Chest. 2012 May;141(5):1160-9. doi: 10.1378/chest.11-1766. Epub 2011 Dec 29.
The association between a Darc gene polymorphism and clinical outcomes in African American patients with acute lung injury.
Kangelaris KN,
Sapru A,
Calfee CS,
Liu KD,
Pawlikowska L,
Witte JS,
Vittinghoff E,
Zhuo H,
Auerbach AD,
Ziv E,
Matthay MA;
National Heart, Lung, and Blood Institute ARDS Network.
Hudson L, Hough C, Neff M, Sims K, Watkins T, Steingrub J, Tidswell M, DeSouza L, Kardos C, Kozikowski L, Kozikowski K, Guntupalli K, Bandi V, Pope C, Brower R, Fessler H, Hager D, Mendez-Tellez P, Oakjones K, Needham D, Sevransky J, Workneh A, Han S, Murray S, Shanholtz C, Netzer G, Rock P, Sampaio A, Titus J, Harrington T, Herr D, Lee B, Bolouri N, Wiedemann HP, Ashton RW, Culver DA, Frederick T, Komara JJ, Guzman JA, Reddy AJ, Hejal R, Andrews M, Haney D, Connors AF, Lasalvia S, Thornton J, Warren EL, Moss M, Benson A, Burnham E, Clark B, Gray L, Higgins C, Maloney BJ, Mealer M, Frankel S, Bost T, Dennen P, Hodgin K, Douglas I, Overdier K, Thompson K, Wolken R, MacIntyre N, Brown L, Cox C, Gentile M, Govert J, Knudsen N, Carson S, Chang L, Lanier J, Wheeler A, Bernard GR, Hays M, Mogan S, Rice T, Hite RD, Morris PE, Howard A, Harvey A, Bender K, Wright P, Gross S, McLean J, Overton A, Truwit J, Enfield K, Marshall M, Clemmer T, Weaver L, Zenger M, Krueger J, Morris A, Ahmed A, Austin A, Dean N, Grissom C, Hirshberg E, Kumar N, Miller R, Napoli L, Orme J, Pandita S, Schreiber G, Struck L, Thomas F, Thomsen G, Lawton C, Leung F, Kim P, Fujii T, Baughman J, Kerwin B, Hanselman D, Sundar K, Alward W, Hill T, Campbell E, Ludwig K, Nielsen D, Pearce M, Matthay MA, Calfee C, Daniel B, Eisner M, Garcia O, Johnson E, Kallet R, Kordesch K, Liu K, Zhou H, Peterson M, Blaauw J, Albertson T, Vlastelin E, Hubmayr R, Brown D, Gajic O, Hinds R, Holets S, Kor DJ, Passe M, deBoisblanc B, Lauto P, Romaine C, Meyaski G, Hunt J, Marr A, Long EK, Brierre S, LeBlanc C, Taylor D, Jain S, Seoane L, Simeone F, Fearon J, Duchesne J, Schoenfeld D, Aquino M, Dorer D, Guha M, Hammond E, Lavery N, Lazar P, Molina I, Morse R, Oldmixon C, Rawal B, Ringwood N, Shui A, Smoot E, Thompson BT, Harabin A, Bredow S, Waclawiw M, Weinmann G, Spragg RG, Slutsky A, Levy M, Markovitz B, Petkova E, Weijer C, Willson D, Sznajder J, Begg M, Israel E, Lewis J, Parsons P.
Source
Department of Medicine, Division of General Internal Medicine, University of California, San Francisco, San Francisco, CA 94143-0131, USA. kkangelaris@medicine.ucsf.edu
Abstract
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.
- PMID:
- 22207676
- [PubMed - indexed for MEDLINE]
- PMCID:
- PMC3342784
Free PMC ArticleFigure 1.
Flowchart of inclusion and exclusion criteria. * = ARDS Network Trials: ALVEOLI (Assessment of Low Tidal Volume and Increased End-Expiratory Volume to Obviate Lung Injury), FACTT (Fluid and Catheter Treatment Trial), and ALTA (Albuterol for the Treatment of Acute Lung Injury) trials. NHLBI = National Heart, Lung, and Blood Institute.
Chest. 2012 May;141(5):1160-1169.
Figure 3.
Probability of survival to hospital discharge during the first 60 days according to Duffy status. Duffy-null individuals have increased risk of in-hospital death across the follow-up period. This is statistically significant (P = .04).
Chest. 2012 May;141(5):1160-1169.
Figure 2.
A, Estimated ancestry proportion score (APS) in ancestral African (HapMap CEPH-YRI), ancestral European (HapMap CEPH-CEU), and in African American ARDS Network study sample; each black line represents estimated APS for each individual. Although ancestral populations derived on HapMap exhibited relatively uniform proportions of African ancestry, the proportion of African ancestry varied widely in this sample of African Americans. Mean APS: Ancestral African = 0.99; Ancestral European = 0.02; ARDS Network sample = 0.82. B, Comparison of proportion African ancestry among African Americans in ARDS Network according to Darc rs2814778 genotype. The line in the middle of the box represents the median and the lines that form the box correspond to the 25th and 75th percentiles. *Kruskal-Wallis equality-of-populations rank test. The C allele was significantly associated with increased estimated African ancestry (P = .008), with a median APS of 0.87 among patients with the C/C genotype, 0.82 among those with the C/T genotype, and 0.72 among those with the T/T genotype.
Chest. 2012 May;141(5):1160-1169.
Publication Types
MeSH Terms
Substances
Grant Support
Full Text Sources
Other Literature Sources