Kedir N Turi1, Christopher McKennan2, Tebeb Gebretsadik3, Brittney Snyder1, Christine M Seroogy4, Robert F Lemanske4, Edward Zoratti5, Suzanne Havstad6, Carole Ober7, Susan Lynch8, Kathyrn McCauley8, Chang Yu3, Daniel J Jackson4, James E Gern9, Tina V Hartert10. 1. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn. 2. Department of Statistics, Pittsburgh University, Pittsburgh, Pa. 3. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tenn. 4. Department of Pediatrics, University of Wisconsin, Madison, Wis. 5. Department of Internal Medicine, Henry Ford Hospital, Detroit, Mich. 6. Department of Public Health Sciences, Henry Ford Hospital, Detroit, Mich. 7. Department of Human Genetics, University of Chicago, Chicago, Ill. 8. Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, Calif. 9. Department of Pediatrics, University of Wisconsin, Madison, Wis. Electronic address: gern@medicine.wisc.edu. 10. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn. Electronic address: tina.hartert@vumc.org.
Abstract
BACKGROUND: Wheeze and allergic sensitization are the strongest early-life predictors of childhood asthma development; the molecular origins of these early-life phenotypes are poorly understood. OBJECTIVES: We sought to identify metabolites associated with early-life wheeze, allergic sensitization, and childhood asthma. METHODS: We conducted a nested case-control study using Environmental influences on Child Health Outcomes Program cohorts for discovery and independent replication. Wheeze and allergic sensitization were defined by number of wheeze episodes and positive specific IgE at age 1 year, respectively. Asthma was defined as physician diagnosis of asthma at age 5 or 6 years. We used untargeted metabolomics, controlling for observed and latent confounding factors, to assess associations between the plasma metabolome and early-life wheeze, allergy, and childhood asthma. RESULTS: Eighteen plasma metabolites were associated with first-year wheeze in the discovery cohort (n = 338). Z,Z unconjugated bilirubin (UCB) and its related metabolites exhibited a dose-response relationship with wheeze frequency; UCB levels were 13% (β = 0.87; 95% CI, 0.74-1.02) and 22% (β = 0.78; 95% CI, 0.68-0.91) lower in children with 1 to 3 and 4+ wheeze episodes compared with those who never wheezed, respectively. UCB levels were also associated with childhood asthma (β = 0.82; 95% CI, 0.68-0.98). Similar trends were observed in 2 independent cohorts. UCB was significantly negatively correlated with eicosanoid- and oxidative stress-related metabolites. There were no significant associations between metabolites and allergic sensitization. CONCLUSIONS: We identified a novel inverse, dose-dependent association between UCB and recurrent wheeze and childhood asthma. Inflammatory lipid mediators and oxidative stress byproducts inversely correlated with UCB, suggesting that UCB modulates pathways critical to the development of early-life recurrent wheeze and childhood asthma.
BACKGROUND: Wheeze and allergic sensitization are the strongest early-life predictors of childhood asthma development; the molecular origins of these early-life phenotypes are poorly understood. OBJECTIVES: We sought to identify metabolites associated with early-life wheeze, allergic sensitization, and childhood asthma. METHODS: We conducted a nested case-control study using Environmental influences on Child Health Outcomes Program cohorts for discovery and independent replication. Wheeze and allergic sensitization were defined by number of wheeze episodes and positive specific IgE at age 1 year, respectively. Asthma was defined as physician diagnosis of asthma at age 5 or 6 years. We used untargeted metabolomics, controlling for observed and latent confounding factors, to assess associations between the plasma metabolome and early-life wheeze, allergy, and childhood asthma. RESULTS: Eighteen plasma metabolites were associated with first-year wheeze in the discovery cohort (n = 338). Z,Z unconjugated bilirubin (UCB) and its related metabolites exhibited a dose-response relationship with wheeze frequency; UCB levels were 13% (β = 0.87; 95% CI, 0.74-1.02) and 22% (β = 0.78; 95% CI, 0.68-0.91) lower in children with 1 to 3 and 4+ wheeze episodes compared with those who never wheezed, respectively. UCB levels were also associated with childhood asthma (β = 0.82; 95% CI, 0.68-0.98). Similar trends were observed in 2 independent cohorts. UCB was significantly negatively correlated with eicosanoid- and oxidative stress-related metabolites. There were no significant associations between metabolites and allergic sensitization. CONCLUSIONS: We identified a novel inverse, dose-dependent association between UCB and recurrent wheeze and childhood asthma. Inflammatory lipid mediators and oxidative stress byproducts inversely correlated with UCB, suggesting that UCB modulates pathways critical to the development of early-life recurrent wheeze and childhood asthma.
Authors: Kedir N Turi; Lindsey Romick-Rosendale; Tebeb Gebretsadik; Miki Watanabe; Steven Brunwasser; Larry J Anderson; Martin L Moore; Emma K Larkin; Ray Stokes Peebles; Tina V Hartert Journal: Metabolomics Date: 2018-10-01 Impact factor: 4.290
Authors: Andrew M Tager; Peter LaCamera; Barry S Shea; Gabriele S Campanella; Moisés Selman; Zhenwen Zhao; Vasiliy Polosukhin; John Wain; Banu A Karimi-Shah; Nancy D Kim; William K Hart; Annie Pardo; Timothy S Blackwell; Yan Xu; Jerold Chun; Andrew D Luster Journal: Nat Med Date: 2007-12-09 Impact factor: 53.440
Authors: Hatice S Zahran; Cathy M Bailey; Scott A Damon; Paul L Garbe; Patrick N Breysse Journal: MMWR Morb Mortal Wkly Rep Date: 2018-02-09 Impact factor: 17.586
Authors: James E Gern; Daniel J Jackson; Robert F Lemanske; Christine M Seroogy; Umberto Tachinardi; Mark Craven; Stephen Y Hwang; Carol M Hamilton; Wayne Huggins; George T O'Connor; Diane R Gold; Rachel Miller; Meyer Kattan; Christine C Johnson; Dennis Ownby; Edward M Zoratti; Robert A Wood; Cynthia M Visness; Fernando Martinez; Anne Wright; Susan Lynch; Carole Ober; Gurjit K Khurana Hershey; Patrick Ryan; Tina Hartert; Leonard B Bacharier Journal: Respir Res Date: 2019-06-10