Role of genetics in lung transplant complications
D. Ruttens1, E. Vandermeulen1 , S.E. Verleden1, H. Bellon1, R. Vos1, D.E. Van
Raemdonck1, L. Dupont, B.M. Vanaudenaerde1, G.M. Verleden1
1
KULeuven,and UZ Leuven, Dept of Clinical and experimental Medicine, lab of pneumology,
lung transplant unit
Running title: Genetics and outcome after LTx
Grants: 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. SEV is funded by the research fund
FWO. RV is supported by FWO and KOF UZ Leuven.
Address for correspondence:
Prof. Dr. Geert Verleden
Lab of Pneumology, Lung Transplantation Unit
KU Leuven
Herestraat 49, B-3000 Leuven, Belgium
Tel: + 32 16 330 195 Fax: + 32 16 347124
E-mail: geert.verleden@med.kuleuven.be
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, CLAD and mortality. Several of
these studies could or were not confirmed or reproduced in other cohorts. However, large
multi-centric 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.
Key words:
Lung transplantation - outcome - mortality - primary graft dysfunction- acute rejection chronic rejection - chronic lung allograft dysfunction- single nucleotide polymorphisms
Key message:
- 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 multicentric prospective studies to reveal the clinical
consequence of SNP’s.
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 (1). Chronic rejection, also
defined as chronic lung allograft dysfunction (CLAD), with bronchiolitis obliterans syndrome
(BOS) and restrictive CLAD being the most frequent presentations, is characterized by an
irreversible lung function and threatens over 50% of the lung transplant recipients within 5
years after LTx Chronic rejection is characterized by an irreversible lung function decline in
forced expiratory volume in 1 second of at least 20% compared to the 2 best post-operative
values (2). Lately, it became 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 led to a new classification system which takes the different
manifestations of chronic rejection into account (3), including restrictive CLAD (or restrictive
allograft dysfunction, RAS) and the classical form of CLAD which is obstructive and is best
known as BOS (4). 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.BOS 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 (2-4). 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 (1;5).
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 (6).
These studies so far ignored the vast genetic diversity within transplant recipients and donors.
It is well known that in large patients’ cohorts genetic background can be linked to human
health and disease (7;8). Genetic predisposition has already proven to be important in many
pulmonary diseases for example delta F508 mutation (9) in cystic fibrosis, MUC5B
polymorphism in interstitial lung diseases (10), etc. Therefore, genetic predisposition may
also play a role after LTx, although this has not yet been thoroughly investigated. The last
decade, several groups 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 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 (6). PGD is characterized by hypoxemia and radiographic infiltrates
occurring within 72 h of LTx (11). PGD is subdivided in different grades (0, 1, 2, 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 (11). The primary
outcome in all published genetic studies so far was any grade 3 PGD within 72 hours of
reperfusion versus PDG <3. In such early phase after LTx, it seems logical that donor-related
factors play a role in the development of PGD (12). 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 (13). In this multi-centric study, blood samples of 654 LTx patients were
included with genotyping of 10 haplotypes of PTX3. Two single nucleotid 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
24h after LTx in patients with IPF (13 subjects with PGD compared to 34 without PGD) (14).
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 (15). Activation of the
receptor inhibits activation and proliferation of T cells, driving cellular immunity (16). 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 1800
investigated genes in this LTOG study were associated with the development of PGD (17).
More details are demonstrated in table 1.
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 (18). AR and LB were defined
on histopathology according to the ISHLT guidelines, and graded according to the severity of
lymphocytic infiltration (A1-4/B1R-B2R) (19). The first study describing the association
between genetic background and acute rejection (grade>A2) was done by the Pittburgh group.
Hundred nineteen LTx patients were analyzed for interleukin-10 (IL-10) genotype. IL-10 is an
anti-inflammatory cytokine that is expressed in healthy airways (20) and has a possible
protective effect in allografts (21;22). The genotype with functional increased IL-10 showed
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 (23). A few years before,
Jackson et al did not find an association with acute rejection (definition unclear) and 8 SNP’s
of INF-γ, TNF-α, TGF- β1, IL-6 or IL-10 in 77 lung LTx patients (24).
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 (25). Toll-like
receptors (TLR) are a family of innate immune receptors critical for initiation of innate
responses to microbial pathogens (26). 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 costimulatory molecules on alveolar macrophages,
which facilitate recruitment of additional immune cells and promote an effective adaptive
immune response (27). 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 (28). 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 (29). 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 (30). 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 (31;32).
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 (33).
In the last two years the Leuven lung transplant unit published three studies of genetic
polymorphisms with 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 (34). In 503 LTx recipients the polymorphism in
CAV gene (rs3807989), however, did not have an effect on AR, nor on LB (35). Also, a
polymorphism in the immunoglobulin G receptor polymorphism (IgGR) demonstrated no
association with AR (36). The only study of the Leuven Lung transplant group that showed a
correlation between a genetic polymorphism and acute rejection was interleukin-17 receptor
(IL-17R, rs879574). IL-17 is an inducer of airway neutrophilia with a proven effect in acute
rejection (≥A1) (37). 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 (38) (table 2).
Infections
Mitsani et al 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 (39). No association between TNF-α,
IL-10 and IL-6 SNP’s and CMV infections was found. Palmer et al did not find an association
between SNPs in TLR4 and infectious complications (40). 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 increased number of respiratory infections (41). 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)(38).
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 (42). A functional gene of
INF-γ, an inflammatory cytokine that has been implicated in the development of fibrosis in
inflamed tissues (43), 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 (44). This SNP
was also associated with an increased risk of post-LTx alveolar graft fibrosis (45). 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 (Cytosine dilatation) was also associated with
allograft fibrosis (46). In 2002, Lu et al published 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.
Although in this study, no association was found between CLAD and genetic polymorphisms
of TNF-α, TGF- β1 and IL-10 (47).
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 SNP’s of INF-γ, TNF-α, TGFβ1, IL-6 and IL-10, neither did Snyder et al in 2 independent cohorts (48).
The TLR-4 genotype (rs4986790, rs4986791) had an effect on the acute rejection rate as
previously described, but had no effect on CLAD development (29;40), 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 (33). Six SNPs for mannose binding lectin (MBL), a recognition molecule for innate
immunity (49), 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 (50;51). The recipients who received a graft from a donor with a heterozygote
variant of a MBL SNP located in a promotor region developed less CLAD compared to those
with the homozygote variant (52).
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
TLRs genes (TLR1 to TLR10) in 110 LTx patients. They showed an association of TLR2
(rs1898830 and rs7656411), TLR 4 (rs1927911) and TLR9 (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 minor allele of rs7656411 and rs1927911 had an increased risk to develop
CLAD compared to the carriers of the minor allele (53). A second study in the same cohort, of
a SNP of matrix metalloproteinases-7(MMP-7), important in lung repair (54), 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 (55). In the
third of the Utrecht group, 4 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 (56).
In 2012 D’Ovidio and colleagues published 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 (57). Patients with low SP-A mRNA levels
associated with specific genetic phenotype in the donor lungs were detected, but there w as no
clear relation with CLAD (58). Compared to the study of two genetic polymorphisms of SPD, which has a comparable mechanism of SP-A (57), an association with CLAD was found in
one SNP. In 191 LTx patients, the homozygote variant of a genetic polymorphism, altering
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 (59).
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 for to small airway repair processes and epithelium integrity (60). In
63 LTx patients, this polymorphism was associated with an increased risk of CLAD and a
functional decrease in CCSP BAL levels was observed (61).
The studies published by our own group on the CAV-1 and IgG polymorphisms did not find
an association with development of CLAD (35;36). The study of the IL-17R polymorphism
(rs879574), not only an inducer of acute but also CLAD (37), 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 before, this polymorphism had a functional
increased risk of BAL neutrophilia (38). For a summary and more details see table 3.
Mortality
A lot of the previously described studies do not only have CLAD (and more specifically
BOS) as an endpoint, they also described the association between genetic polymorphisms and
mortality. The Manchester group was the first to described 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 (45). The TLR4 study of
Palmer and colleagues in 2004 could not find and association with mortality (40). 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 (48). The TT genotype of a CD14 SNP (rs2569190) was associated with enhanced
immune activation, exhibiting not only an increased risk for developing acute/ CLAD, but the
TT genotype was also associated with increased mortality in 226 recipients (33). The same
observation was seen in the study of donor MBL promotor 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
(52). D’Ovidio et al demonstrated that several SP-A2 polymorphisms were associated with
lower SP-A mRNA expression and with increased mortality (58). In addition to this study, a
homozygote variant of a genetic polymorphism SP-D, altering 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 (59). In 63 LTx patients, the functional donor CCSP SNP was associated
with an increased risk of mortality (61).
In contrast to CLAD, for which no association was found with CAV-1 and the IgGR
polymorphism, mortality was affected by these 2 genetic polymorphisms. The (AA+AG)
genotypes of rs3807989 (CAV-1 SNP) resulted in a worse survival compared to the GG
genotype (35). The IgGR (rs12746613) polymorphism was associated with a higher risk of
mortality in the TT-genotype compared with the CC-genotype in 418 patients (36). In the IL17 polymorphism study, no significant association was found with mortality (38).
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, post-operative complications and not always due to CLAD. Even late post-operative
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.
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, whereas some cohorts go back to 1990 for inclusion
of the first patients. Since then, lots of improvements were made in donor preservation,
selection recipients, operative techniques, post-operative 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 prospectives
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 multi-centric
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 a 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 possible 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, longterm alterations in the transcriptional potential of a cell that are not necessarily heritable (62).
In the hope 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 (63).
Conclusion
Several SNPs have been associated with various outcome parameters after LTx. However,
there is a stringent need for prospective multi-centric 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 important, to achieve improved treatment
or prevention, resulting in better outcome after LTx.
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Reference
n
PGD
Age
Male
(%)
DLTx
(%)
Race
White(%)
D/R
ID number
Gene
function
Location
Funct
Diamond(14)
654
52
337(52)
NA
553(81)
R
Diamond(18)
680
Yes
Yes
No
No
No
No
No
No
No
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
53
359(53)
NA
572(84)
R
rs2120243
rs2305619
rs9289983
rs1456099
rs35948036
rs3816527
rs55757068
rs3845978
rs35415718
rs4478039
rs13283456
rs11957406
rs4434423
rs4133101
rs2996044
rs2925956
rs13132184
rs7973796
rs3024388
rs12452616
rs237865
rs17588591
rs16836965
rs260400
rs3772843
rs1881597
rs17004504
Long pentraxin-3(PTX3)
Long pentraxin-3(PTX3)
Long pentraxin-3(PTX3)
Long pentraxin-3(PTX3)
Long pentraxin-3(PTX3)
Long pentraxin-3(PTX3)
Long pentraxin-3(PTX3)
Long pentraxin-3(PTX3)
Long pentraxin-3(PTX3)
Long pentraxin-3(PTX3)
PTGES2
PTGER4
PTGER4
PTGER4
TBC1D1
TBC1D1
TBC1D1
PMCH
F13A1
GAA
CAV3
COL4A1
CASP8
IRX4
ITGB5
PRKG1
FTCD
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Prostaglandin E2 synthesis
Prostaglandin E receptor(EP4)
Prostaglandin E receptor(EP4)
Prostaglandin E receptor(EP4)
Cell growth and differentiation
Cell growth and differentiation
Cell growth and differentiation
Hypothalamic neurotransmitter
Coagulation cascade
Glycogen degradation
Muscle development
Extracellular matrix
Cell death and tumor regulation
Ventricular differentiation
Cell adhesion
Platelet aggregation
Folate metabolism
5′ UTR
Intron
5′ UTR
5′ UTR
Exon
Exon
Intron
Intron
Exon
Exon
Coding
Intron
5′ UTR
5′ UTR
Intron
Intron
Intron
5′ UTR
Intron
Intron
5′ UTR
Intron
Intron
5′ UTR
Intron
3′ UTR
Intron
No
Yes
NA
NA
NA
NA
NA
NA
NA
NA
No
No
Yes
No
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
Table 1: Overview of all studies with possible associations between genetic background and PGD after LTx. PGD= primary graft dysfunction, DLTx= bilateral
lung transplantation, D/R= material from donor/receptor, funct= functionality, NA= Not available/ stated. Yes/no describes the possible association between
the SNP and PGD. Functionally gives an indication whether the SNP is associated with changes in gene related protein expression or activity.
Reference
n
rejection
Rejection
Age
Male
(%)
DLTx
SSLTx
(%)
Jackson(25)
77
NA
NA
NA
Zheng(24)
119
49
55(46)
Palmer(30)
147
49
Palmer(34)
Ruttens(39)
226
497
Vandermeulen(36)
Ruttens(37)
503
418
No
No
No
No
No
No
No
No
No
No
Yes
No
No
Yes
Yes
Yes
Yes
No
No
No
No
No
No
No
Race
Race
White(%)
White
D/R
ID number
Gene
Function
function
Location
Funct
NA
R
TNF-α
TGF-β1
TGF-β1
IL-10
IL-10
IL-10
IL-6
INF-γ
41(34)
NA
R
81(54)
116(79)
133(89)
D/R
49
48
130(58)
263(53)
190(84)
374(75)
204(90)
485(98)
R
R
48
48
268(53)
208(50)
373(74)
314(75)
491(98)
408(98)
R
R
-308
Codon 20
Codon 25
-1082
-819
-592
-174
+874
NA
NA
NA
NA
NA
rs4986790
rs4986791
rs2569190
rs879574
rs2201841
rs10489628
rs2066808
rs1343151
rs1569922
rs3807989
rs12746613
Cell death
Cell growth and differentiation
Cell growth and differentiation
Immunoregulation
Immunoregulation
Immunoregulation
Acute phase response
Pro-inflammatory
Cell death
Cell growth and differentiation
Immunoregulation
Acute phase response
Pro-inflammatory
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Tissue homeostasis
IgG receptor/ metabolisme
Promotor
Codon
Codon
Promotor
Promotor
Promotor
Promotor
Intron
NA
NA
NA
NA
NA
Coding
Coding
5′ UTR
Intron
Intron
Intron
Intron
Intron
Intron
Intron
1q23.3
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
Yes
NA
NA
Yes
Yes
Yes
Yes
NA
NA
NA
NA
NA
Yes
Yes
TNF-α
TGF-β1
IL-10
IL-6
INF-γ
TLR-4
TLR-4
CD14
IL-17R
IL-23R
IL-23R
IL-23A
IL-23R
IL-23R
CAV-1
FCGRA2
Table 2: overview of all studies with possible associations between genetic background and acute rejection. n= n-value, DLTx= bilateral lung
transplantation,D/R= donor/ receptor, funct= functionality , NA= Not available/ stated. Yes/no describes the possible association between the SNP and
acute rejection. Functionally gives an indication whether the SNP is associated with changes in gene related protein expression or activity.
Reference
n
CLAD
Age
Male
(%)
DLTx
(%)
Race
White(%)
D/R
ID number
Gene
Function
Location
Funct
Awad(45)
El-Gamel(48)
82
91
NA
39
NA
NA
NA
50(55)
NA
NA
R
R
Awad(49)
95
NA
NA
NA
NA
R
Jackson(25)
77
NA
NA
NA
NA
R
Lu(50)(64)(65)(67)
93
NA
NA
NA
NA
R
Palmer(30)
170
49
94(55)
139(82)
153(90)
R
Snyder(51)
78
198
44
49
40(51)
110(56)
38(49)
165(83)
69(88)
180(91)
R
R
Palmer(34)
Munster(55)
226
277
Yes
No
Yes
No
No
Yes
No
Yes
No
No
No
No
No
No
No
No
Yes
Yes
No
No
No
No
No
No
No
No
No
No
Yes
No
Yes
No
No
No
No
49
43
130(58)
150(54)
190(84)
216(78)
204(90)
NA
R
D+R
NA
+869
+915
-800
-509
+72
+869
+915
-308
Codon 20
Codon 25
-1082
-819
-592
-174
+874
NA
NA
NA
NA
NA
rs4986790
rs4986791
NA
NA
NA
NA
NA
rs2569190
-619
-290
-66
+154
+161
+170
INF-γ
TGF-β1
TGF-β1
TGF-β1
TGF-β1
TGF-β1
TGF-β1
TGF-β1
TNF-α
TGF-β1
TGF-β1
IL-10
IL-10
IL-10
IL-6
INF-γ
INF-γ
IL-6
IL-10
TGF-β1
TNF-α
TLR4
TLR4
INF-γ
IL-6
IL-10
TGF-β1
TNF-α
CD14
MBL
MBL
MBL
MBL
MBL
MBL
Pro-inflammatory
Cell growth and differentiation
Cell growth and differentiation
Cell growth and differentiation
Cell growth and differentiation
Cell growth and differentiation
Cell growth and differentiation
Cell growth and differentiation
Cell death
Cell growth and differentiation
Cell growth and differentiation
Immunoregulation
Immunoregulation
Immunoregulation
Acute phase response
Pro-inflammatory
Pro-inflammatory
Acute phase response
Immunoregulation
Cell growth and differentiation
Cell death
Innate immune activity
Innate immune activity
Pro-inflammatory
Acute phase response
Immunoregulation
Cell growth and differentiation
Cell death
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Intron
Exon
Exon
5′ UTR
5′ UTR
NA
Exon
Exon
Promotor
Codon
Codon
Promotor
Promotor
Promotor
Promotor
Intron
NA
NA
NA
NA
NA
Coding
Coding
NA
NA
NA
NA
NA
5′ UTR
5′ UTR
5′ UTR
5′ UTR
Intron
Intron
Intron
Yes
No
No
No
No
No
No
No
NA
NA
NA
NA
NA
NA
NA
NA
No
NA
NA
NA
NA
Yes
Yes
NA
NA
NA
NA
NA
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Reference
nn
Kastelijn(56)
110
Kastelijn(58)
110
Kastelijn(59)
110
D’Ovidio(61)
42
Aramini(62)
191
Bourin(64)
Ruttens(39)
63
497
Vandermeulen(36)
Ruttens(37)
503
418
CLAD
CLAD Age
Age
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
No
No
No
Yes
No
Yes
Yes
No
No
No
No
No
No
No
Male
Male SSLTx
DLTx Race
Race D/R D/R
ID number
ID number
Gene
(%)
(%) White
White(%)
50
54(49)
93(85)
NA
R
50
54(49)
93(85)
NA
R
50
54(49)
93(85)
NA
R
50
23(55)
33(79)
NA
D
57
90(47)
141(74)
155(51)
D
49
48
30(48)
263(53)
49(78)
374(75)
NA
485(98)
D+R
R
48
48
268(53)
208(50)
373(74)
314(75)
491(98)
408(98)
R
R
rs1898830
rs7656411
rs1927911
rs352162
rs187084
59 SNPs
rs17098318
rs11568818
rs12285347
rs10502001
rs1996352
rs11568819
rs12154695
rs10256914
rs3807989
rs3807994
NA
NA
Met11Thr
Ala160Thr
A38G
rs879574
rs2201841
rs10489628
rs2066808
rs1343151
rs1569922
rs3807989
rs12746613
Gene
function
Function
TLR2
TLR2
TLR4
TLR9
TLR9
TLR1-10
MMP-7
MMP-7
MMP-7
MMP-7
MMP-7
MMP-7
CAV-1
CAV-1
CAV-1
CAV-1
SP-A1
SP-A2
SP-D
SP-D
CCSP
IL-17R
IL-23R
IL-23R
IL-23R
IL-23R
IL-23R
CAV-1
FCGRA2
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Lung repair
Lung repair
Lung repair
Lung repair
Lung repair
Lung repair
Tissue homeostasis
Tissue homeostasis
Tissue homeostasis
Tissue homeostasis
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Lung repair
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Tissue homeostasis
IgG receptor/metabolism
Location
Location
Intron
3’UTR
Intron
3’UTR
5′ UTR
NA
5′ UTR
5′ UTR
Intron
Exon
Intron
5′ UTR
NA
Intron
Intron
Intron
NA
NA
Coding
Coding
NA
Intron
Intron
Intron
Intron
Intron
Intron
Intron
1q23.3
Table 3: different genetic background studies with an association with CLAD after lung transplantation after LTx. CLAD= chronic lung allograft dysfunction,
DLTx= bilateral lung transplantation, D/R= material from donor/receptor, funct= functionality, NA= Not available/ stated. Yes/no describes the possible
association between the SNP and chronic rejection. Functionally gives an indication whether the SNP is associated with changes in gene related protein
expression or activity.
Funct
No
No
No
No
No
Yes
No
Yes
Yes
No
NA
NA
No
No
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
NA
NA
NA
NA
NA
Yes
Yes
Reference
n
MOR
Age
Male
(%)
DLTx
(%)
Race
White(%)
D/R
ID number
Gene
Function
Location
Funct
El-Gamel(48)
91
39
NA
50(55)
NA
R
Palmer(30)
170
49
94(55)
139(82)
153(90)
R
Snyder(51)
78
198
44
49
40(51)
110(56)
38(49)
165(83)
69(88)
180(91)
R
R
Palmer(34)
Munster(55)
226
277
49
43
130(58)
150(54)
190(84)
216(78)
204(90)
NA
R
D+R
D’Ovidio(61)
42
50
23(55)
33(79)
NA
D
Aramini(62)
191
57
90(47)
141(74)
155(51)
D
Bourin(64)
Ruttens(39)
63
497
49
48
30(48)
263(53)
49(78)
374(75)
NA
485(98)
D+R
R
Vandermeulen(36)
Ruttens(37)
503
418
Yes
Yes
No
No
No
No
No
No
No
Yes
No
Yes
No
No
No
No
No
Yes
Yes
No
Yes
No
No
No
No
No
No
Yes
Yes
48
48
268(53)
208(50)
373(74)
314(75)
491(98)
408(98)
R
R
+869
+915
rs4986790
rs4986791
NA
NA
NA
NA
NA
rs2569190
-619
-290
-66
+154
+161
+170
NA
NA
Met11Thr
Ala160Thr
A38G
rs879574
rs2201841
rs10489628
rs2066808
rs1343151
rs1569922
rs3807989
rs12746613
TGF-β1
TGF-β1
TLR4
TLR4
INF-γ
IL-6
IL-10
TGF-β1
TNF-α
CD14
MBL
MBL
MBL
MBL
MBL
MBL
SP-A1
SP-A2
SP-D
SP-D
CCSP
IL-17R
IL-23R
IL-23R
IL-23R
IL-23R
IL-23R
CAV-1
FCGRA2
Cell growth and differentiation
Cell growth and differentiation
Innate immune activity
Innate immune activity
Pro-inflammatory
Acute phase response
Immunoregulation
Cell growth and differentiation
Cell death
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Lung repair
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Innate immune activity
Tissue homeostasis
IgG receptor/metabolism
Exon
Exon
Coding
Coding
NA
NA
NA
NA
NA
5′ UTR
5′ UTR
5′ UTR
5′ UTR
Intron
Intron
Intron
NA
NA
Coding
Coding
NA
Intron
Intron
Intron
Intron
Intron
Intron
Intron
1q23.3
No
No
Yes
Yes
NA
NA
NA
NA
NA
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
NA
NA
NA
NA
NA
Yes
Yes
Table 4: different genetic background studies with an association with mortality after lung transplantation after LTx. MOR= mortality, DLTx= bilateral lung
transplantation, D/R= material from donor/receptor, funct= functionality, NA= Not available/ stated. N-value(%).Yes/no describes the possible association
between the SNP and mortality. Functionally gives an indication whether the SNP is associated with changes in gene related protein expression or activity.