TOLLIP, MUC5B, and the response to N-acetylcysteine among individuals with idiopathic pulmonary fibrosis

Justin Oldham, Shwu Fan Ma, Fernando J. Martinez, Kevin J. Anstrom, Ganesh Raghu, David A. Schwartz, Eleanor Valenzi, Leah Witt, Cathryn Lee, Rekha Vij, Yong Huang, Mary E. Strek, Imre Noth

Research output: Contribution to journalArticle

111 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1475-1482
Number of pages8
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume192
Issue number12
DOIs
StatePublished - Dec 15 2015
Externally publishedYes

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Idiopathic Pulmonary Fibrosis
Acetylcysteine
Genotype
Single Nucleotide Polymorphism
Odds Ratio
Clinical Trials
Confidence Intervals
Off-Label Use
Azathioprine
Therapeutics
Immunosuppressive Agents
Survival Analysis
Prednisone
Lung Diseases
Hospitalization
Antioxidants
Transplantation
Lung
Genes

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 journalArticle

Oldham, J, Ma, SF, Martinez, FJ, Anstrom, KJ, Raghu, G, Schwartz, DA, Valenzi, E, Witt, L, Lee, C, Vij, R, Huang, Y, Strek, ME & Noth, I 2015, 'TOLLIP, MUC5B, and the response to N-acetylcysteine among individuals with idiopathic pulmonary fibrosis', American Journal of Respiratory and Critical Care Medicine, vol. 192, no. 12, pp. 1475-1482. https://doi.org/10.1164/rccm.201505-1010OC
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. / TOLLIP, MUC5B, and the response to N-acetylcysteine among individuals with idiopathic pulmonary fibrosis. In: American Journal of Respiratory and Critical Care Medicine. 2015 ; Vol. 192, No. 12. pp. 1475-1482.
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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.",
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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

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