Variation in PTX3 is associated with primary graft dysfunction after lung transplantation

Abstract

Rationale: Elevated long pentraxin-3 (PTX3) levels are associated with the development of primary graft dysfunction (PGD) after lung transplantation. Abnormalities in innate immunity, mediated by PTX3 release, may play a role in PGD pathogenesis.

Objectives: Our goal was to test whether variants in the gene encoding PTX3 are risk factors for PGD.

Methods: We performed a candidate gene association study in recipients from the multicenter, prospective Lung Transplant Outcomes Group cohort enrolled between July 2002 and July 2009. The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD within 72 hours of transplantation. Targeted genotyping of 10 haplotype-tagging PTX3 single-nucleotide polymorphisms (SNPs) was performed in lung transplant recipients. The association between PGD and each SNP was evaluated by logistic regression, adjusting for pretransplantation lung disease, cardiopulmonary bypass use, and population stratification. The association between SNPs and plasma PTX3 levels was tested across genotypes in a subset of recipients with idiopathic pulmonary fibrosis.

Measurements and main results: Six hundred fifty-four lung transplant recipients were included. The incidence of PGD was 29%. Two linked 5' region variants, rs2120243 and rs2305619, were associated with PGD (odds ratio, 1.5; 95% confidence interval, 1.1 to 1.9; P = 0.006 and odds ratio, 1.4; 95% confidence interval, 1.1 to 1.9; P = 0.007, respectively). The minor allele of rs2305619 was significantly associated with higher plasma PTX3 levels measured pretransplantation (P = 0.014) and at 24 hours (P = 0.047) after transplantation in patients with idiopathic pulmonary fibrosis.

Conclusions: Genetic variants of PTX3 are associated with PGD after lung transplantation, and are associated with increased PTX3 plasma levels.

Figure 1.

Gene structure of pentraxin-3 (PTX3), with approximate positions of single-nucleotide polymorphisms (SNPs) included for analysis. Exons are depicted as solid rectangles, whereas introns are open rectangles, and 5′ and 3′ untranslated regions (UTRs) are hatched.

Figure 2.

Linkage disequilibrium (LD) structure of PTX3 in the study population. LD values and shading represent R² values, with higher numbers and darker shading reflecting a higher degree of LD. Each single-nucleotide polymorphism in the haplotype is listed by its reference sequence (rs) number.

Figure 3.

Box plot of plasma pentraxin-3 (PTX3) concentration 24 hours after transplantation stratified genotype at rs2305619 locus. (A) Eighty-two patients with PTX3 genotyping and plasma concentration measurements. (B) Forty-seven patents with a preoperative diagnosis of idiopathic pulmonary fibrosis (IPF) with PTX3 genotyping and plasma concentration measurements. Each horizontal line indicates median concentration. The upper and lower limits of each box indicate the interquartile range. The P value reported is from nonparametric test for trend.