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Right arrow Transplantation - heart

Ann Thorac Surg 2004;77:875-880
© 2004 The Society of Thoracic Surgeons

Original article: cardiovascular

Influence of IFN-{gamma} polymorphism on the development of coronary vasculopathy after cardiac transplantation

Cameron G. Densem, MRCPa*, Ian V. Hutchinson, BSc, PhDb, Nizar Yonan, FRCSb, Nicholas H. Brooks, FRCPa

a Cardiothoracic Transplant Unit, Wythenshawe Hospital, United Kingdom
b and School of Biological Sciences, Manchester University, Manchester, United Kingdom

Accepted for publication July 30, 2003.

* Address reprint requests to Dr Densem, Department of Cardiology, Wythenshawe Hospital, Southmoor Rd, Wythenshawe, Manchester M23 9LT, UK
e-mail: cameron.d{at}virgin.net


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: The development of coronary vasculopathy (CV) limits survival after cardiac transplantation. Interferon (IFN)-{gamma} is an important immunomodulator affecting the growth and function of T cells and macrophages, free radical formation, adhesion molecule, and MHC class I and II expression, which are important processes for CV formation. IFN-{gamma} is expressed early after transplantation and neutralization or genetic absence of the cytokine can abrogate CV development. The expression of IFN-{gamma} is influenced by a dinucleotide repeat in the first intron of the IFN-{gamma} gene. We investigated the effect of this polymorphism on the development of CV.

METHODS: Using sequence specific primers to the IFN-{gamma} polymorphic region, polymerase chain reaction (PCR) and gel electrophoresis identified the genotype in 144 cardiac transplant recipients and 134 donors. An association was sought between the presence of a high, intermediate or low IFN-{gamma} producing genotype and the development of CV diagnosed by routine surveillance posttransplant angiography.

RESULTS: High, intermediate, and low IFN-{gamma} producers made up 29.2%, 44.4%, 26.4% and 24.6%, 40.3%, 35.1% of recipients and donors respectively (p = NS). IFN-{gamma} polymorphism in cardiac graft recipients had no impact on the time to first diagnosis of CV; high producers 4.03 years (± 129.9 days), intermediate producers 3.40 years (± 79.7 days), low producers 4.01 years (± 102.9 days); p = 0.16. Similar results were found on investigating donor polymorphism; high producers (3.68 years ± 120.1 days), intermediate producers (3.83 years ± 105.9 days), low producers (3.3 years ± 77.7 days); p = 0.35. Multivariate analysis identified the number of rejection episodes of ISHLT grade 3 or greater and increasing donor age to be independent risk factors for CV development.

CONCLUSIONS: Dinucleotide repeat polymorphism in the first intron of the human IFN-{gamma} gene does not influence CV development and cannot be used as a genetic risk marker.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
An accelerated coronary vasculopathy (CV) limits survival after cardiac transplantation [1]. Diffuse, concentric, intimal proliferation is the classic appearance consisting of inflammatory cells, medial smooth muscle cells, ground substance, and lipids [1]. CV may be a T-cell driven allogeneic process critically dependent upon interferon (IFN)-{gamma}, an immunomodulatory cytokine [2]. Conversely, IFN-{gamma} stimulates the expression of vascular cell adhesion molecule 1 (VCAM-1) on endothelial cells [3], class II major histocompatibility complex (MHC-II) on macrophages and smooth muscle cells [4], and lipoprotein receptors in smooth muscle cells [5], all proatherogenic properties. IFN-{gamma} expression occurs early after transplant, being sustained in cardiac allografts undergoing chronic rejection [6, 7]. Disease severity correlates to the degree of IFN-{gamma} production [6, 8]. In murine models the serologic neutralization [9, 10] or genetic absence [2, 9, 10] of IFN-{gamma} markedly reduced intimal proliferation whereas exogenous IFN-{gamma} induced arteriosclerosis [11].

The human IFN-{gamma} gene has been mapped to chromosome 12q24.1. The DNA sequence (accession number M37265) has a variable length CA repeat in the first intron 875 base pairs downstream from the start of the first exon. This area represents a regulatory region [12, 13]. Five alleles of the microsatellite have been described; #1 (11 CA repeats), #2 (12 CA repeats), #3 (13 CA repeats), #4 (14 CA repeats), and #5 (15 CA repeats) respectively. Allele #2 correlates with a higher production of IFN-{gamma} after mitogen stimulation of peripheral blood mononuclear cells in vitro [12, 13]; (see Table 1). The dinucleotide repeat sequence itself may have a regulatory function or linkage with functional polymorphisms in the IFN-{gamma} gene first intron may account for differences in cytokine production. The presence of allele #2 has been associated with posttransplant lung allograft fibrosis [14] and acute renal rejection [15].


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  		Table 1. IFN-{gamma} Allele and Corresponding Level of Cytokine Production

 
We investigated the influence of IFN-{gamma} polymorphism on the development of CV.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Study patients
Cardiac allograft recipients transplanted between April 1987 and August 1996 at the Wythenshawe Cardiothoracic Transplant Center, UK, were studied. A triple drug combination consisting of cyclosporine, azathioprine, and prednisolone was used for all patients. Methylprednisolone and rabbit antithymocyte globulin were utilized peri-transplant. Donor hearts were obtained from brain dead individuals whose history, electrocardiogram, and circumstances of death did not support the existence of coronary artery disease thus minimizing the effects of donor transmitted coronary artery disease.

Coronary arteriography and criteria for diagnosis of CV
Routine surveillance coronary arteriography, beginning 2 years after transplantation, was performed by a percutaneous femoral or brachial approach. Standard orthogonal views of the right and left coronary arteries were acquired. CV was defined as any angiographic luminal irregularity of the major epicardial coronary arteries. Two angiographers, blinded to clinical information, independently reviewed all studies. In the event of disparity a consensus opinion was recorded. Serial films taken over a number of years were studied side-by side to ensure recognition of diffuse vessel "pruning."

Diagnosis of acute rejection
Acute rejection was diagnosed in accordance with the International Society for Heart and Lung Transplantation (ISHLT) Grading system. Symptomatic grades 2, 3a, 3b, and 4 were treated. Percutaneous biopsy was performed weekly for the first 4 weeks, fortnightly for 2 months, monthly for the next 3 months, 2 monthly up to 1 year, and then 6 monthly thereafter or when indicated. If a recipient suffered no rejection routine biopsies were stopped after 5 years. After a treated rejection the recipients were rebiopsied 7–10 days later.

Sample collection
Patients gave informed consent to the collection and storage of blood, isolation of DNA, and determination of the cytokine gene polymorphisms. Ethical approval was obtained from the South Manchester Medical Research Ethics Committee. Blood samples were mixed with ethylenediaminetetraacetic acid (EDTA) for preservation and stored at -80°C before further processing. DNA or stored leukocytes of deceased patients and donors was acquired from the Tissue Typing Laboratory, Manchester Royal Infirmary.

Primer sequences
Sequence specific primers to the IFN-{gamma} gene polymorphic region were designed according to the human IFN-{gamma} gene sequence deposited in Genbank; sense GCT GTC ATA ATA ATA TTC AGA C; antisense CGA GCT TTA AAA GAT AGT TCC. Lyophilized oligonucleotide probes were manufactured by Genosys (Genosys, Cambridge, UK). The primers were prepared to a working concentration of 50 mmol/L by the addition of measured quantities of PCR grade water. DNA samples for the recipients and donors were amplified by PCR after extraction from peripheral blood leukocytes.

Polymerase chain reaction
Each reaction mixture comprised 3 µl P-buffer, 3 µl 25 mmol magnesium chloride, 3 mM each dATP, dCTP, dGTP, and dTTP, 7.5 µl 4 M betaine, 2 µl DNA (50–200 ng), 2 µl of sense and antisense primers, 0.2U Taq thermoprime DNA polymerase, and 7.5 µl PCR grade water. The reaction mixture was aliquoted into separate thin-walled PCR tubes.

A Techne GeniusTM (Techne, Inc, Burlington, NJ) controlled the thermal cycle of 95°C initially for 5 minutes followed by 30 cycles of 95°C for 30 seconds, 60°C for 30 seconds, and 72°C for 30 seconds with a final holding temperature of 4°C.

Electrophoresis of PCR products
The genotype was identified by polyacrylamide gel electrophoresis of the PCR products. Polyacrylamide gels comprised 480 ml 10% ammonium persulphate, 28.3 ml distilled water, 14.4 ml acrylamide, 4.8 ml x 10 tris borate EDTA (TBE), and 50 ml tetramethylethylenediamine (TEMED) left between two glass plates to polymerise. After electrophoresis, gels were stained with ethidium bromide, visualized with ultraviolet (UV) light on a transilluminator, and photographed for the subsequent identification of alleles (Fig 1).



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  		Fig 1. Polymerase chain reaction products for interferon (IFN)-{gamma} polymorphism after electrophoretic separation through acrylamide gel.

 
Statistical analysis
Genotype groups were compared for equality of demographic and laboratory variables using analysis of variance (ANOVA) with Scheffe post-hoc analysis. The occurrence of CV was calculated according to the mean time to first diagnosis of CV and compared against the cytokine genotypes using Kaplan–Meier actuarial estimation and the log-rank test. Multivariate analysis, using a Cox proportional hazard model, enabled risk factor identification. Risk factors involved the analysis included recipient and donor age, sex, cytomegalovirus (CMV) serology, and body mass index, pretransplant diagnosis, ischemic time, human lymphocyte antigen (HLA) data, fibrinogen, lipids, cyclosporine dosage, and the prevalence of acute rejection.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
One hundred and forty four cardiac transplant recipients and 134 cardiac graft donors were studied; 83.4% male recipients, average age 47.4 years, mean donor age 27.9 years. On univariate analysis of recipient characteristics, including donor and recipient sex and age, reason for transplant, ischemic time, CMV status, acute rejection, HLA mismatch, body mass index, pretransplant and posttransplant fibrinogen and lipid levels, and immunosuppressant dosages, high producers were found to have a higher pretransplant total cholesterol level than intermediate and low producers (5.6 mmol/l (± 0.3) versus 5.0 mmol/l (± 0.2) and 4.5 mmol/l (± 0.2) respectively; p = 0.023). By post-hoc analysis the difference was statistically significant between the high and low producing cohorts.

Follow-up was equivalent between the high, intermediate and low producing groups; 4.86 years (± 169 days), 3.93 years (± 92 days), and 4.41 years (± 122 days), respectively, p = NS.

Overall 41% of patients during the course of follow-up developed evidence for CV at any time point. The prevalence of CV increased dramatically with time; 3 and 5 years, 21% and 33% of recipients, respectively.

Genotype and phenotype prevalence
The distribution of the IFN-{gamma} polymorphism and the phenotype for IFN-{gamma} production deduced from the genotype is represented in Tables 2 and 3. There were no significant differences in genotype or phenotype frequencies between recipients and donors. There were no significant differences between our cohorts and other published control groups. No phenotype was overrepresented in patients transplanted for ischemic or nonischemic myocardial dysfunction.


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  		Table 2. Frequency of Recipient and Donor IFN-{gamma} Genotypes. No Significant Differences Were Observed

 

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  		Table 3. Frequency of IFN-{gamma} Recipient and Donor Phenotypes. No Significant Differences Were Observed (p = 0.42)

 
Influence of recipient interferon-{gamma} polymorphism
No difference was observed in the development of CV between the IFN-{gamma} phenotypes; high producers 4.03 years (± 0.36), intermediate producers 3.4 years (± 0.22), and low producers 4.01 years (± 0.28); p = 0.16. Post-hoc analysis failed to detect any significant difference between any of the three groups. By multivariate analysis the number of rejection episodes of ISHLT grade 3 or greater [hazard ratio 1.13 (95% confidence interval (CI)), 1.00–1.26]; p = 0.04] and increasing donor age [hazard ratio 1.07 (95% CI, 1.04–1.1); p < 0.00001] were independent risk factors for CV. Using Kaplan–Meier actuarial analysis with the log-rank test, recipient IFN-{gamma} polymorphism did not significantly affect the freedom from vasculopathy; (p = 0.85); (Fig 2).



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  		Fig 2. Kaplan–Meier actuarial curve for estimating time-related freedom from coronary vasculopathy (CV) according to recipient interferon (IFN)-{gamma} genotype.

 
Influence of interferon-{gamma} polymorphism in donor hearts
Donor IFN-{gamma} polymorphism had no significant impact on the time to first diagnosis of disease; high producers (3.68 years ± 0.33), intermediate producers (3.83 years ± 0.29), low producers (3.3 years ± 0.21); p = 0.35. By multivariate analysis the number of rejection episodes of ISHLT grade 3 or greater [hazard ratio 1.66 (95% CI, 1.03–1.3]; p = 0.014) and increasing donor age [hazard ratio 1.07 (95% CI, 1.03–1.1]; p < 0.0001) were again independent risk factors for CV.

Kaplan–Meier actuarial analysis (Fig 3) with the log-rank test did not indicate a significant relation between IFN-{gamma} polymorphism and freedom from CV for the donor genotype; p = 0.52. No phenotypic combination was found to significantly increase the risk of CV when considering donors and recipients separately or together.



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  		Fig 3. Kaplan–Meier actuarial curve for estimating time-related freedom from coronary vasculopathy (CV) according to donor interferon (IFN)-{gamma} genotype.

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
CV formation may be critically dependent upon IFN-{gamma}[2, 6–9]. This study investigated the effect of IFN-{gamma} polymorphism on the development of CV. Although slight variation occurred in the time to first diagnosis of CV no phenotype in the recipient or donor grafts had any significant influence.

The lack of association between IFN-{gamma} polymorphism and CV has a number of possible explanations. Immunosuppressants could abrogate the genetic influence at many levels of cytokine production. Azathioprine and cyclosporin A (CsA) directly inhibit IFN-{gamma} gene activation [16] and cytokine production [17]. CsA may inhibit the activation of key promoter sites, for example, the binding of nuclear factor of activated T cells (NFAT). The P1 and P2 sequence in the IFN-{gamma} promoter are NFAT binding sites that influence CsA sensitivity of IFN-{gamma} production [18]. CsA may also activate methylation of the IFN-{gamma} gene promoter region leading to gene inhibition [19]. The proximal element (73–48 bp) of the 5-flanking sequence from the IFN-{gamma} gene is a target for methylation at its central CpG dinucleotide. Methylation here incapacitates T cells from expressing IFN-{gamma} [20].

Experimentally IFN-{gamma} can be antiatherogenic by inhibiting the proliferation of, and collagen synthesis by, smooth muscle cells [21], endothelial cell division and platelet-derived growth factor (PDGF) production [6], matrix synthesis [7], myofibroblast collagen synthesis, and hence intimal expansion in response to mechanical injury [22] within the arterial wall. Locally synthesized nitric oxide regulates vascular tone, endothelial permeability, platelet aggregation, adhesion molecule expression, and scavenges free radicals, all of which may protect against CV. Nitric oxide synthase is strongly promoted by IFN-{gamma} in vascular tissue [23]. Conversely IFN-{gamma} may promote vascular smooth muscle cell growth through upregulation of PDGF b-receptors [24], as well as other proatherogenic properties [3–5]. These opposing effects could lead to a neutral influence on lesion development and progression and nullify subtle genetic influences.

High-producing recipients tended to a higher pretransplant total cholesterol level. This may have been expected to increase the risk of CV. However, this finding was unexpected as experimentally IFN-{gamma} lowers cholesterol levels by enhancing low-density lipoprotein (LDL) cholesterol uptake or macrophage cholesterol metabolism [25]. Interestingly hyperlipidemia may lead to a switch from Th1 to Th2 responses which may have influenced the effect of the polymorphism [26].

No difference in IFN-{gamma} expression has been detected between chronically rejecting liver [27] and renal [28] allografts and normal tissues in conflict with the importance of Th1 cytokines suggested by knockout models. It has been proposed that Th2-driven immune responses rather than Th1-driven immune responses are involved in the progression of chronic allograft rejection. However, a report evaluating alloimmune responses associated with chronic rejection revealed intragraft expression of both Th1 [interleukin (IL)-2 and IFN-{gamma}] and Th2 (IL-4, IL-6, and transforming growth factor-ß) cytokines [29]. Interestingly inhibition of Th1 and Th2 function through simultaneous blockade of CD28-B7 and CD40L-CD40 costimulatory pathways ablates both acute and chronic rejection of skin and cardiac allografts [30].

Finally the absence of a correlation between CV and IFN-{gamma} genotype is because the rat and mouse experimental models of CV are not predictive of the clinical setting and may represent completely different disease entities. It is likely that human transplant related vasculopathy is a multivariable process and cannot be predicted by a single risk factor, for example a polymorphic genotype. This is exemplified by the finding of two risk factors for CV development discussed below.

Increasing donor age and the number of acute rejection episodes of ISHLT grade 3 or greater were independent risk factors for CV within both groups. Donor age has been previously reported as a risk factor [31, 32]. By actuarial analysis only 62% of patients with donor age greater than 25 years were free of CV at 5 years compared with 80% of those with donor age less than 25 years [31]. Allografts from donors greater than 20 years had a greater risk of developing CV than donors aged less than 20 years [32]. It is possible that donor hearts from older patients are less tolerant to injury. This is an important finding as graft shortages are leading to acceptance of organs from older donors.

Upregulation of class II HLA on allograft endothelial cells during acute rejection is a critical event leading to immune-mediated endothelial cell activation and smooth muscle proliferation. This leads to rapidly progressive CV. A direct relationship between acute rejection and CV has been demonstrated in a rabbit heart model [33] as well as in human studies [34]. A single episode of allogeneic injury can lead to CV even without additional T-cell mediated injury. This has been proposed to be IFN-{gamma} dependent [2]. Activation of arterial wall cells during episodes of acute rejection might trigger or exacerbate the development of CV. Once the process has begun, or enough injury achieved, propagation of CV may not require continuous allogeneic stimulation [2]. Therefore, it may be important that in our cohort increasing episodes of rejection were a risk factor for CV that may have negated the polymorphic influence.

One potential drawback of this study was the use of coronary angiography, as opposed to intravascular ultrasound (IVUS), for detecting CV. Angiography has been shown to underestimate the prevalence of disease [35, 36]; the diffuse nature of the disease makes subtle luminal irregularity difficult to detect. Using IVUS intimal thickening can be demonstrated in up to 40% of recipients 1 month after transplant (may represent donor transmitted disease) and 75% by 1 year [37]. Greater than 1 year 100% of recipients have demonstrable intimal thickening often in the presence of normal angiograms [38]. Our transplant program began in 1987 at which time IVUS was not available to us. Bearing these problems in mind we chose a binary method of classifying CV as either evidence for luminal irregularity, regardless of severity, or not. The angiographic appearance is important for risk stratification being a reliable predictor of death from CV and event free survival. [39, 40] When compared with noninvasive investigation a normal coronary angiogram was the better predictor of event free survival [40]. When CV is defined as "any luminal irregularity" angiography has 77% sensitivity for prediction of coronary events. If redefined as being greater than or equal to a 50% stenosis in at least one vessel, the sensitivity falls to 33%. Our ultimate intention was to link a genetic factor to an established predictor of risk, angiographic appearance. Future work should incorporate IVUS data.

In conclusion, although a dinucleotide repeat polymorphism influences an individual's production of IFN-{gamma}, this allelic variation does not affect the propensity to develop cardiac transplant related vasculopathy and cannot be used as a risk factor.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
Dr Densem was supported by a grant from the National Heart Research Fund. The study was funded by the Wythenshawe Cardiology Research Fund and the New Heart, New Start appeal.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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