Association Between AGT SNPs, Plasma AGT Levels, and Risk for IPS After Allogeneic HCT

Background: Idiopathic pneumonia syndrome (IPS) is a severe respiratory complication that can occur in 2-15% of allogeneic hematopoietic cell transplant (HCT) recipients. IPS is clinically characterized by widespread alveolar injury, not caused by infection, cardiac dysfunction, acute renal failure, or fluid overload. Although current understanding of IPF pathogenesis is limited, human and animal models of IPS and acute lung injury suggest that inflammatory and fibrotic pathways may be involved. We investigated whether single nucleotide polymorphisms (SNPs) in and near candidate genes previously found to be associated with acute lung injury may influence the risk for developing IPS.

Methods: We conducted a genetic association study using clinical data and DNA from 67 IPS and 783 control patients. IPS was defined by chart review according to American Thoracic Society Guidelines. All SNPs within the candidate gene and +/-50kb identified from the 1000 Genome Project were either genotyped using the Affymetrix GeneChip® Genome-Wide SNP 5.0 (n=470) or the Illumina 1M Quad (n=380), or imputed using previously published methods. All SNPs were analyzed in additive, dominant, and recessive multivariate genetic models and the Bonferroni method was used to adjust for multiple comparisons. Association between the AGT SNPs and plasma AGT levels was evaluated in an independent cohort of 378 allogeneic HCT patients.

Results: A total of 1277 SNPs (31 genotyped in both cohorts, 293 genotyped in one cohort and imputed in another, 953 imputed in both cohorts) in 8 candidate genes (ACE, AGT, SP-B, RANTES, DARC, MCP-1, TNFa and TNFR II) were evaluated.  Six SNPs in AGT (rs3827749, rs3789666, rs3789667, rs2478545, rs2478544 and rs1078499, five out six are imputed) met the significance threshold and were associated with an increase in IPS risk in a recessive genetic model (hazard ratio range 3.58 – 4.71, p-value range 0.001 – 0.0004). In an independent cohort, all 6 SNPs were found to be significantly associated with lower plasma AGT levels in the recessive genetic model (mean AGT levels: homozygous recessive 17.8 – 22.4 ng/mL, heterozygous and homozygous wild type 27.3 ng/mL, p-value range 0.002 – 0.00001).

Conclusions: These results suggest that renin-angiotensin system may be involved in the pathogenesis of IPS after allogeneic HCT.