Abstract
Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology. The genes TOLLIP and MUC5B play important roles in lung host defense, which is an immune process influenced by oxidative signaling. Whether polymorphisms in TOLLIP and MUC5B modify the effect of immunosuppressive and antioxidant therapy in individuals with IPF is unknown. Objectives: To determine whether single-nucleotide polymorphisms (SNPs) within TOLLIP andMUC5B modify the effect of interventions in subjects participating in the Evaluating the Effectiveness of Prednisone, Azathioprine, and N-Acetylcysteine in Patients with Idiopathic Pulmonary Fibrosis (PANTHER-IPF) clinical trial. Methods: SNPs within TOLLIP (rs5743890/rs5743894/rs5743854/rs3750920) and MUC5B (rs35705950) were genotyped. Interaction modeling was conducted with multivariable Cox regression followed by genotype-stratified survival analysis using a composite endpoint of death, transplantation, hospitalization, or a decline of≥10% in FVC. Measurements and Main Results: Significant interaction was observed between N-acetylcysteine (NAC) therapy and rs3750920 within TOLLIP (Pinteraction = 0.001). After stratifying by rs3750920 genotype, NAC therapy was associated with a significant reduction in composite endpoint risk (hazard ratio, 0.14; 95% confidence interval, 0.02-0.83; P = 0.03) in those with a TT genotype, but a nonsignificant increase in composite endpoint risk (hazard ratio, 3.23; 95% confidence interval, 0.79-13.16; P = 0.10) was seen in those with a CC genotype. These findings were then replicated in an independent IPF cohort. Conclusions: NAC may be an efficacious therapy for individuals with IPF with an rs3750920 (TOLLIP) TT genotype, but it was associated with a trend toward harm in those with a CC genotype. A genotype-stratified prospective clinical trial should be conducted before any recommendation regarding the use of off-label NAC to treat IPF.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1475-1482 |
| Number of pages | 8 |
| Journal | American Journal of Respiratory and Critical Care Medicine |
| Volume | 192 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 15 2015 |
| Externally published | Yes |
Fingerprint
Keywords
- Drug-gene interaction
- Host defense
- IPF
- N-acetylcysteine
- Pharmacogenetics
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Critical Care and Intensive Care Medicine
Cite this
TOLLIP, MUC5B, and the response to N-acetylcysteine among individuals with idiopathic pulmonary fibrosis. / Oldham, Justin; Ma, Shwu Fan; Martinez, Fernando J.; Anstrom, Kevin J.; Raghu, Ganesh; Schwartz, David A.; Valenzi, Eleanor; Witt, Leah; Lee, Cathryn; Vij, Rekha; Huang, Yong; Strek, Mary E.; Noth, Imre.
In: American Journal of Respiratory and Critical Care Medicine, Vol. 192, No. 12, 15.12.2015, p. 1475-1482.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - TOLLIP, MUC5B, and the response to N-acetylcysteine among individuals with idiopathic pulmonary fibrosis
AU - Oldham, Justin
AU - Ma, Shwu Fan
AU - Martinez, Fernando J.
AU - Anstrom, Kevin J.
AU - Raghu, Ganesh
AU - Schwartz, David A.
AU - Valenzi, Eleanor
AU - Witt, Leah
AU - Lee, Cathryn
AU - Vij, Rekha
AU - Huang, Yong
AU - Strek, Mary E.
AU - Noth, Imre
PY - 2015/12/15
Y1 - 2015/12/15
N2 - Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology. The genes TOLLIP and MUC5B play important roles in lung host defense, which is an immune process influenced by oxidative signaling. Whether polymorphisms in TOLLIP and MUC5B modify the effect of immunosuppressive and antioxidant therapy in individuals with IPF is unknown. Objectives: To determine whether single-nucleotide polymorphisms (SNPs) within TOLLIP andMUC5B modify the effect of interventions in subjects participating in the Evaluating the Effectiveness of Prednisone, Azathioprine, and N-Acetylcysteine in Patients with Idiopathic Pulmonary Fibrosis (PANTHER-IPF) clinical trial. Methods: SNPs within TOLLIP (rs5743890/rs5743894/rs5743854/rs3750920) and MUC5B (rs35705950) were genotyped. Interaction modeling was conducted with multivariable Cox regression followed by genotype-stratified survival analysis using a composite endpoint of death, transplantation, hospitalization, or a decline of≥10% in FVC. Measurements and Main Results: Significant interaction was observed between N-acetylcysteine (NAC) therapy and rs3750920 within TOLLIP (Pinteraction = 0.001). After stratifying by rs3750920 genotype, NAC therapy was associated with a significant reduction in composite endpoint risk (hazard ratio, 0.14; 95% confidence interval, 0.02-0.83; P = 0.03) in those with a TT genotype, but a nonsignificant increase in composite endpoint risk (hazard ratio, 3.23; 95% confidence interval, 0.79-13.16; P = 0.10) was seen in those with a CC genotype. These findings were then replicated in an independent IPF cohort. Conclusions: NAC may be an efficacious therapy for individuals with IPF with an rs3750920 (TOLLIP) TT genotype, but it was associated with a trend toward harm in those with a CC genotype. A genotype-stratified prospective clinical trial should be conducted before any recommendation regarding the use of off-label NAC to treat IPF.
AB - Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology. The genes TOLLIP and MUC5B play important roles in lung host defense, which is an immune process influenced by oxidative signaling. Whether polymorphisms in TOLLIP and MUC5B modify the effect of immunosuppressive and antioxidant therapy in individuals with IPF is unknown. Objectives: To determine whether single-nucleotide polymorphisms (SNPs) within TOLLIP andMUC5B modify the effect of interventions in subjects participating in the Evaluating the Effectiveness of Prednisone, Azathioprine, and N-Acetylcysteine in Patients with Idiopathic Pulmonary Fibrosis (PANTHER-IPF) clinical trial. Methods: SNPs within TOLLIP (rs5743890/rs5743894/rs5743854/rs3750920) and MUC5B (rs35705950) were genotyped. Interaction modeling was conducted with multivariable Cox regression followed by genotype-stratified survival analysis using a composite endpoint of death, transplantation, hospitalization, or a decline of≥10% in FVC. Measurements and Main Results: Significant interaction was observed between N-acetylcysteine (NAC) therapy and rs3750920 within TOLLIP (Pinteraction = 0.001). After stratifying by rs3750920 genotype, NAC therapy was associated with a significant reduction in composite endpoint risk (hazard ratio, 0.14; 95% confidence interval, 0.02-0.83; P = 0.03) in those with a TT genotype, but a nonsignificant increase in composite endpoint risk (hazard ratio, 3.23; 95% confidence interval, 0.79-13.16; P = 0.10) was seen in those with a CC genotype. These findings were then replicated in an independent IPF cohort. Conclusions: NAC may be an efficacious therapy for individuals with IPF with an rs3750920 (TOLLIP) TT genotype, but it was associated with a trend toward harm in those with a CC genotype. A genotype-stratified prospective clinical trial should be conducted before any recommendation regarding the use of off-label NAC to treat IPF.
KW - Drug-gene interaction
KW - Host defense
KW - IPF
KW - N-acetylcysteine
KW - Pharmacogenetics
UR - http://www.scopus.com/inward/record.url?scp=84952037891&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84952037891&partnerID=8YFLogxK
U2 - 10.1164/rccm.201505-1010OC
DO - 10.1164/rccm.201505-1010OC
M3 - Article
C2 - 26331942
AN - SCOPUS:84952037891
VL - 192
SP - 1475
EP - 1482
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
SN - 1073-449X
IS - 12
ER -