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Original Research: CRITICAL CARE |

The Association Between a Darc Gene Polymorphism and Clinical Outcomes in African American Patients With Acute Lung InjuryDarc Gene Variant and Acute Lung Injury Outcomes

Kirsten Neudoerffer Kangelaris, MD; Anil Sapru, MD; Carolyn S. Calfee, MD; Kathleen D. Liu, MD, PhD; Ludmila Pawlikowska, PhD; John S. Witte, PhD; Eric Vittinghoff, PhD; Hanjing Zhuo, MD, MPH; Andrew D. Auerbach, MD, MPH; Elad Ziv, MD; Michael A. Matthay, MD, FCCP; the National Heart, Lung, and Blood Institute ARDS Network
Author and Funding Information

From the Department of Medicine, Division of General Internal Medicine (Drs Kangelaris and Ziv), Division of Hospital Medicine (Drs Kangelaris and Auerbach), Division of Pulmonary and Critical Care (Drs Calfee, Zhuo, and Matthay), and Division of Nephrology (Dr Liu); the Department of Pediatrics, Division of Critical Care (Dr Sapru); the Department of Epidemiology and Biostatistics (Drs Witte and Vittinghoff); and the Department of Anesthesia and Perioperative Care (Drs Calfee, Liu, Pawlikowska, and Matthay), University of California, San Francisco, San Francisco, CA.

Correspondence to: Kirsten Neudoerffer Kangelaris, MD, Box 0131, 533 Parnassus Ave, UC Hall, University of California, San Francisco, San Francisco, CA 94143-0131; e-mail: kkangelaris@medicine.ucsf.edu


A complete list of study participants is located in e-Appendix 1.

For editorial comment see page 1132

Funding/Support: This work was supported by contracts with the National Heart, Lung, and Blood Institute (NHLBI) [NO1-HR 46054, 46055, 46056, 46057, 46058, 46059, 46060, 46061, 46062, 46063, and 46064]. At the time the research was conducted, Dr Kangelaris was supported by the National Research Service Award Institutional Grant [T32 HP19025], the Society of Hospital Medicine Young Researcher’s Award, and Dr Matthay by NHLBI [Grant R37HL51856]. Dr Sapru was supported by NHLBI [Grant K23 HL085526] and National Institute of Child Health and Human Development [Grant HD047349] and Dr Calfee by NHLBI [Grant HL090833] and the Flight Attendant Medical Research Institute.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2012 American College of Chest Physicians


Chest. 2012;141(5):1160-1169. doi:10.1378/chest.11-1766
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Background:  Acute lung injury (ALI) mortality is increased among African Americans compared with Americans of European descent, and genetic factors may be involved. A functional T-46C polymorphism (rs2814778) in the promoter region of Duffy antigen/receptor for chemokines (Darc) gene, present almost exclusively in people of African descent, results in isolated erythrocyte DARC deficiency and has been implicated in ALI pathogenesis in preclinical and murine models, possibly because of an increase in circulating Duffy-binding, proinflammatory chemokines like IL-8. We sought to determine the effect of the functional rs2814778 polymorphism, C/C genotype (Duffy null state), on clinical outcomes in African Americans with acute lung injury.

Methods:  Clinical data and biologic specimens from African American patients with ALI who enrolled in three randomized controlled trials were analyzed. Multivariate analysis accounted for proportion of African ancestry, sex, cirrhosis, and severity of illness on presentation.

Results:  Among 132 subjects, 88 (67%) were Duffy null (C/C genotype). The Duffy null state was associated with a 17% absolute risk increase (95% CI, 1.4%-33%) in mortality at 60 days, a median of 8 fewer ventilator-free days (95% CI, 1-18.5), and 4.5 fewer organ failure-free days (95% CI, 0-18) compared with individuals with the C/T or T/T genotypes (all P values < .05). Estimates were similar on multivariate analysis. In African Americans without the null variant, clinical outcomes were similar to those in patients of European descent. A subgroup analysis suggested that plasma IL-8 levels are increased in Duffy null individuals.

Conclusions:  Our results provide evidence that the functional rs2814778 polymorphism in the gene encoding DARC is associated with worse clinical outcomes among African Americans with ALI, possibly via an increase in circulating IL-8.

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