The association between a Darc gene polymorphism and clinical outcomes in African American patients with acute lung injury.
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.
Department of Medicine, Division of General Internal Medicine, University of California, San Francisco, San Francisco, CA; Division of Hospital Medicine, University of California, San Francisco, San Francisco, CA. Electronic address: kkangelaris@medicine.ucsf.edu.
Kirsten Neudoerffer
KN
Kangelaris
Department of Pediatrics, Division of Critical Care, University of California, San Francisco, San Francisco, CA.
Anil
A
Sapru
Division of Pulmonary and Critical Care, University of California, San Francisco, San Francisco, CA; Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA.
Carolyn S
CS
Calfee
Division of Nephrology, University of California, San Francisco, San Francisco, CA; Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA.
Kathleen D
KD
Liu
Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA.
Ludmila
L
Pawlikowska
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA.
John S
JS
Witte
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA.
Eric
E
Vittinghoff
Division of Pulmonary and Critical Care, University of California, San Francisco, San Francisco, CA.
Hanjing
H
Zhuo
Division of Hospital Medicine, University of California, San Francisco, San Francisco, CA.
Andrew D
AD
Auerbach
Department of Medicine, Division of General Internal Medicine, University of California, San Francisco, San Francisco, CA.
Elad
E
Ziv
Division of Pulmonary and Critical Care, University of California, San Francisco, San Francisco, CA; Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA.
Michael A
MA
Matthay
D055371:Acute Lung Injury / Q000235:genetics* / Q000401:mortality; D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000483:Alleles; D002423:Cause of Death; D015331:Cohort Studies; D004375:Duffy Blood-Group System / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D017052:Hospital Mortality; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D011110:Polymorphism, Genetic / Q000235:genetics*; D011336:Probability; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics*; D016019:Survival Analysis; D015996:Survival Rate; D014481:United States
C473745:ACKR1 protein, human; D004375:Duffy Blood-Group System; D016209:Interleukin-8; D011956:Receptors, Cell Surface