Genetic variants of SP-D confer susceptibility to radiation pneumonitis in lung cancer patients undergoing thoracic radiation therapy

Abstract

Background: Surfactant protein D (SP-D) is an innate immunity molecule in the alveoli. However, the associations between genetic variants of SP-D and radiation pneumonitis (RP) have never been investigated.

Methods: The Linkage disequilibrium of SP-D and tagSNPs were analyzed by using Haploview 4.1. Eight tagSNPs were genotyped among 396 lung cancer patients who received thoracic radiation therapy with follow-up time (median [P25, P75]: 11[6, 18]) using improved multiplex ligation detection reaction (iMLDR). The associations between clinical characteristics, tagSNP alleles, genotypes, haplotypes and onset time of grade ≥2 or ≥3 RP were evaluated by using univariate and multivariate Cox proportional hazard regression model.

Results: Three tagSNPs of SP-D (rs1998374, rs911887 and rs2255326) were significantly associated with grade ≥2 RP in multivariate analysis with multiple testing (Q test). The rs199874 had a protective effect for grade ≥2 RP in the dominant model (Hazard ratio (HR), 0.575; 95% confidence interval (CI), 0.378-0.875). The homozygous mutant genotype for rs911887 had risk effect for grade ≥2 RP (HR, 2.209; 95% CI, 1.251-3.902). The A mutant allele of rs2255326 also showed an elevated risk for grade ≥2 RP (HR, 1.777; 95% CI, 1.283-2.461) and this risk effect was still significant in the recessive genetic model (HR, 3.320; 95% CI, 1.659-6.644) and dominant genetic model (HR, 1.773; 95% CI, 1.166-2.696). Compared to the lung cancer patients bearing the most common haplotype C-G-T, the patients bearing the haplotype T-A-C (rs1998374-rs2255326-rs911887) showed a significant risk of both grade ≥2 RP (HR, 1.885; 95% CI, 1.284-2.765) and grade ≥3 RP (HR, 2.256; 95% CI, 1.248-4.080).

Conclusions: Genetic variants of SP-D were associated with risk of RP development in lung cancer patients receiving thoracic radiotherapy.

Keywords: SP-D; genetic polymorphisms; lung cancer; radiation pneumonitis; susceptibility gene.

Figure 1

Kaplan‐Meier curve and log–rank test comparing the cumulative RP‐free probability of time to an adverse outcome between patients with alleles and genotypes of rs1998374, rs911887 and rs2255326. K‐M allele analysis of rs1998374, rs911887 and rs2255326 for grade ≥2 RP were (A‐C) and for grade ≥3 RP were (D‐F) respectively. K‐M genotype analysis of rs1998374, rs911887 and rs2255326 for grade ≥2 RP were (G‐I) and for grade ≥3 RP were (J‐L), respectively