Cytotoxic T-lymphocyte Associated Antigen-4 (CTLA-4) Polymorphism, Cancer, and Autoimmune Diseases

Maryam Tanhapour; Asad Vaisi-Raygani; Mozafar Khazaei; Zohreh Rahimi; Tayebeh Pourmotabbed; Maryam Tanhapour; Asad Vaisi-Raygani; Mozafar Khazaei; Zohreh Rahimi; Tayebeh Pourmotabbed

doi:10.3934/medsci.2017.4.395

AIMS Medical Science

2017, Volume 4, Issue 4: 395-412. doi: 10.3934/medsci.2017.4.395

Previous Article Next Article

Review

Cytotoxic T-lymphocyte Associated Antigen-4 (CTLA-4) Polymorphism, Cancer, and Autoimmune Diseases

1.
Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
2.
Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
3.
Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, U.S.A.

Received: 03 May 2017 Accepted: 09 October 2017 Published: 19 October 2017

Immune system dysfunction is one of the key features in onset and development of cancer and autoimmunity. Cytotoxic T-lymphocyte-antigen-4 (CTLA-4), as a leader immune checkpoint plays a crucial effects in the regulation of immune suppression and tolerance. In this review, role of CTLA-4 and its three important polymorphisms (SNP), CTLA-4 +49A/G, CTLA-4 CT60 A/G and CTLA-4 −318C/T in development of cancer and autoimmune diseases have been discussed. The evidences revealed that CTLA-4 +49A/G, A allele increases the risk of cervical cancer and CTLA-4 +49A/G G allele decreases the risk of breast cancer in Asian population. The presence of G allele of CTLA-4 +49A/G SNP is strongly correlates with increased risk of Graves and systemic lupus erythematous (SLE), in Asian and European population. G allele of CTLA-4 +49A/G SNP may be a risk factor for rheumatoid arthritis susceptibility (RA). Evidence suggests that the presence of CTLA-4 +49 G allele reduces the inhibitory function of CTLA-4 on T cells. Therefore, it is logical to propose that G allele of CTLA-4 +49 A/G increases the immune system activity and decreases the risk of cancer. The evidence on the effect of CTLA-4 CT60 A/G SNP on the risk of cancer development and autoimmune disorders is inconclusive. No association was found between the CTLA-4 −318C/T polymorphism with autoimmune diseases.
- CTLA-4,
- cancer,
- autoimmunity,
- polymorphism,
- Graves
Citation: Maryam Tanhapour, Asad Vaisi-Raygani, Mozafar Khazaei, Zohreh Rahimi, Tayebeh Pourmotabbed. Cytotoxic T-lymphocyte Associated Antigen-4 (CTLA-4) Polymorphism, Cancer, and Autoimmune Diseases[J]. AIMS Medical Science, 2017, 4(4): 395-412. doi: 10.3934/medsci.2017.4.395

Related Papers:

Abstract

Immune system dysfunction is one of the key features in onset and development of cancer and autoimmunity. Cytotoxic T-lymphocyte-antigen-4 (CTLA-4), as a leader immune checkpoint plays a crucial effects in the regulation of immune suppression and tolerance. In this review, role of CTLA-4 and its three important polymorphisms (SNP), CTLA-4 +49A/G, CTLA-4 CT60 A/G and CTLA-4 −318C/T in development of cancer and autoimmune diseases have been discussed. The evidences revealed that CTLA-4 +49A/G, A allele increases the risk of cervical cancer and CTLA-4 +49A/G G allele decreases the risk of breast cancer in Asian population. The presence of G allele of CTLA-4 +49A/G SNP is strongly correlates with increased risk of Graves and systemic lupus erythematous (SLE), in Asian and European population. G allele of CTLA-4 +49A/G SNP may be a risk factor for rheumatoid arthritis susceptibility (RA). Evidence suggests that the presence of CTLA-4 +49 G allele reduces the inhibitory function of CTLA-4 on T cells. Therefore, it is logical to propose that G allele of CTLA-4 +49 A/G increases the immune system activity and decreases the risk of cancer. The evidence on the effect of CTLA-4 CT60 A/G SNP on the risk of cancer development and autoimmune disorders is inconclusive. No association was found between the CTLA-4 −318C/T polymorphism with autoimmune diseases.

References

[1]	Caspi RR (2008) Immunotherapy of autoimmunity and cancer: The penalty for success. Nat Rev Immunol 8: 970-976. doi: 10.1038/nri2438
[2]	Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by ctla-4 blockade. Science 271: 1734.
[3]	Janeway Jr CA, Travers P, Walport M, et al. (2001) The major histocompatibility complex and its functions. Immunobiology.
[4]	Goldrath AW, Bevan MJ (1999) Selecting and maintaining a diverse t-cell repertoire. Nature 402: 255-262.
[5]	Chambers CA, Kuhns MS, Egen JG, et al. (2001) Ctla-4-mediated inhibition in regulation of t cell responses: Mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 19: 565-594. doi: 10.1146/annurev.immunol.19.1.565
[6]	Rudd CE, Taylor A, Schneider H (2009) Cd28 and ctla‐4 coreceptor expression and signal transduction. Immunol Rev 229: 12-26.
[7]	Rutkowski R, Moniuszko T, Stasiak-Barmuta A, et al. (2003) Cd80 and cd86 expression on lps-stimulated monocytes and the effect of cd80 and cd86 blockade on il-4 and ifn-gamma production in nanotopic bronchial asthma. Arch Immunol Ther Exp (Warsz) 51: 421-428.
[8]	Linsley PS, Clark EA, Ledbetter JA (1990) T-cell antigen cd28 mediates adhesion with b cells by interacting with activation antigen b7/bb-1. Proc Natl Acad Sci U S A 87: 5031-5035. doi: 10.1073/pnas.87.13.5031
[9]	Greenwald RJ, Freeman GJ, Sharpe AH (2005) The b7 family revisited. Annu Rev Immunol 23: 515-548. doi: 10.1146/annurev.immunol.23.021704.115611
[10]	Collins AV, Brodie DW, Gilbert RJ, et al. (2002) The interaction properties of costimulatory molecules revisited. Immunity 17: 201-210.
[11]	Sansom D (2000) Cd28, ctla‐4 and their ligands: Who does what and to whom? Immunology 101: 169-177.
[12]	Wang XB, Zheng CY, Giscombe R, et al. (2001) Regulation of surface and intracellular expression of ctla‐4 on human peripheral t cells. Scand J Immunol 54: 453-458. doi: 10.1046/j.1365-3083.2001.00985.x
[13]	Linsley PS, Greene J, Tan P, et al. (1992) Coexpression and functional cooperation of ctla-4 and cd28 on activated t lymphocytes. J Exp Med 176: 1595-1604. doi: 10.1084/jem.176.6.1595
[14]	Buc M (1996) Immunopathogenic mechanisms in autoimmune processes: Autoantigens. Bratisl Lek Listy 97: 187-195.
[15]	Ribas A, Camacho LH, Lopez-Berestein G, et al. (2005) Antitumor activity in melanoma and anti-self responses in a phase i trial with the anti-cytotoxic t lymphocyte–associated antigen 4 monoclonal antibody cp-675,206. J Clin Oncol 23: 8968-8977. doi: 10.1200/JCO.2005.01.109
[16]	Maker AV, Phan GQ, Attia P, et al. (2005) Tumor regression and autoimmunity in patients treated with cytotoxic t lymphocyte–associated antigen 4 blockade and interleukin 2: A phase i/ii study. Ann Surg Oncol 12: 1005-1016. doi: 10.1245/ASO.2005.03.536
[17]	Buchbinder EI, Desai A (2016) Ctla-4 and pd-1 pathways: Similarities, differences, and implications of their inhibition. Am J Clin Oncol 39: 98. doi: 10.1097/COC.0000000000000239
[18]	Quezada SA, Peggs KS, Curran MA, et al. (2006) Ctla4 blockade and gm-csf combination immunotherapy alters the intratumor balance of effector and regulatory t cells. J Clin Invest 116: 1935-1945. doi: 10.1172/JCI27745
[19]	Phan GQ, Yang JC, Sherry RM, et al. (2003) Cancer regression and autoimmunity induced by cytotoxic t lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 100: 8372-8377.
[20]	Hodi FS, Mihm MC, Soiffer RJ, et al. (2003) Biologic activity of cytotoxic t lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A 100: 4712-4717. doi: 10.1073/pnas.0830997100
[21]	Ribas A, Glaspy JA, Lee Y, et al. (2004) Role of dendritic cell phenotype, determinant spreading, and negative costimulatory blockade in dendritic cell-based melanoma immunotherapy. J Immunother 27: 354-367. doi: 10.1097/00002371-200409000-00004
[22]	Wolchok JD, Saenger Y (2008) The mechanism of anti-ctla-4 activity and the negative regulation of t-cell activation. Oncologist 13: 2-9.
[23]	Cooper GS, Miller FW, Pandey JP (1999) The role of genetic factors in autoimmune disease: Implications for environmental research. Environ Health Perspect 107: 693. doi: 10.1289/ehp.99107s5693
[24]	Remmersl EF, Longmanl RE, Dul Y, et al. (1996) A genome scan localizes five non-mhc loci controlling. Nat Genet 14.
[25]	Gupta B, Hawkins RD (2015) Epigenomics of autoimmune diseases. Immunol Cell Biol 93: 271-276. doi: 10.1038/icb.2015.18
[26]	Maurano MT, Humbert R, Rynes E, et al. (2012) Systematic localization of common disease-associated variation in regulatory DNA. Science 337: 1190-1195.
[27]	Kamel AM, Mira MF, Mossallam GI, et al. (2014) Lack of association of ctla-4 +49 a/g polymorphism with predisposition to type 1 diabetes in a cohort of egyptian families. Egypt J Med Hum Genet 15: 25-30. doi: 10.1016/j.ejmhg.2013.09.002
[28]	Steiner K, Moosig F, Csernok E, et al. (2001) Increased expression of ctla‐4 (cd152) by t and b lymphocytes in wegener's granulomatosis. Clin Exp Immunol 126: 143-150. doi: 10.1046/j.1365-2249.2001.01575.x
[29]	Teft WA, Kirchhof MG, Madrenas J (2006) A molecular perspective of ctla-4 function. Annu Rev Immunol 24: 65-97. doi: 10.1146/annurev.immunol.24.021605.090535
[30]	Prans E (2010) Allelic variants of ctla-4 gene as important markers of immune regulation in type 1 diabetes.
[31]	Pawlak E, Kochanowska IE, Frydecka I, et al. (2005) The soluble ctla-4 receptor: A new marker in autoimmune diseases. Arch Immunol Ther Exp (Warsz) 53: 336.
[32]	Ueda H, Howson JM, Esposito L, et al. (2003) Association of the t-cell regulatory gene ctla4 with susceptibility to autoimmune disease. Nature 423: 506-511. doi: 10.1038/nature01621
[33]	Chistiakov D, Turakulov R (2003) Ctla-4 and its role in autoimmune thyroid disease. J Mol Endocrinol 31: 21-36. doi: 10.1677/jme.0.0310021
[34]	Magistrelli G, Jeannin P, Herbault N, et al. (1999) A soluble form of ctla‐4 generated by alternative splicing is expressed by nonstimulated human t cells. Eur J Immunol 29: 3596-3602. doi: 10.1002/(SICI)1521-4141(199911)29:11<3596::AID-IMMU3596>3.0.CO;2-Y
[35]	Jakubczik F, Jones K, Nichols J, et al. (2016) A snp in the immunoregulatory molecule ctla-4 controls mrna splicing in vivo but does not alter diabetes susceptibility in the nod mouse. Diabetes 65: 120-128.
[36]	Ghaderi A (2011) Ctla4 gene variants in autoimmunity and cancer: A comparative review. Iran J Immunol 8: 127.
[37]	Valk E, Rudd CE, Schneider H (2008) Ctla-4 trafficking and surface expression. Trends Immunol 29: 272-279. doi: 10.1016/j.it.2008.02.011
[38]	Gerold KD, Zheng P, Rainbow DB, et al. (2011) The soluble ctla-4 splice variant protects from type 1 diabetes and potentiates regulatory t-cell function. Diabetes 60: 1955-1963. doi: 10.2337/db11-0130
[39]	Rudd CE (2008) The reverse stop-signal model for ctla4 function. Nat Rev Immunol 8: 153-160. doi: 10.1038/nri2253
[40]	Walker LS, Sansom DM (2011) The emerging role of ctla4 as a cell-extrinsic regulator of t cell responses. Nat Rev Immunol 11: 852-863. doi: 10.1038/nri3108
[41]	Parry RV, Chemnitz JM, Frauwirth KA, et al. (2005) Ctla-4 and pd-1 receptors inhibit t-cell activation by distinct mechanisms. Mol Cell Biol 25: 9543-9553. doi: 10.1128/MCB.25.21.9543-9553.2005
[42]	Chikuma S, Imboden JB, Bluestone JA (2003) Negative regulation of t cell receptor–lipid raft interaction by cytotoxic t lymphocyte–associated antigen 4. J Exp Med 197: 129-135. doi: 10.1084/jem.20021646
[43]	Choi JM, Ahn MH, Chae WJ, et al. (2006) Intranasal delivery of the cytoplasmic domain of ctla-4 using a novel protein transduction domain prevents allergic inflammation. Nat Med 12: 574-579. doi: 10.1038/nm1385
[44]	Thompson CB, Allison JP (1997) The emerging role of ctla-4 as an immune attenuator. Immunity 7: 445-450.
[45]	Schneider H, Downey J, Smith A, et al. (2006) Reversal of the tcr stop signal by ctla-4. Science 313: 1972-1975. doi: 10.1126/science.1131078
[46]	Uyttenhove C, Pilotte L, Théate I, et al. (2003) Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2, 3-dioxygenase. Nat med 9: 1269-1274. doi: 10.1038/nm934
[47]	Hwang SL, Chung NP-y, Chan JK-y, et al. (2005) Indoleamine 2, 3-dioxygenase (ido) is essential for dendritic cell activation and chemotactic responsiveness to chemokines. Cell res 15: 167-175. doi: 10.1038/sj.cr.7290282
[48]	Munn DH, Mellor AL (2007) Indoleamine 2, 3-dioxygenase and tumor-induced tolerance. J Clin Invest 117: 1147-1154. doi: 10.1172/JCI31178
[49]	Vignali DA, Collison LW, Workman CJ (2008) How regulatory t cells work. Nat Rev Immunol 8: 523-532. doi: 10.1038/nri2343
[50]	Gorelik L, Flavell RA (2000) Abrogation of tgfβ signaling in t cells leads to spontaneous t cell differentiation and autoimmune disease. Immunity 12: 171-181.
[51]	Qureshi OS, Zheng Y, Nakamura K, et al. (2011) Trans-endocytosis of cd80 and cd86: A molecular basis for the cell-extrinsic function of ctla-4. Science 332: 600-603. doi: 10.1126/science.1202947
[52]	Carreno BM, Bennett F, Chau TA, et al. (2000) Ctla-4 (cd152) can inhibit t cell activation by two different mechanisms depending on its level of cell surface expression. J Immunol 165: 1352-1356. doi: 10.4049/jimmunol.165.3.1352
[53]	Sharpe AH, Freeman GJ (2002) The b7–cd28 superfamily. Nat Rev Immunol 2: 116-126. doi: 10.1038/nri727
[54]	Krummey SM, Ford ML (2014) Braking bad: Novel mechanisms of ctla‐4 inhibition of t cell responses. Am J Transplant 14: 2685-2690. doi: 10.1111/ajt.12938
[55]	Grosso JF, Jure-Kunkel MN (2013) Ctla-4 blockade in tumor models: An overview of preclinical and translational research. Cancer Immun 13: 5.
[56]	Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: Integrating immunity's roles in cancer suppression and promotion. Science 331: 1565-1570. doi: 10.1126/science.1203486
[57]	Palacios R, Comas D, Elorza J, et al. (2008) Genomic regulation of ctla4 and multiple sclerosis. J Neuroimmunol 203: 108-115. doi: 10.1016/j.jneuroim.2008.06.021
[58]	Ramirez SA, Lao O, Soldevila M, et al. (2005) Haplotype tagging efficiency in worldwide populations in ctla4 gene. Genes Immun 6: 646-657.
[59]	Zheng J, Yu X, Jiang L, et al. (2010) Association between the cytotoxic t-lymphocyte antigen 4 + 49g> a polymorphism and cancer risk: A meta-analysis. BMC cancer 10: 522. doi: 10.1186/1471-2407-10-522
[60]	Pérez-García A, De la Cámara R, Román-Gómez J, et al. (2007) Ctla-4 polymorphisms and clinical outcome after allogeneic stem cell transplantation from hla-identical sibling donors. Blood 110: 461-467. doi: 10.1182/blood-2007-01-069781
[61]	Tanhapour M, Vaisi-Raygani A, Bahrehmand F, et al. (2016) Association between the cytotoxic t-lymphocyte antigen-4 mutations and the susceptibility to systemic lupus erythematosus; contribution markers of inflammation and oxidative stress. Cell Mol Biol (Noisy-le-grand) 62: 56.
[62]	Ling V, Wu PW, Finnerty HF, et al. (1999) Complete sequence determination of the mouse and human ctla4 gene loci: Cross-species DNA sequence similarity beyond exon borders. Genomics 60: 341-355.
[63]	Yanagawa T, Hidaka Y, Guimaraes V, et al. (1995) Ctla-4 gene polymorphism associated with graves' disease in a caucasian population. J Clin Endocrinol Metab 80: 41-45.
[64]	Vaidya B, Pearce S (2004) The emerging role of the ctla-4 gene in autoimmune endocrinopathies. Eur J Endocrinol 150: 619-626. doi: 10.1530/eje.0.1500619
[65]	Ting WH, Chien MN, Lo FS, et al. (2016) Association of cytotoxic t-lymphocyte-associated protein 4 (ctla4) gene polymorphisms with autoimmune thyroid disease in children and adults: Case-control study. PloS one 11: e0154394. doi: 10.1371/journal.pone.0154394
[66]	Paula AV, Lourdes C, RicardoV GM, et al. (2011) Association of ctla4 gene polymorphism with ophthalmopathy of graves' disease in a spanish population. Int J Endocrinol Metabolism 9: 397-402.
[67]	Du P, Ma X, Wang C (2014) Associations of ctla4 gene polymorphisms with graves' ophthalmopathy: A meta-analysis. Int J Genomics.
[68]	Khalilzadeh O, Amiri HM, Tahvildari M, et al. (2009) Pretibial myxedema is associated with polymorphism in exon 1 of ctla-4 gene in patients with graves' ophthalmopathy. Arch Dermatol Res 301: 719-723. doi: 10.1007/s00403-008-0919-1
[69]	Han S, Zhang S, Zhang W, et al. (2006) Ctla4 polymorphisms and ophthalmopathy in graves' disease patients: Association study and meta-analysis. Hum Immunol 67: 618-626. doi: 10.1016/j.humimm.2006.05.003
[70]	Si X, Zhang X, Tang W, et al. (2012) Association between the ctla-4 +49a/g polymorphism and graves' disease: A meta-analysis. Exp Ther Med 4: 538-544. doi: 10.3892/etm.2012.618
[71]	Devaraju P, Gulati R, Singh B, et al. (2014) The ctla4 +49 a/g (rs231775) polymorphism influences susceptibility to sle in south indian tamils. Tissue Antigens 83: 418-421. doi: 10.1111/tan.12363
[72]	Liu J, Zhang H-X (2013) Ctla-4 polymorphisms and systemic lupus erythematosus: A comprehensive meta-analysis. Genet Test Mol Biomarkers 17: 226-231. doi: 10.1089/gtmb.2012.0302
[73]	Kimkong I, Nakkuntod J, Sae-Ngow S, et al. (2011) Association between ctla-4 polymorphisms and the susceptibility to systemic lupus erythematosus and graves' disease in thai population. Asian Pac J Allergy Immunol 29: 229.
[74]	Chua KH, Puah SM, Chew CH, T et al. (2010) Study of the ctla-4 gene polymorphisms in systemic lupus erythematosus (sle) samples from malaysia. Ann Hum Biol 37: 275-281. doi: 10.3109/03014460903325185
[75]	Ahmed S, Ihara K, Kanemitsu S, et al. (2001) Association of ctla‐4 but not cd28 gene polymorphisms with systemic lupus erythematosus in the japanese population. Rheumatology 40: 662-667.
[76]	Katkam SK, Kumaraswami K, Rupasree Y, T et al. (2016). Association of ctla4 exon-1 polymorphism with the tumor necrosis factor-α in the risk of systemic lupus erythematosus among south indians. Hum Immunol 77: 158-164. doi: 10.1016/j.humimm.2015.11.002
[77]	Barreto M, Santos E, Ferreira R, et al. (2004) Evidence for ctla4 as a susceptibility gene for systemic lupus erythematosus. Eur J Hum Genet 12: 620-626. doi: 10.1038/sj.ejhg.5201214
[78]	Zhai JX, Zou LW, Zhang ZX, et al. (2013) Ctla-4 polymorphisms and systemic lupus erythematosus (sle): A meta-analysis. Mol Biol Rep 40: 5213-5223. doi: 10.1007/s11033-012-2125-7
[79]	Narooie NM, Taji O, Tamandani DMK, et al. (2017) Association of CTLA-4 gene polymorphisms−318c/t and +49a/g and hashimoto's thyroidits in zahedan, iran. Biomed Rep 6: 108-112. doi: 10.3892/br.2016.813
[80]	Liu J, Zhang HX (2014) Ctla-4 gene and the susceptibility of multiple sclerosis: An updated meta-analysis study including 12,916 cases and 15,455 controls. J Neurogenet 28: 153-163. doi: 10.3109/01677063.2014.880703
[81]	Farra C, Awwad J, Fadlallah A, et al. (2012) Genetics of autoimmune thyroid disease in the lebanese population. J Community Genet 3: 259-264. doi: 10.1007/s12687-012-0085-1
[82]	Bicek A, Zaletel K, Gaberscek S, et al. (2009) 49a/g and ct60 polymorphisms of the cytotoxic t-lymphocyte-associated antigen 4 gene associated with autoimmune thyroid disease. Hum Immunol 70: 820-824.
[83]	Sameem M, Rani A, Bashir R, et al. (2015) Ctla-4 +49 polymorphism and susceptibility to rheumatoid arthritis in pakistani population. Pakistan J Zool 47: 1731-1737.
[84]	Li G, Shi F, Liu J, et al. (2014) The effect of ctla-4 a49g polymorphism on rheumatoid arthritis risk: A meta-analysis. Diagn Pathol 9: 157. doi: 10.1186/s13000-014-0157-0
[85]	Vaidya B, Pearce S, Charlton S, et al. (2002) An association between the ctla4 exon 1 polymorphism and early rheumatoid arthritis with autoimmune endocrinopathies. Rheumatology 41: 180-183.
[86]	Dai Z, Tian T, Wang M, et al. (2017) Ctla-4 polymorphisms associate with breast cancer susceptibility in asians: A meta-analysis. Peer J 5: e2815.
[87]	Liu P, Xu L, Sun Y, et al. (2014) The association between cytotoxic t lymphocyte-associated antigen-4 and cervical cancer. Tumor Biol 35: 2893-2903.
[88]	Han W-JW (2016) Association of cytotoxic t-lymphocyte antigen-4 polymorphisms with malignant bone tumors risk: A meta-analysis. Asian Pac J Cancer Prev 17: 3785-3791.
[89]	Sáenz LP, Vázquez AF, Romero JM, et al. (2009) Polymorphisms in inflammatory response genes in metastatic renal cancer. Actas Urol Esp 33: 474-481.
[90]	Jaiswal PK, Singh V, Mittal RD (2014) Cytotoxic t lymphocyte antigen 4 (ctla4) gene polymorphism with bladder cancer risk in north indian population. Mol Biol Rep 41: 799-807. doi: 10.1007/s11033-013-2919-2
[91]	Hu L, Liu J, Chen X, et al. (2010) Ctla-4 gene polymorphism +49 a/g contributes to genetic susceptibility to two infection-related cancers-hepatocellular carcinoma and cervical cancer. Hum Immunol 71: 888-891. doi: 10.1016/j.humimm.2010.05.023
[92]	Cheng TY, Lin JT, Chen LT, et al. (2006) Association of t-cell regulatory gene polymorphisms with susceptibility to gastric mucosa-associated lymphoid tissue lymphoma. J Clin Oncol 24: 3483-3489. doi: 10.1200/JCO.2005.05.5434
[93]	Gao X, Zhang S, Qiao X, et al. (2014) Association of cytotoxic t lymphocyte antigen-4 +49a/g polymorphism and cancer risk: An updated meta-analysis. Cancer Biomark 14: 287-294. doi: 10.3233/CBM-140403
[94]	Minhas S, Bhalla S, Shokeen Y, et al. (2014) Lack of any association of the ctla-4 +49 g/a polymorphism with breast cancer risk in a north indian population. Asian Pac J Cancer Prev 15: 2035-2038.
[95]	Qiu H, Tang W, Yin P, et al. (2013) Cytotoxic t-lymphocyte-associated antigen‑4 polymorphisms and susceptibility to cervical cancer: A meta-analysis. Mol Med Rep 8: 1785-1794.
[96]	Khaghanzadeh N, Erfani N, Ghayum MA, et al. (2010) Ctla4 gene variations and haplotypes in patients with lung cancer. Cancer Genet Cytogenet 196: 171-174. doi: 10.1016/j.cancergencyto.2009.09.001
[97]	Su T-H, Chang T-Y, Lee Y-J, et al. (2007) Ctla-4 gene and susceptibility to human papillomavirus-16-associated cervical squamous cell carcinoma in taiwanese women. Carcinogenesis 28: 1237-1240. doi: 10.1093/carcin/bgm043
[98]	Bharti V, Mohanti BK, Das SN (2013) Functional genetic variants of ctla-4 and risk of tobacco-related oral carcinoma in high-risk north indian population. Hum Immunol 74: 348-352. doi: 10.1016/j.humimm.2012.12.008
[99]	Touma Z, Hamdan A, Shamseddeen W, et al. (2008) CTLA-4 gene variants are not associated with Behçet's disease or its clinical manifestations. Clin Exp Rheumatol 26: S132.
[100]	Wang L, Li D, Fu Z, et al. (2007) Association of ctla-4 gene polymorphisms with sporadic breast cancer in chinese han population. BMC cancer 7: 173. doi: 10.1186/1471-2407-7-173
[101]	Perez-Garcia A, Brunet S, Berlanga J, et al. (2009) Ctla-4 genotype and relapse incidence in patients with acute myeloid leukemia in first complete remission after induction chemotherapy. Leukemia 23: 486-491.
[102]	Erfani N, Haghshenas MR, Hoseini MA, et al. (2012) Strong association of ctla-4 variation (ct60a/g) and ctla-4 haplotypes with predisposition of iranians to head and neck cancer. Iran J Immunol 9: 188.
[103]	Torres B, Aguilar F, Franco E, et al. (2004) Association of the ct60 marker of the ctla4 gene with systemic lupus erythematosus. Arthritis Rheum 50: 2211-2215. doi: 10.1002/art.20347
[104]	Lu L, Wang W, Feng R, et al. (2016) Association between cytotoxic t lymphocyte antigen-4 gene polymorphisms and gastric cancer risk: A meta-analysis of case-control studies. Int J Clin Exp Med 9: 10639-10650.
[105]	Chong KK, Chiang SW, Wong GW, et al. (2008) Association of ctla-4 and il-13 gene polymorphisms with graves' disease and ophthalmopathy in chinese children. Invest Ophthalmol Vis Sci 49: 2409-2415. doi: 10.1167/iovs.07-1433
[106]	Tomoyose T, Komiya I, Takara M, et al. (2002) Cytotoxic t-lymphocyte antigen-4 gene polymorphisms and human t-cell lymphotrophic virus-1 infection: Their associations with hashimoto's thyroiditis in japanese patients. Thyroid 12: 673-677.
[107]	Hudson LL, Rocca K, Song YW, et al. (2002) Ctla-4 gene polymorphisms in systemic lupus erythematosus: A highly significant association with a determinant in the promoter region. Hum Genet 111: 452-455. doi: 10.1007/s00439-002-0807-2

Reader Comments

Your name:*

Email:*
© 2017 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)