Abstract
There is increasing knowledge that patients can be predisposed to a certain disease by genetic variations in their DNA. Extensive genetic variation has been described in molecules involved in short- and long-term complications after lung transplantation (LTx), such as primary graft dysfunction (PGD), acute rejection, respiratory infection, chronic lung allograft dysfunction (CLAD), and mortality. Several of these studies could not be confirmed or were not reproduced in other cohorts. However, large multicenter prospective studies need to be performed to define the real clinical consequence and significance of genotyping the donor and receptor of a LTx. The current review presents an overview of genetic polymorphisms (SNP) investigating an association with different complications after LTx. Finally, the major drawbacks, clinical relevance, and future perspectives will be discussed.
Genetic background may play an important role in the outcome after lung transplantation.
Some genetic polymorphisms were associated with functional changes influencing outcome after lung transplantation.
There is a stringent need for multicenter prospective studies to reveal the clinical consequence of SNPs.
Introduction
Lung transplantation (LTx) is the ultimate treatment option for selected patients suffering from specific end-stage pulmonary disorders. However, after LTx, mortality rates remain relatively high, mainly due to the occurrence of chronic rejection (Citation1). Chronic rejection is characterized by an irreversible lung function decline in forced expiratory volume in 1 s of at least 20% compared to the two best postoperative values (Citation2). Lately, it has become increasingly clear that different phenotypes of chronic rejection exist, which has important clinical and scientific implications. As a consequence, the term chronic lung allograft dysfunction (CLAD) has been introduced, which encompasses all forms of chronic rejection. This has led to a new classification system which takes the different manifestations of chronic rejection into account (Citation3), including restrictive CLAD (or restrictive allograft dysfunction, RAS) and the classical form of CLAD which is obstructive and is best known as bronchiolitis obliterans syndrome (BOS) (Citation4). Many of the old studies cited in this paper used the old terminology, and hence when they were investigating the prevalence of BOS they were most likely investigating the incidence of CLAD. CLAD is accepted to be both an alloantigen dependent and independent process for which many risk factors have been identified, including acute rejection, lymphocytic bronchiolitis, the presence of auto-antibodies against collagen V, colonization with micro-organisms, and air pollution (Citation2–4). These insults will activate the immune system and increase airway neutrophilia, which will lead to epithelial damage, excessive airway wall repair, and finally fibrosis/obliteration of the airways (Citation1,Citation5). The underlying mechanisms of CLAD remain to be elucidated. Not only CLAD but also primary graft dysfunction (PGD), acute rejection, and respiratory infections are risk factors for mortality after LTx (Citation6).
These studies have so far ignored the vast genetic diversity within transplant recipients and donors. It is well known that in large patient cohorts genetic background can be linked to human health and disease (Citation7,Citation8). Genetic predisposition has already proven to be important in many pulmonary diseases, for example delta F508 mutation (Citation9) in cystic fibrosis, MUC5B polymorphism in interstitial lung diseases (Citation10), etc. Therefore, genetic predisposition may also play a role after LTx, although this has not yet been thoroughly investigated. In the last decade, several groups have provided evidence for the importance of the underlying genetic background regarding the outcome after LTx. Herein, we review current but also historic evidence for the role of genetic predisposition in predicting the outcome after lung transplantation. We will specifically focus on complications after LTx, such as PGD, acute rejection, respiratory infection, CLAD, and mortality. The major drawbacks, clinical relevance, and future perspectives on genotyping donor and/or recipient will also be discussed.
Primary graft dysfunction (PGD)
PGD, with an incidence of 10%–30%, is the main cause of mortality and morbidity within the first 30 days after LTx (Citation6). PGD is characterized by hypoxemia and radiographic infiltrates occurring within 72 h of LTx (Citation11). PGD is subdivided in different grades (grades 0, 1, 2, and 3) according to the presence of diffuse alveolar infiltrates and the PaO2/FiO2 ratio; PGD grade 3 is defined as PaO2/FiO2 less than 200 with pulmonary infiltrates on X-ray (Citation11). The primary outcome in all published genetic studies so far was any grade 3 PGD within 72 hours of reperfusion versus PGD < 3. In such an early phase after LTx, it seems logical that donor-related factors play a role in the development of PGD (Citation12). The Lung Transplant Outcome Group (LTOG) studies described specific pathways that are associated with the development of PGD, namely long pentraxin-3 (PTX3) and the prostaglandin E2 (PGE2) family. PTX3 is a phylogenetically conversed mediator of the innate immune response, shown to be involved in PGD development (Citation13). In this multicenter study, blood samples of 654 LTx patients were included with genotyping of 10 haplotypes of PTX3. Two single-nucleotide polymorphisms (SNP) (rs2120243 and rs2305619) were associated with PGD. Because the levels of plasma PTX3 demonstrated a wider variability among patients with idiopathic pulmonary fibrosis (IPF) compared with those with chronic obstructive pulmonary disease, functional analysis of both SNPs focused on patients transplanted with IPF as underlying disease. The minor allele of the SNP (rs2305619) was functionally associated with higher levels of PTX3 before and 24 h after LTx in patients with IPF (13 subjects with PGD compared to 34 without PGD) (Citation14).
Secondly, they also studied the effect of PGE2 genetic polymorphisms on the development of PGD in 680 lung recipients. Four SNPs in two genes of the PGE2 family, Prostaglandin E2 synthesis (rs13283456) and Prostaglandin E2 receptor (rs11957406, rs4434423, rs4133101), were associated with PGD. The prostaglandin E2 receptor plays a central role in the immunomodulation and the control of inflammation mediated by PGE2 (Citation15). Activation of the receptor inhibits activation and proliferation of T cells, driving cellular immunity (Citation16). The immunosuppressive role of the PGE2 receptor was functionally demonstrated in 42 patients with increased Treg suppressor function in cells possessing the rs4434423 T allele, which was associated with lower PGD risk (24 subjects with PGD compared to 18 without PGD). Thirteen other SNPs, coding for various other functions, from the in total about 1,800 investigated genes in this LTOG study were associated with the development of PGD (Citation17). More details are demonstrated in .
Table I. Overview of all studies with possible associations between genetic background and PGD after LTx.
Acute rejection
The diagnosis of acute rejection relies on the identification of lymphocytic infiltrates in lung tissue. Several studies have demonstrated that acute vascular (AR, acute rejection) or airway (LB, lymphocytic bronchiolitis) rejection are the main risk factors for chronic rejection, the most common cause of death beyond the first year after LTx (Citation18). AR and LB were defined on histopathology according to the International society of heart and lung transplantation (ISHLT) guidelines and graded according to the severity of lymphocytic infiltration (A1-4/B1R-B2R) (Citation19). The first study describing the association between genetic background and acute rejection (grade > A2) was done by the Pittsburg group. A total of 119 LTx patients were analyzed for interleukin-10 (IL-10) genotype. IL-10 is an anti-inflammatory cytokine that is expressed in healthy airways (Citation20) and has a possible protective effect in allografts (Citation21,Citation22). The genotype with functional increased IL-10 was shown to be protective for the development of acute rejection. No direct correlations between acute rejection and specific genotypes for tumor necrosis factor α (TNF-α), transforming growth factor β1 (TGF-β1), IL-6, and interferon-γ (INF-γ) were found (Citation23). A few years before, Jackson et al. did not find an association with acute rejection (definition unclear) and eight SNPs of INF-γ, TNF-α, TGF-β1, IL-6, or IL-10 in 77 lung LTx patients (Citation24).
In the past 10 years, Palmer and colleagues were the most prominent researchers investigating the genetic background of acute rejection after LTx. They proposed that innate immune immunity is primarily responsible for developing acute lung rejection (Citation25). Toll-like receptors (TLR) are a family of innate immune receptors critical for initiation of innate responses to microbial pathogens (Citation26). In the lung, TLR-4 is highly expressed on the alveolar macrophages and on the airway epithelium. Activation of TLR-4 induces an increased production of proinflammatory cytokines and chemokines and also increases the expression of major histocompatibility complex and co-stimulatory molecules on alveolar macrophages, which facilitate recruitment of additional immune cells and promote an effective adaptive immune response (Citation27). Two SNPs in the TLR-4 gene (Asp299Gly and Thr399Ile, respectively, rs4986790 and rs4986791) were shown to be functionally associated with endotoxin hyporesponsiveness and reduced rate of acute allograft rejection (Citation28). The presence of these TLR-4 polymorphisms in the genetic profile of 147 receptors, and not of the donors, was associated with reduced frequency, severity, and incidence of acute rejection (≥ A1), without influencing chronic rejection. This finding confirmed that innate immunity contributes in the development of acute rejection after LTx (Citation29). The second study of this group described a polymorphism of CD14, an innate pattern recognition receptor that binds to lipopolysaccharide and promotes signaling through TLR-4 (Citation30). The TT genotype of the SNP, located in the promoter of CD14 gene, has been associated with enhanced transcriptional activity of this gene (30%) and increased levels of soluble CD14 in peripheral blood (Citation31,Citation32). The TT genotype of this SNP (rs2569190) was associated with enhanced immune activation, exhibiting increased risk for developing acute rejection (A or B grade) in 226 recipients (Citation33).
In the last two years the Leuven lung transplant unit has published three studies of genetic polymorphisms with the primary outcomes chronic rejection and mortality, and secondary endpoints like acute rejection, clearly subdivided in AR and LB. Caveolin-1 (CAV-1) is involved in tissue homeostasis, as it has anti-inflammatory and anti-oxidative effects and it also increases apoptosis and bacterial clearance (Citation34). In 503 LTx recipients the polymorphism in the CAV gene (rs3807989), however, did not have an effect on AR, nor on LB (Citation35). Also, a polymorphism in the immunoglobulin G receptor polymorphism (IgGR) demonstrated no association with AR (Citation36). The only study of the Leuven lung transplant group that showed a correlation between a genetic polymorphism and acute rejection was the interleukin-17 receptor (IL-17R, rs879574). IL-17 is an inducer of airway neutrophilia with a proven effect in acute rejection (≥ A1) (Citation37). The genetic polymorphism (AA and AT) of the IL-17R in 497 LTx recipients was associated with an increased risk of developing AR, but not LB, with a functional increased risk of BAL neutrophilia compared to the TT genotype (Citation38) ().
Table II. Overview of all studies with possible associations between genetic background and acute rejection.
Infections
Mitsani et al. (Citation39) described a polymorphism in 170 LTx recipients linked with elevated levels of INF-γ which was associated with an increased risk of cytomegalovirus disease (CMV). CMV is an accepted risk factor for the development of CLAD (Citation40). No association between TNF-α, IL-10, and IL-6 SNPs and CMV infections was found. Palmer et al. did not find an association between SNPs in TLR-4 and infectious complications (Citation41). In the previously described studies of IL-17 and CAV-1 polymorphisms, no association was demonstrated with respiratory infections. There was, however, a genetic link between the IgG receptor SNP and respiratory infections. IgG is a protein representing approximately 75% of serum immunoglobulins. Low levels of IgG were associated with an increased number of respiratory infections (Citation42). The genotype (TT) at risk resulted in more respiratory infections and respiratory infections per patient compared to the other genotypes. The finding of the increased risk for respiratory infections was probably an indirect proof of the functionality of this SNP (rs12746613) (Citation38).
CLAD
As mentioned before, most of these studies looked at CLAD, without making a distinction between the different forms of CLAD. The first study to describe a link between genetic polymorphisms and CLAD after LTx was performed by Awad et al. (Citation43). A functional gene of INF-γ, an inflammatory cytokine that has been implicated in the development of fibrosis in inflamed tissues (Citation44), was associated, with increased alveolar graft fibrosis, in 82 transplant recipients. In a second study, this group demonstrated one SNP (major allele codon 25), to be associated with an increased production of TGF-β1, a profibrotic cytokine (Citation45). This SNP was also associated with an increased risk of post-LTx alveolar graft fibrosis (Citation46). The third study of this group confirmed the findings of the TGF-β1 SNP (major allele codon 25) and demonstrated that a second TGF-β1 SNP was also associated with allograft fibrosis (Citation47). In 2002, Lu et al. published paper on a genetic polymorphism of INF-γ and concluded that there was an earlier development of CLAD after LTx, in recipients (n = 93) with the genotype at risk. The same association was found with an IL-6 polymorphism. However, in this study no association was found between CLAD and genetic polymorphisms of TNF-α, TGF-β1, and IL-10 (Citation48).
These positive studies for IL-6, INF-γ, and TGF-β1 were not confirmed in other studies; Jackson et al. did not find an association between CLAD and SNPs of INF-γ, TNF-α, TGF-β1, IL-6, and IL-10, and neither did Snyder et al. in two independent cohorts (Citation49).
The TLR-4 genotype (rs4986790, rs4986791) had an effect on the acute rejection rate as previously described, but had no effect on CLAD development (Citation29,Citation41), whereas in the study of Palmer et al., regarding CD14 (rs2569190), an association with CLAD was indeed present. LTx recipients with the TT genotype had a higher incidence and earlier development of CLAD (Citation33). Six SNPs for mannose binding lectin (MBL), a recognition molecule for innate immunity (Citation50), were studied in 181 donors and 198 LTx recipients a few years later. MBL deficiency has been associated with increased morbidity and mortality in other solid organ transplantations (Citation51,Citation52). The recipients who received a graft from a donor with a heterozygote variant of a MBL SNP located in a promoter region developed less CLAD compared to those with the homozygote variant (Citation53).
In 2010 and 2011 the group of Utrecht published several papers studying genetic polymorphisms and CLAD after LTx. The first study described 64 polymorphisms, in 10 TLR genes (TLR-1 to TLR-10) in 110 LTx patients. They showed an association of TLR-2 (rs1898830 and rs7656411), TLR-4 (rs1927911), and TLR-9 (rs352162 and rs187084) with CLAD: homozygotes of the major allele of rs187084, rs1898830, and rs352162 had an increased risk to develop CLAD compared to the carriers of the minor allele, and the homozygotes of the minor allele of rs7656411 and rs1927911 had an increased risk to develop CLAD compared to the carriers of the minor allele (Citation54). A second study in the same cohort, of a SNP of matrix metalloproteinase-7 (MMP-7), important in lung repair (Citation55), demonstrated an increased risk for CLAD development. The increased risk was found in patients with a homozygote variant for the major alleles of rs177098318, rs11568818, and rs12285347 and the minor allele of rs10502001. Two other studied SNPs revealed no association with CLAD. Functionally, patients homozygous for the major alleles of rs11568818 and rs12285347 had lower concentrations of MMP-7 compared to homozygotes of the minor allele (Citation56). In the third study of the Utrecht group, four SNPs of the already described CAV-1 gene were genotyped. Homozygosity of the minor allele of rs3807989 was associated with an increased risk for CLAD, and this SNP was also associated with increased levels blood of CAV-1 (Citation57).
A study of a surfactant protein A (SP-A) SNP, playing an important role in the innate host defense and which may serve as cross-talk protein between innate and adaptive immune response (Citation58). Patients with low SP-A mRNA levels associated with specific genetic phenotype in the donor lungs were detected, but there was no clear relation with CLAD (Citation59). Compared to the study of two genetic polymorphisms of SP-D, which has a comparable mechanism of SP-A (Citation58), an association with CLAD was found in one SNP. In 191 LTx patients, the homozygote variant of a genetic polymorphism, altering an amino acid in the mature protein N-terminal domain codon 11 (Met11Thr) of donor DNA had an increased rate of CLAD compared to the heterozygote variant (Citation60).
Bourdin and colleagues studied a donor and receptor clara cell secretory protein (CCSP) polymorphism. Clara cells are bronchiolar stem cells characterized by unique morphologic features and are crucial to small airway repair processes and epithelium integrity (Citation61). In 63 LTx patients, this polymorphism was associated with an increased risk of CLAD, and a functional decrease in CCSP BAL levels was observed (Citation62).
The studies published by our own group on the CAV-1 and IgG polymorphisms did not find an association with development of CLAD (Citation35,Citation36). The study of the IL-17R polymorphism (rs879574), not only an inducer of acute but also CLAD (Citation37), in a cohort of 497 LTx patients revealed that the allele at risk (AA/AT compared to TT) was associated with an increased susceptibility to CLAD. As already mentioned, this polymorphism had a functional increased risk of BAL neutrophilia (Citation38). For a summary and more details see .
Table III. Different genetic background studies with an association with CLAD after lung transplantation after LTx. .
Mortality
A lot of the previously described studies do not only have CLAD as an endpoint, they also described the association between genetic polymorphisms and mortality. The Manchester group was the first to describe an association between genetic polymorphisms and mortality in 91 LTx patients. While only one SNP of TGF-β1 had an effect on CLAD, LTx recipients who were homozygous for both one non-functional variant and the functional genetic variant of TGF-β1 showed poor survival (Citation46). The TLR-4 study of Palmer and colleagues in 2004 could not find an association with mortality (Citation41). In the first cohort (n = 76) of Snyder et al., the IL-6 polymorphism (GG and GC) was associated with a worse survival, while in the second bigger cohort (n = 198) this association could not be confirmed (Citation49). The TT genotype of a CD14 SNP (rs2569190) was associated with enhanced immune activation, exhibiting not only an increased risk for developing acute rejection/CLAD, but the TT genotype was also associated with increased mortality in 226 recipients (Citation33). The same observation was seen in the study of donor MBL promoter SNP, whereas the recipients who received a graft from a donor with a homozygote variant of an MBL SNP had higher mortality compared to recipients who received a graft from a donor with the wild-type variant (Citation53). D’Ovidio et al. demonstrated that several SP-A2 polymorphisms were associated with lower SP-A mRNA expression and with increased mortality (Citation59). In addition to this study, a homozygote variant of a genetic polymorphism SP-D, altering an amino acid in the mature protein N-terminal domain codon 11(Thr11Thr) of donor DNA in 191 LTx patients, not only resulted in an increased rate of CLAD, but also in a worse survival compared to the heterozygote variant (Citation60). In 63 LTx patients, the functional donor CCSP SNP was associated with an increased risk of mortality (Citation62).
In contrast to CLAD, for which no association was found with CAV-1 and the IgGR polymorphism, mortality was affected by these two genetic polymorphisms. The (AA+ AG) genotypes of rs3807989 (CAV-1 SNP) resulted in a worse survival compared to the GG genotype (Citation35). The IgGR (rs12746613) polymorphism was associated with a higher risk of mortality in the TT genotype compared with the CC genotype in 418 patients (Citation36). In the IL-17 polymorphism study, no significant association was found with mortality (Citation38).
Some of the studies showed a difference in CLAD, but not in mortality. This is possibly due to the fact that mortality after lung transplantation is related to different causes such as infection and postoperative complications, and not always due to CLAD. Even late postoperative mortality can be totally unrelated to CLAD but due to, for example, cancer or infection. It would be interesting to look at CLAD-related mortality, but unfortunately this was not done in the majority of the cited studies. For a summary and more details see .
Table IV. Different genetic background studies with an association with mortality after lung transplantation after LTx.
Major drawbacks and clinical relevance
Genetic influences on LTx outcomes belong to complex disease pathways, where not only the patient (receptor) but also the donor should be considered. This statement already indicates the first concern in the interpretation of genetic studies. Most of the studies were performed on the receptor DNA without taking the genetic profile of the donors into account. There is also an important lack of reproducibility of some results which may be due to several reasons: 1) inadequate (too low) power, 2) poorly defined endpoints, 3) failure to correct for confounders, 4) retrospective studies, 5) short follow-up time, and 6) no replication cohort. Another problem is the historical effect: some cohorts go back to 1990 for inclusion of the first patients; since then, lots of improvements have been made in donor preservation, selection of recipients, operative techniques, postoperative management, medications, etc., and it is very difficult to correct for this. Nevertheless, the genetic background of a recipient or donor lung can be considered to be important for later post-LTx outcome. Knowing the genetic profile of the donor and receptor could be used in a preventive way, indicating that closer follow-up might prevent complications. For example, if one knows that there is a higher risk for infections, broader prophylactic precautions may be warranted.
Future perspectives
LTx is a rather infrequent treatment option which makes acquiring a high number of patients for genetic analysis difficult. As a consequence, there is certainly need for multicenter studies of patients with comparable genetic background, as nowadays performed by the LTOG, to increase the number of patients. Secondly, it would be ideal to confirm findings in a comparable, replication cohort. Thirdly, the genetic variations that are studied should ideally be functional, for example as is obvious from other solid organ transplantations, or functionality should at least be confirmed, for example by measuring protein levels that are affected by the investigated gene. Fourthly, genetic analysis could be very interesting in the ongoing discussion of the different phenotypes of CLAD. Genetic information could be important in the search for potential differential mechanisms driving BOS and RAS as both forms of CLAD are likely to have different genetic risks. The progress in genotyping techniques makes it now possible to test large cohorts with a large set of genetic variations in terms of genome-wide association studies (GWAS). The strength of the genome-wide screening is its ability to reveal not only the gene that would be expected to play a role but also other genes, leading to new insights into pathophysiology. There may also possibly be a role for epigenetic studies in LTx. This is the study of changes in gene expression caused by certain base pairs in DNA, or RNA, being ‘turned off’ or ‘turned on’ again, through chemical reactions. Epigenetics is mostly the study of heritable changes that are not caused by changes in the DNA sequence; to a lesser extent, epigenetics also describe the study of stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable (Citation63). The hope is that epigenetics reveal differences in the pathophysiological mechanisms of the phenotypes of CLAD and that altering epigenetics in transplanted organs will ultimately lead to a higher quality of life for transplant patients (Citation64).
Conclusion
Several SNPs have been associated with various outcome parameters after LTx. However, there is a stringent need for prospective multicenter studies and replication of these findings, in order to make current data more robust and to reveal the clinical consequences. Despite the limitations of using data obtained from genetic studies in LTx, the challenge of incorporating this research into clinical care must be pursued in order to improve our understanding of pathogenesis of post-LTx complications and, more importantly, to achieve improved treatment or prevention, resulting in better outcomes after LTx.
Funding: Glaxo Smith Kline (Belgium) chair in respiratory pharmacology at the KU Leuven; grants from the Research Foundation Flanders (FWO) [G.0723.10, G.0679.12 and G.0705.12]; grant from the KU Leuven [OT10/050]. S.E.V. is funded by the research fund FWO. R.V. is supported by FWO and KOF UZ Leuven.
Declaration of interest: The authors report no conflicts of interest.
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