Genotypes and haplotypes of VEGF gene are associated with higher ARDS Mortality and lower VEGF plasma levels

Rihong Zhai ¹, Michelle N Gong ², Wei Zhou ¹, Taylor B Thompson ³, Peter Kraft ¹, Li Su ¹ and David C Christiani ^4*

¹ Harvard School of Public Health, United States
² Mount Sinai School of Medicine, United States
³ Massachusetts General Hospital, United States
⁴ Harvard School of Public Health, Harvard Medical School, United States

^* To whom correspondence should be addressed. E-mail: dchristi{at}hsph.harvard.edu.

Accepted 9 January 2007

Abstract

Background Endothelial injury is an important prognostic factor in acute respiratory distress syndrome (ARDS). Vascular endothelial growth factor (VEGF) plays a critical role in endothelial destruction and angiogenesis. Genetic variations of VEGF have been associated with VEGF production. A study was undertaken to investigate the impact of VEGF gene polymorphisms on ARDS development and clinical outcomes.

Methods Three VEGF polymorphisms (-460C/T, +405C/G, and +936C/T) were determined in 1253 ICU patients with risk factors for ARDS. Among them 394 patients developed ARDS. Patients were followed for 60-day survival. Plasma VEGF levels were measured in 71 patients with ARDS.

Results The +936TT (OR=4.29; 95%CI, 1.12-16.40; p=0.03) and +936CT+TT (OR=1.98; 95%CI, 1.14-3.42; p=0.01) genotypes were significantly associated with increased ARDS mortality. Plasma VEGF levels in ARDS patients with the +936CT+TT genotype (median 49pg/ml, IQR 16-98pg/ml) were significantly (p=0.02) lower than that in subjects with the +936CC genotype (median 112pg/ml, IQR 47-162pg/ml). At haplotype levels, haplotype TCT (-460T+405C+936T) was significantly associated with higher ARDS mortality (OR=2.89; 95%CI, 1.30-6.43; p=0.009). Haplotype CGT (- 460C+405G+936T) was associated less strongly with increased ARDS mortality (OR=1.90; 95%CI, 0.94-3.84; p=0.07). Lower plasma VEGF levels were correlated to the probability of haplotype CGT (coefficient=-0.26, p<0.05) but the same trend of correlation was not significant to haplotype TCT.

Conclusions VEGF polymorphisms may contribute to ARDS prognosis and inter-individual variations in circulating VEGF levels.

Keywords: ARDS mortality, VEGF polymorphisms, plasma level

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