, J.C.; McGeachie, M.J.; Dahlin, A.; Tantisira, K.; Huang, M.; et al. Pharmacometabolomics of Bronchodilator Response in Asthma and the Role of Age-Metabolite Interactions. Metabolites 2019, 9, 179. https://doi.org/10.3390/metabo9090179
Kelly RS, Sordillo JE, Lutz SM, Avila L, Soto-Quiros M, Celedón JC, McGeachie MJ, Dahlin A, Tantisira K, Huang M, et al. Pharmacometabolomics of Bronchodilator Response in Asthma and the Role of Age-Metabolite Interactions. Metabolites. 2019; 9(9):179. https://doi.org/10.3390/metabo9090179
Chicago/Turabian StyleKelly, Rachel S., Joanne E. Sordillo, Sharon M. Lutz, Lydiana Avila, Manuel Soto-Quiros, Juan C. Celedón, Michael J. McGeachie, Amber Dahlin, Kelan Tantisira, Mengna Huang, and et al. 2019. "Pharmacometabolomics of Bronchodilator Response in Asthma and the Role of Age-Metabolite Interactions" Metabolites 9, no. 9: 179. https://doi.org/10.3390/metabo9090179