- Email: [email protected]
Association of IL-17F Gene Polymorphisms With Renal Transplantation Outcome
Association of IL-17F Gene Polymorphisms With Renal Transplantation Outcome H. Park, S. Shin, M.H. Park, Y.S. Kim, C. Ahn, J. Ha, and E.Y. Song ABSTRACT Objective. Although interleukin 17 (IL-17) has some roles in renal transplantation, the influence of IL-17 gene single-nucleotide polymorphisms (SNPs) on renal transplantation has not been studied. Methods. The associations of 5 IL-17F gene SNPs (e1507G/A, 6329G/A, 7384A/G, 7470G/A, and 7489A/G) with renal transplantation outcome were analyzed. Polymerase chain reaction with sequence-specific primers (for e1507G/A and 6329G/A) and direct sequencing (for 7384A/G, 7470G/A, and 7489A/G) were performed on 282 renal transplantation recipients and 210 healthy controls. Results. IL-17F SNPs were not associated with acute rejection. Recipients with G allele on 7489A/G showed lower graft survival than recipients without G allele (P ¼ .04). In multivariate analysis, G allele on 7489A/G was an independent risk factor for graft failure (odds ratio ¼ 2.77, P ¼ .03). Conclusion. IL-17F gene SNP 7489A/G was associated with renal graft failure. Further studies are needed in larger number of patients.
W
ITH THE INTRODUCTION of improved pretransplant evaluation and the development of posttransplantation immunosuppressive therapy, short-term graft survival in kidney transplantation has been remarkably improved. However, long-term graft outcome is still not satisfactory. Immunologic responses of the host play an important role in graft rejection or recurrence of underlying renal disease. T-helper (Th) cells consist of Th1 cells and Th2 cells. The former two T-regulatory cells are involved in proinflammatory, humoral, and antiinflammatory reaction, respectively. And another important T helper cell, Th17, involved in proinflammatory reaction, has been discovered [1]. Interleukin-17 (IL-17) is a critical cytokine responsible for Th17 cell reaction. IL17A and IL-17F are two important members in IL-17 cytokine family [2] with 55% sequence homology at the amino acid level [3]. Recently, IL-17F gene polymorphisms have been reported to be associated with various autoimmune or immunologic diseases [4e11]. The roles of IL-17 in renal transplantation have also been suggested [12e14]. But the association of IL-17 gene polymorphism with renal graft outcome has not been studied so far. We analyzed 5 single nucleotide polymorphisms (SNPs) of IL-17F gene in renal transplantation recipients and their associations with renal transplantation outcome. ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 121e123 (2014)
METHODS Subjects Two hundred eighty-two kidney transplantations between January 1, 1996 and July 31, 2004 in Seoul National University Hospital were included in this study. For healthy controls, 210 parents were selected from the members of 107 Korean families previously enrolled in another HLA study [15]. This study was conducted under the approval of Institutional Review Board (H1008-024-326) and according to Declaration of Helsinki.
Analysis of Interleukin-17F Gene SNPs Five SNPs of IL-17F gene: e1507G/A (rs1889570), 6329G/A (rs766748), 7384A/G (rs2397084), 7470G/A (rs11465553), and 7489A/G (rs763780) were analyzed. Allele-specific polymerase chain reaction (PCR) was performed for 2 SNPs (e1507G/A and 6329G/A) as previously reported [9]. For 7384A/G, 7470G/A, and 7489A/G From the Departments of Laboratory Medicine (H.P., S.S., M.H.P., E.Y.S.), Internal Medicine (Y.S.K., C.A.), and Surgery (J.H.), Seoul National University College of Medicine, Seoul, Korea. This study was supported by a grant number 0420100290 from the SNUH research fund. Address reprint requests to Eun Young Song, MD, PhD, Department of Laboratory Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea. E-mail: [email protected] 0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.05.015 121
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Table 1. Association of IL-17F Genotype With Acute Rejection or Recurrence of Primary Renal Disease Recurrence of primary renal disease, n (%)
Acute rejection, n (%) Genotype
()
e1507G/A GG 78 (40.6) GA 89 (46.4) AA 25 (13.0) 6329G/A GG 85 (44.5) GA 79 (41.4) AA 27 (14.1) 7384A/G AA 190 (98.4) AG 3 (1.6) 7470G/A GG 188 (97.4) GA 5 (2.6) 7489A/G AA 156 (80.8) AG 36 (18.7) GG 1 (0.5)
(þ)
P value
()
(þ)
.645 39 (44.3) 41 (46.6) 8 (9.1)
.599 106 (41.9) 10 (37.0) 116 (45.8) 15 (55.6) 31 (12.3) 2 (7.4)
.659 40 (45.5) 39 (44.3) 9 (10.2)
.518 114 (45.2) 11 (40.7) 104 (41.3) 14 (51.9) 34 (13.5) 2 (7.4)
.380 86 (96.6) 3 (3.4)
.018 250 (98.4) 26 (92.9) 4 (1.6) 2 (7.1)
.669 88 (98.9) 1 (1.1)
.441 248 (97.6) 28 (100) 6 (2.4) 0 (0.0)
.479 68 (76.4) 21 (23.6) 0 (0.0)
P value
.873 201 (79.1) 23 (82.1) 52 (20.5) 5 (17.9) 1 (0.4) 0 (0.0)
SNPs, direct sequencing was performed with previously reported primers [4]. PCR was performed using 3 mL of genomic DNA, 4 mL of primer mixture (2 mL of 10 pmole/mL forward and reverse primer, each), 4 mL of 10 buffer, 3.2 mL of 2.5 mmol/L deoxynucleotide triphosphate, 0.25 mL of Taq polymerase (Roche, Mannheim, Germany), and 25.55 mL of distilled water under the following conditions: 30 cycles of PCR consisting of initial denaturation for 5 minutes at 95 C followed by denaturation for 30 seconds at 95 C, annealing for 30 seconds at 61 C extension for 30 seconds at 72 C and a final extension for 5 minutes at 72 C in a thermocycler (PTC200, MJ Research, Waltham, Mass, United States). After PCR products were purified using QIAEX II gel extraction kit (Qiagen, Hilden, Germany), they were used as template DNA for direct sequencing analysis using the ABI Prism 3730XL Genetic Analyzer (Applied Biosystems, Foster City, Calif, United States).
Clinical Data The following characteristics of recipients were retrospectively collected: age and gender of recipient; age and gender of donor; type of donor (living vs cadaveric donor); primary renal disease causing end-stage renal disease; number of HLA mismatches; number of HLA-DR mismatches; the duration of hemodialysis; type of immunosuppression; time of transplantation; occurrence and time point of biopsy-proven acute rejection; recurrence of primary renal disease and its time point; 1-, 3-, 5-, 10-year creatinine levels post-transplantation; occurrence and time of graft failure, defined as graft nephrectomy or return to hemodialysis.
Statistical Analysis Differences of allele frequency and genotype frequency were compared using 2-sided chi-square test or Fisher’s exact test, as appropriate. Continuous variables between 2 groups were analyzed with Student t test. The logistic regression analysis was used to determine the independent association between presence/absence of alleles and disease while adjusting for the covariates. Variables with P < .25 from univariate logistic regression analyses were
Fig 1. Kaplan-Meier analysis of graft survival time in 282 kidney recipients. AA genotype of IL-17F gene on 7489A/G (n ¼ 224) are compared with AG or GG genotype (n ¼ 58). included in multivariate analysis, which performed by backward stepwise selection. The odds ratio (OR) was calculated using a 95% confidence intervals. Death-censored graft survival was analyzed using Kaplan-Meier method and log-rank test. P value of < .05 was considered statistically significant. SPSS for Windows version 12.0 (SPSS, Chicago, Ill, United States) was used for statistical analysis.
RESULTS
The allele frequencies and genotype frequencies of 5 SNPs studied were not significantly different between renal transplantation recipients and healthy controls (data not shown). All 5 SNPs studied showed no association with occurrence of acute allograft rejection (Table 1). Recipients with G allele on 7489A/G (AG or GG genotype) showed lower death-censored graft survival than recipients without G allele (AA genotype; P ¼ .04; Fig 1). In multivariate analysis including covariates with P < .25 in univariate analyses (age of recipient and donor, G allele on 7489A/G, tacrolimus-based immunosuppression, acute rejection, deceased donor, number of HLA mismatches, number of HLA-DR mismatches, recurrence of primary renal disease, and date of transplantation), G allele on 7489A/G was an independent risk factor for graft failure (OR ¼ 2.77, P ¼ .03). Age of recipients and donors, acute rejection, and recurrence of primary renal disease were also significant risk factors for graft failure (P < .037, OR ¼ 0.97; P ¼ .013, OR ¼ 0.96; P < .001, OR ¼ 10.42; P ¼ .002, OR ¼ 4.88, respectively; Table 2). DISCUSSION
SNPs of various cytokines such as interferon-gamma, tumor necrosis factor-alpha, transforming growth factor-beta, IL-2,
IL-17F GENE POLYMORPHISMS
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Table 2. Multivariate Analyses of Risk Factors Affecting Renal Allograft Failure Risk factor
P value
Recipient age Donor age G allele on 7489A/G Acute rejection Recurrence of primary renal disease
.037 .013 .03 <.001 .002
OR (95% CI)
0.97 0.96 2.77 10.42 4.88
(0.94-0.99) (0.93-0.99) (1.10-6.96) (4.26-25.46) (1.77-13.53)
Abbreviations: OR, odds ratio; CI, confidence interval.
IL-6 and IL-10 have been reported to be associated with clinical outcomes of renal transplantation [16e18]. The roles of IL-17 in renal transplantation were suggested in mouse models [12,13], and the blood level of IL-17 was significantly higher in renal transplantation recipients with acute rejection than in those without acute rejection [14]. In our study, among 5 SNPs studied, no association was observed with acute rejection. However, G allele of 7489A/G was an independent risk factor for graft failure and associated with shorter graft survival time. SNP of 7489A/G is on exon 3 of the IL-F gene, which makes change of His to Arg on 161 amino acids. Recently, associations of SNP of 7489A/G with various kinds of autoimmune or immunologic diseases such as Graves disease [5], chronic immune thrombocytopenia [7], asthma [9], and ulcerative colitis [10] have been reported. From our study, it can be postulated that G allele on 7489A/G plays some roles in chronic inflammatory process of chronic allograft rejection. In conclusion, 7489A/G SNP of IL-17F gene was associated with graft survival in renal transplantation. The limitation of our study was lack of functional studies of IL-17F gene SNPs, which correlates blood level or expression of IL-17 on biopsy specimen. Further studies on larger number of patients that include IL-17F expression are needed. REFERENCES [1] Mangan PR, Harrington LE, O’Quinn DB, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006;441:231. [2] Rutitzky LI, Lopes da Rosa JR, Stadecker MJ. Severe CD4 T cell-mediated immunopathology in murine schistosomiasis is dependent on IL-12p40 and correlates with high levels of IL-17. J Immunol 2005;175:3920.
[3] Ishigame H, Kakuta S, Nagai T, et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 2009;30:108. [4] Jang WC, Nam YH, Ahn YC, et al. Interleukin-17F gene polymorphisms in Korean patients with Behcet’s disease. Rheumatol Int 2008;29:173. [5] Yan N, Yu YL, Yang J, et al. Association of interleukin-17A and -17F gene single-nucleotide polymorphisms with autoimmune thyroid diseases. Autoimmunity 2012;45:533. [6] Paradowska-Gorycka A, Wojtecka-Lukasik E, Trefler J, et al. Association between IL-17F gene polymorphisms and susceptibility to and severity of rheumatoid arthritis (RA). Scand J Immunol 2010;72:134. [7] Saitoh T, Tsukamoto N, Koiso H, et al. Interleukin-17F gene polymorphism in patients with chronic immune thrombocytopenia. Eur J Haematol 2011;87:253. [8] Shu Q, Yang P, Hou S, et al. Interleukin-17 gene polymorphism is associated with Vogt-Koyanagi-Harada syndrome but not with Behçet’s disease in a Chinese Han population. Hum Immunol 2010;71:988. [9] Kawaguchi M, Takahashi D, Hizawa N, et al. IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity. J Allergy Clin Immunol 2006;117:795. [10] Arisawa T, Tahara T, Shibata T, et al. The influence of polymorphisms of interleukin-17A and interleukin-17F genes on the susceptibility to ulcerative colitis. J Clin Immunol 2008;28:44. [11] Metzger K, Frémont M, Roelant C, et al. Lower frequency of IL-17F sequence variant (His161Arg) in chronic fatigue syndrome patients. Biochem Biophys Res Commun 2008;376:231. [12] Yuan X, Paez-Cortez J, Schmitt-Knosalla I, et al. A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy. J Exp Med 2008;205:3133. [13] Loong CC, Hsieh HG, Lui WY, et al. Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection. J Pathol 2002;197:322. [14] Crispim JC, Grespan R, Martelli-Palomino G, et al. Interleukin-17 and kidney allograft outcome. Transplant Proc 2009;41: 1562. [15] Song EY, Park MH, Kang SJ, et al. HLA class II allele and haplotype frequencies in Koreans based on 107 families. Tissue Antigens 2002;59:475. [16] Alakulppi NS, Kyllonen LE, Jantti VT, et al. Cytokine gene polymorphisms and risks of acute rejection and delayed graft function after kidney transplantation. Transplantation 2004;78:1422. [17] Satoh S, Saito M, Inoue K, et al. Association of cytokine polymorphisms with subclinical progressive chronic allograft nephropathy in Japanese renal transplant recipients: preliminary study. Int J Urol 2007;14:990. [18] Israni AK, Li N, Cizman BB, Snyder J, et al. Association of donor inflammation- and apoptosis-related genotypes and delayed allograft function after kidney transplantation. Am J Kidney Dis 2008;52:331.
W
ITH THE INTRODUCTION of improved pretransplant evaluation and the development of posttransplantation immunosuppressive therapy, short-term graft survival in kidney transplantation has been remarkably improved. However, long-term graft outcome is still not satisfactory. Immunologic responses of the host play an important role in graft rejection or recurrence of underlying renal disease. T-helper (Th) cells consist of Th1 cells and Th2 cells. The former two T-regulatory cells are involved in proinflammatory, humoral, and antiinflammatory reaction, respectively. And another important T helper cell, Th17, involved in proinflammatory reaction, has been discovered [1]. Interleukin-17 (IL-17) is a critical cytokine responsible for Th17 cell reaction. IL17A and IL-17F are two important members in IL-17 cytokine family [2] with 55% sequence homology at the amino acid level [3]. Recently, IL-17F gene polymorphisms have been reported to be associated with various autoimmune or immunologic diseases [4e11]. The roles of IL-17 in renal transplantation have also been suggested [12e14]. But the association of IL-17 gene polymorphism with renal graft outcome has not been studied so far. We analyzed 5 single nucleotide polymorphisms (SNPs) of IL-17F gene in renal transplantation recipients and their associations with renal transplantation outcome. ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 121e123 (2014)
METHODS Subjects Two hundred eighty-two kidney transplantations between January 1, 1996 and July 31, 2004 in Seoul National University Hospital were included in this study. For healthy controls, 210 parents were selected from the members of 107 Korean families previously enrolled in another HLA study [15]. This study was conducted under the approval of Institutional Review Board (H1008-024-326) and according to Declaration of Helsinki.
Analysis of Interleukin-17F Gene SNPs Five SNPs of IL-17F gene: e1507G/A (rs1889570), 6329G/A (rs766748), 7384A/G (rs2397084), 7470G/A (rs11465553), and 7489A/G (rs763780) were analyzed. Allele-specific polymerase chain reaction (PCR) was performed for 2 SNPs (e1507G/A and 6329G/A) as previously reported [9]. For 7384A/G, 7470G/A, and 7489A/G From the Departments of Laboratory Medicine (H.P., S.S., M.H.P., E.Y.S.), Internal Medicine (Y.S.K., C.A.), and Surgery (J.H.), Seoul National University College of Medicine, Seoul, Korea. This study was supported by a grant number 0420100290 from the SNUH research fund. Address reprint requests to Eun Young Song, MD, PhD, Department of Laboratory Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea. E-mail: [email protected] 0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.05.015 121
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Table 1. Association of IL-17F Genotype With Acute Rejection or Recurrence of Primary Renal Disease Recurrence of primary renal disease, n (%)
Acute rejection, n (%) Genotype
()
e1507G/A GG 78 (40.6) GA 89 (46.4) AA 25 (13.0) 6329G/A GG 85 (44.5) GA 79 (41.4) AA 27 (14.1) 7384A/G AA 190 (98.4) AG 3 (1.6) 7470G/A GG 188 (97.4) GA 5 (2.6) 7489A/G AA 156 (80.8) AG 36 (18.7) GG 1 (0.5)
(þ)
P value
()
(þ)
.645 39 (44.3) 41 (46.6) 8 (9.1)
.599 106 (41.9) 10 (37.0) 116 (45.8) 15 (55.6) 31 (12.3) 2 (7.4)
.659 40 (45.5) 39 (44.3) 9 (10.2)
.518 114 (45.2) 11 (40.7) 104 (41.3) 14 (51.9) 34 (13.5) 2 (7.4)
.380 86 (96.6) 3 (3.4)
.018 250 (98.4) 26 (92.9) 4 (1.6) 2 (7.1)
.669 88 (98.9) 1 (1.1)
.441 248 (97.6) 28 (100) 6 (2.4) 0 (0.0)
.479 68 (76.4) 21 (23.6) 0 (0.0)
P value
.873 201 (79.1) 23 (82.1) 52 (20.5) 5 (17.9) 1 (0.4) 0 (0.0)
SNPs, direct sequencing was performed with previously reported primers [4]. PCR was performed using 3 mL of genomic DNA, 4 mL of primer mixture (2 mL of 10 pmole/mL forward and reverse primer, each), 4 mL of 10 buffer, 3.2 mL of 2.5 mmol/L deoxynucleotide triphosphate, 0.25 mL of Taq polymerase (Roche, Mannheim, Germany), and 25.55 mL of distilled water under the following conditions: 30 cycles of PCR consisting of initial denaturation for 5 minutes at 95 C followed by denaturation for 30 seconds at 95 C, annealing for 30 seconds at 61 C extension for 30 seconds at 72 C and a final extension for 5 minutes at 72 C in a thermocycler (PTC200, MJ Research, Waltham, Mass, United States). After PCR products were purified using QIAEX II gel extraction kit (Qiagen, Hilden, Germany), they were used as template DNA for direct sequencing analysis using the ABI Prism 3730XL Genetic Analyzer (Applied Biosystems, Foster City, Calif, United States).
Clinical Data The following characteristics of recipients were retrospectively collected: age and gender of recipient; age and gender of donor; type of donor (living vs cadaveric donor); primary renal disease causing end-stage renal disease; number of HLA mismatches; number of HLA-DR mismatches; the duration of hemodialysis; type of immunosuppression; time of transplantation; occurrence and time point of biopsy-proven acute rejection; recurrence of primary renal disease and its time point; 1-, 3-, 5-, 10-year creatinine levels post-transplantation; occurrence and time of graft failure, defined as graft nephrectomy or return to hemodialysis.
Statistical Analysis Differences of allele frequency and genotype frequency were compared using 2-sided chi-square test or Fisher’s exact test, as appropriate. Continuous variables between 2 groups were analyzed with Student t test. The logistic regression analysis was used to determine the independent association between presence/absence of alleles and disease while adjusting for the covariates. Variables with P < .25 from univariate logistic regression analyses were
Fig 1. Kaplan-Meier analysis of graft survival time in 282 kidney recipients. AA genotype of IL-17F gene on 7489A/G (n ¼ 224) are compared with AG or GG genotype (n ¼ 58). included in multivariate analysis, which performed by backward stepwise selection. The odds ratio (OR) was calculated using a 95% confidence intervals. Death-censored graft survival was analyzed using Kaplan-Meier method and log-rank test. P value of < .05 was considered statistically significant. SPSS for Windows version 12.0 (SPSS, Chicago, Ill, United States) was used for statistical analysis.
RESULTS
The allele frequencies and genotype frequencies of 5 SNPs studied were not significantly different between renal transplantation recipients and healthy controls (data not shown). All 5 SNPs studied showed no association with occurrence of acute allograft rejection (Table 1). Recipients with G allele on 7489A/G (AG or GG genotype) showed lower death-censored graft survival than recipients without G allele (AA genotype; P ¼ .04; Fig 1). In multivariate analysis including covariates with P < .25 in univariate analyses (age of recipient and donor, G allele on 7489A/G, tacrolimus-based immunosuppression, acute rejection, deceased donor, number of HLA mismatches, number of HLA-DR mismatches, recurrence of primary renal disease, and date of transplantation), G allele on 7489A/G was an independent risk factor for graft failure (OR ¼ 2.77, P ¼ .03). Age of recipients and donors, acute rejection, and recurrence of primary renal disease were also significant risk factors for graft failure (P < .037, OR ¼ 0.97; P ¼ .013, OR ¼ 0.96; P < .001, OR ¼ 10.42; P ¼ .002, OR ¼ 4.88, respectively; Table 2). DISCUSSION
SNPs of various cytokines such as interferon-gamma, tumor necrosis factor-alpha, transforming growth factor-beta, IL-2,
IL-17F GENE POLYMORPHISMS
123
Table 2. Multivariate Analyses of Risk Factors Affecting Renal Allograft Failure Risk factor
P value
Recipient age Donor age G allele on 7489A/G Acute rejection Recurrence of primary renal disease
.037 .013 .03 <.001 .002
OR (95% CI)
0.97 0.96 2.77 10.42 4.88
(0.94-0.99) (0.93-0.99) (1.10-6.96) (4.26-25.46) (1.77-13.53)
Abbreviations: OR, odds ratio; CI, confidence interval.
IL-6 and IL-10 have been reported to be associated with clinical outcomes of renal transplantation [16e18]. The roles of IL-17 in renal transplantation were suggested in mouse models [12,13], and the blood level of IL-17 was significantly higher in renal transplantation recipients with acute rejection than in those without acute rejection [14]. In our study, among 5 SNPs studied, no association was observed with acute rejection. However, G allele of 7489A/G was an independent risk factor for graft failure and associated with shorter graft survival time. SNP of 7489A/G is on exon 3 of the IL-F gene, which makes change of His to Arg on 161 amino acids. Recently, associations of SNP of 7489A/G with various kinds of autoimmune or immunologic diseases such as Graves disease [5], chronic immune thrombocytopenia [7], asthma [9], and ulcerative colitis [10] have been reported. From our study, it can be postulated that G allele on 7489A/G plays some roles in chronic inflammatory process of chronic allograft rejection. In conclusion, 7489A/G SNP of IL-17F gene was associated with graft survival in renal transplantation. The limitation of our study was lack of functional studies of IL-17F gene SNPs, which correlates blood level or expression of IL-17 on biopsy specimen. Further studies on larger number of patients that include IL-17F expression are needed. REFERENCES [1] Mangan PR, Harrington LE, O’Quinn DB, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006;441:231. [2] Rutitzky LI, Lopes da Rosa JR, Stadecker MJ. Severe CD4 T cell-mediated immunopathology in murine schistosomiasis is dependent on IL-12p40 and correlates with high levels of IL-17. J Immunol 2005;175:3920.
[3] Ishigame H, Kakuta S, Nagai T, et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 2009;30:108. [4] Jang WC, Nam YH, Ahn YC, et al. Interleukin-17F gene polymorphisms in Korean patients with Behcet’s disease. Rheumatol Int 2008;29:173. [5] Yan N, Yu YL, Yang J, et al. Association of interleukin-17A and -17F gene single-nucleotide polymorphisms with autoimmune thyroid diseases. Autoimmunity 2012;45:533. [6] Paradowska-Gorycka A, Wojtecka-Lukasik E, Trefler J, et al. Association between IL-17F gene polymorphisms and susceptibility to and severity of rheumatoid arthritis (RA). Scand J Immunol 2010;72:134. [7] Saitoh T, Tsukamoto N, Koiso H, et al. Interleukin-17F gene polymorphism in patients with chronic immune thrombocytopenia. Eur J Haematol 2011;87:253. [8] Shu Q, Yang P, Hou S, et al. Interleukin-17 gene polymorphism is associated with Vogt-Koyanagi-Harada syndrome but not with Behçet’s disease in a Chinese Han population. Hum Immunol 2010;71:988. [9] Kawaguchi M, Takahashi D, Hizawa N, et al. IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity. J Allergy Clin Immunol 2006;117:795. [10] Arisawa T, Tahara T, Shibata T, et al. The influence of polymorphisms of interleukin-17A and interleukin-17F genes on the susceptibility to ulcerative colitis. J Clin Immunol 2008;28:44. [11] Metzger K, Frémont M, Roelant C, et al. Lower frequency of IL-17F sequence variant (His161Arg) in chronic fatigue syndrome patients. Biochem Biophys Res Commun 2008;376:231. [12] Yuan X, Paez-Cortez J, Schmitt-Knosalla I, et al. A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy. J Exp Med 2008;205:3133. [13] Loong CC, Hsieh HG, Lui WY, et al. Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection. J Pathol 2002;197:322. [14] Crispim JC, Grespan R, Martelli-Palomino G, et al. Interleukin-17 and kidney allograft outcome. Transplant Proc 2009;41: 1562. [15] Song EY, Park MH, Kang SJ, et al. HLA class II allele and haplotype frequencies in Koreans based on 107 families. Tissue Antigens 2002;59:475. [16] Alakulppi NS, Kyllonen LE, Jantti VT, et al. Cytokine gene polymorphisms and risks of acute rejection and delayed graft function after kidney transplantation. Transplantation 2004;78:1422. [17] Satoh S, Saito M, Inoue K, et al. Association of cytokine polymorphisms with subclinical progressive chronic allograft nephropathy in Japanese renal transplant recipients: preliminary study. Int J Urol 2007;14:990. [18] Israni AK, Li N, Cizman BB, Snyder J, et al. Association of donor inflammation- and apoptosis-related genotypes and delayed allograft function after kidney transplantation. Am J Kidney Dis 2008;52:331.