Non-Infectious Pulmonary Complication after Stem Cell Transplantation and Genetic Background
Authors: Onizuka Makoto , Kunii Nanae , Toyosaki Masako , Inamoto Yoshihiro , Sugimoto Kyoko , Miyamura Koichi , Kodera Yoshihisa , Ando Kiyoshi , Inoko Hidetoshi 
Published: April 2020

Abstract
Non-infectious pulmonary dysfunction (NIPD) represents a common and often fatal complication of hematopoietic stem cell transplantation (HSCT). We have investigated genetic polymorphisms of some candidate genes and compared the frequency of developing NIPD with the allele frequency. Especially, we have reported ACE gene polymorphism was associated with NIPD. Recently, one report among Caucasian revealed that bactericidal/permeability-increasing (BPI) haplotypes were associated with increased risk of developing pulmonary dysfunction after HSCT. In order to certify the relationship between BPI and pulmonary dysfunction in the above ethnic group, we performed Japanese cohort study. We retrospectively analyzed the incidence of NIPD and genotype and allele frequency of BPI polymorphism in 124 Japanese patients who underwent HSCT from HLA-identical sibling donors at Japanese Red Cross Nagoya first Hospital. These patients received T cell replete transplantation with short-term methotrexate and cyclosporine as a GVHD prophylaxis. Informed consent was obtained from all patients and donors, and this study was approved by the ethics committees at Tokai University School of Medicine and Japanese Red Cross Nagoya First Hospital. We investigated TNFa (−308G/A), IL-8 (−251A/T), IL10 (−592C/A, −819C/T, −1082A/G), MMP9 (−1562C/T), insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) and BPI single nucleotide polymorphisms (rs5741798, rs1934917, rs5743530, rs2275954), by using RFLP and/or the TaqMan® method. Because there are many difference in allele frequency between Caucasian and Japanese, we selected two BPI SNPs which were not investigated in the last report (rs1934917, rs5743530). According to the International HapMap Project data, we could consider these new SNPs as tagSNPs among Japanese population. NIPD occurred in 21 patients (19.3%). In the patient group, the allele frequencies of rs1934917 and rs5743530 were significantly different in the patients with and without NIPD (allele T 83.3% vs 67.8%; P=0.04; 95% CI, 0.3–1.0 and allele C 70.0% vs 51,4%; P=0.03; 95% CI, 1.1–1.7, respectively). In the donors, the C allele of rs5743530 was more frequent in the NIPD group with NIPD than in the group without NIPD (67.5% vs 49.0%; P=0.03; 95% CI, 1.1–1.8). On the other hand, patients who had ACE DD genotype were significantly high frequency of NIPD group (genotype DD 42.9% vs 11.8%; P=0.0006; 95% CI, 1.8–7.5). No significant relationships were noted between the other genes polymorphisms and the development of NIPD. Although the SNPs in BPI associated with NIPD in Caucasian population did not reach statistical significance in this Japanese cohort study, the other two SNPs did. These findings suggest that the BPI may be associated with the development of NIPD in both the two ethnic groups. But in Japanese population study, ACE gene polymorphism may have more strong impact for developing NIPD.