The Darc Side of Glycobiology in Acute Lung Injury

Despite being common and carrying an estimated mortality in excess of 30%,1 acute lung injury (ALI) remains poorly understood. Few recent developments have improved the clinical management of affected patients. Significant advances in understanding the epidemiology and pathogenesis of ALI have been increasingly reported over the past 20 years; however, there are currently no pharmacologic interventions for the syndrome. To date, lung protective mechanical ventilation stands as the sole intervention to improve outcomes.2 Only a fraction of patients exposed to predisposing environmental insults, such as sepsis or trauma, develop ALI, leading to the hypothesis that genetic variation is a significant contributor to ALI susceptibility and outcomes. Over the past decade, candidate gene approaches have suggested genetic associations related to immune system function and pulmonary permeability.3 This relatively new focus on genetic risk has the potential to elucidate novel pathways involved in the pathogenesis of ALI and contribute to personalized medicine by identifying subgroups of patients that could uniquely benefit from targeted therapy. This is particularly true as newer, larger-scale genetic approaches are applied to ALI.4,5 Despite these findings, the understanding of the genetics of ALI remains in its infancy relative to other diseases, even within pulmonary medicine. The nature of the syndrome as sporadic and requiring a significant environmental insult complicates family-linkage approaches, and its heterogeneity leads to challenges in targeting the correct population and replicating results. In this issue of CHEST (see page 1160), Kangelaris and colleagues6 used a candidate gene approach and report a novel genetic association between the Duffy antigen/receptor for chemokines (Darc) gene and mortality from ALI within a population of African Americans. Specifically, the authors examined whether ALI outcomes differed by carriage of a functional polymorphism in the promoter region of the Darc gene that results in a selective lack of expression of DARC on erythrocytes. Patients who are homozygous for this polymorphism are referred to as “Duffy null” and are nearly exclusively of African descent. The researchers used genetic data from a relatively large cohort of African American patients with ALI to demonstrate the clinical association of the Duffy null state and poor clinical outcomes. Therefore, this genetic polymorphism is hypothesized to explain a portion of the increased risk of ALI reported in African Americans.7 This novel association of a Darc gene polymorphism and ALI mortality provides an excellent example of the role of host-pathogen interactions in the evolution of genetic differences in disease risk among distinct populations. The Duffy blood group system was first recognized as a minor blood group in 1950 and since that time has been identified as a cell surface glycoprotein that acts as a nonspecific receptor for a variety of chemokines.8,9 Murine data suggest that erythrocyte DARC acts as a chemokine reservoir in the setting of system inflammation and therefore acts to modulate the immune system. Historically, variations in functional alleles of blood group antigen genes have been regarded as possible susceptibility factors for infectious diseases. In the case of the Duffy blood group antigens, the malaria parasite Plasmodium vivax has evolved to recognize DARC as its receptor on erythrocyte surfaces.10 The Darc gene promoter polymorphism that results in a lack of expression of DARC in erythrocytes has been demonstrated to confer resistance to malarial infection.11 These types of host-pathogen interactions are major determinants in evolution and likely contributed to Western Africans possessing a nearly 100% prevalence of the Duffy null state in their population. It is hypothesized that these evolutionarily selective pressures have resulted in divergent susceptibility to the diseases of the modern world.12 In the case of the Darc gene, the Duffy null state has been recognized to increase susceptibility to modern ailments, including HIV and asthma.13,14 The newly identified association with ALI further demonstrates how past host-pathogen interactions can result in genetic differences that confer risk of various inflammatory conditions of the modern world. A strength of the study reported by Kangelaris and colleagues6 is the identification of an intriguing genetic association between a polymorphism in the Darc gene and the outcomes of ALI that potentially explains a portion of the recognized racial differences in these outcomes. Whereas a strictly African population would not allow for the separation of the effects of the Darc gene from those of a potentially unrelated genetic factor common among that population, the authors used the genetic structure of African Americans to overcome this impediment. African Americans represent a unique population with some degree of racial admixture, allowing the researchers to adjust for other genetic factors related to ancestry, using genetically determined ancestry informative markers. The authors strengthened their primary conclusion by reporting no difference in ALI outcomes among African Americans without the Duffy null polymorphisms compared with a sample of Americans of European descent. The authors’ findings still require replication in a separate population before they can be widely accepted. However, the association between Darc and outcomes from ALI is intriguing and further emphasizes the importance of the interaction between hematologic cell surface glycoproteins and the immune system in the pathogenesis of the systemic inflammation of ALI. These evolutionarily heterogeneous glycans and glycoproteins have been increasingly recognized for their role in diverse human illnesses including susceptibility to infectious agents and vascular disease. As such, glycobiology represents an exciting future focus of investigation in the pathogenesis of ALI, with the potential of identifying pharmacologic targets and adding to the growing understanding of the genetics of ALI risk and outcomes.