Anna L Lagan1, Gregory J Quinlan1, Sharon Mumby1, Daniel D Melley1, Peter Goldstraw2, Geoff J Bellingan3, Michael R Hill3, David Briggs4, Panagiotis Pantelidis5, Roland M du Bois5, Kenneth I Welsh5, Timothy W Evans6. 1. Unit of Critical Care, Imperial College School of Medicine, Royal Brompton Hospital, London. 2. Department of Cardiothoracic Surgery, Royal Brompton & Harefield NHS Trust, London. 3. Centre for Respiratory Research, Royal Free and University College, London Medical School, Rayne Institute, London. 4. Histocompatibility and Immunogenetics, National Blood Service, Birmingham, UK. 5. Clinical Genomics Group, Imperial College School of Medicine, Royal Brompton Hospital, London. 6. Unit of Critical Care, Imperial College School of Medicine, Royal Brompton Hospital, London. Electronic address: t.evans@rbht.nhs.uk.
Abstract
BACKGROUND: Abnormal plasma and lung iron mobilization is associated with the onset and progression of ARDS and is detectable in specific at-risk populations. Patients with ARDS also have pronounced oxidative and nitrosative stress that can be catalyzed and thereby aggravated by the bioavailability of redox active iron. ARDS of pulmonary and extrapulmonary origin may differ pathophysiologically and require different ventilatory strategies. Evidence suggests that genetic predisposition is relevant to the pathogenesis of ARDS. We therefore explored the hypothesis that polymorphisms from a panel of genes encoding iron-metabolizing proteins determine susceptibility to ARDS. METHODS: Retrospective case-control study conducted at the adult ICUs of two university hospitals. Patients with ARDS (n = 122) and healthy control subjects (n = 193) were genotyped. Sequence-specific primer polymerase chain reaction was used to genotype selected biallelic single-nucleotide polymorphisms. An audit of the patient database was conducted, and 104 of the 122 ARDS patients were eligible for the final data analysis. RESULTS: Preliminary analysis indicated differences between ARDS and healthy control subjects in the incidence of polymorphism of the gene encoding ferritin light chain. Subgroup analysis indicated the prevalence of ferritin light-chain gene -3381GG homozygotes was increased in patients with ARDS of extrapulmonary origin compared to healthy control subjects. Secondly, a common haplotype in the heme oxygenase 2 gene was reduced in patients with ARDS compared to healthy control subjects and was more evident in those with ARDS of direct or pulmonary etiology. CONCLUSIONS: These results provide preliminary evidence to suggest a distinction in the genetic background of the subpopulations studied, inferring that the ferritin light-chain gene genotype confers susceptibility to ARDS, while the heme oxygenase 2 haplotype is protective against the onset of the syndrome. Such data support further previous findings that suggest abnormalities in iron handling resulting in redox imbalance are implicated in the pathogenesis of ARDS.
BACKGROUND: Abnormal plasma and lung iron mobilization is associated with the onset and progression of ARDS and is detectable in specific at-risk populations. Patients with ARDS also have pronounced oxidative and nitrosative stress that can be catalyzed and thereby aggravated by the bioavailability of redox active iron. ARDS of pulmonary and extrapulmonary origin may differ pathophysiologically and require different ventilatory strategies. Evidence suggests that genetic predisposition is relevant to the pathogenesis of ARDS. We therefore explored the hypothesis that polymorphisms from a panel of genes encoding iron-metabolizing proteins determine susceptibility to ARDS. METHODS: Retrospective case-control study conducted at the adult ICUs of two university hospitals. Patients with ARDS (n = 122) and healthy control subjects (n = 193) were genotyped. Sequence-specific primer polymerase chain reaction was used to genotype selected biallelic single-nucleotide polymorphisms. An audit of the patient database was conducted, and 104 of the 122 ARDS patients were eligible for the final data analysis. RESULTS: Preliminary analysis indicated differences between ARDS and healthy control subjects in the incidence of polymorphism of the gene encoding ferritin light chain. Subgroup analysis indicated the prevalence of ferritin light-chain gene -3381GG homozygotes was increased in patients with ARDS of extrapulmonary origin compared to healthy control subjects. Secondly, a common haplotype in the heme oxygenase 2 gene was reduced in patients with ARDS compared to healthy control subjects and was more evident in those with ARDS of direct or pulmonary etiology. CONCLUSIONS: These results provide preliminary evidence to suggest a distinction in the genetic background of the subpopulations studied, inferring that the ferritin light-chain gene genotype confers susceptibility to ARDS, while the heme oxygenase 2 haplotype is protective against the onset of the syndrome. Such data support further previous findings that suggest abnormalities in iron handling resulting in redox imbalance are implicated in the pathogenesis of ARDS.
Authors: Ciara M Shaver; Cameron P Upchurch; David R Janz; Brandon S Grove; Nathan D Putz; Nancy E Wickersham; Sergey I Dikalov; Lorraine B Ware; Julie A Bastarache Journal: Am J Physiol Lung Cell Mol Physiol Date: 2016-01-15 Impact factor: 5.464
Authors: Chau-Chyun Sheu; Rihong Zhai; Zhaoxi Wang; Michelle N Gong; Paula Tejera; Feng Chen; Li Su; B Taylor Thompson; David C Christiani Journal: Intensive Care Med Date: 2009-06-13 Impact factor: 17.440
Authors: Jason D Christie; Mark M Wurfel; Rui Feng; Grant E O'Keefe; Jonathan Bradfield; Lorraine B Ware; David C Christiani; Carolyn S Calfee; Mitchell J Cohen; Michael Matthay; Nuala J Meyer; Cecilia Kim; Mingyao Li; Joshua Akey; Kathleen C Barnes; Jonathan Sevransky; Paul N Lanken; Addison K May; Richard Aplenc; James P Maloney; Hakon Hakonarson Journal: PLoS One Date: 2012-01-25 Impact factor: 3.240