==== Front Onco Targets TherOnco Targets TherOncoTargets and TherapyOncoTargets and therapy1178-6930Dove Medical Press 10.2147/OTT.S161544ott-11-4339Original ResearchPolymorphism of IFN-γ +874T/A associated with production of IFN-γ affects human papillomavirus susceptibility in rural women from Luohe, Henan, China Zhang Qing-wei 1Song Jia-yu 2Yu Jiang-hua 1Sun Ming-zhen 2Tang Si-yuan 1Yang Shao-zhe 1Cao Lei-jia 1Wang Hui-fen 1Cui Li-na 1Fu Xiu-hong 1 1 Department of Obstetrics and Gynaecology, Luohe Central Hospital, Luohe, 462000, Henan, China 2 Department of Pharmacology, Luohe Medical College, Luohe, 462000, Henan, China, songjiayu1986@21cn.comCorrespondence: Jia-yu Song, Department of Pharmacology, Luohe Medical College, No 148, University Road, Yuanhui, Luohe, 462000, Henan, China, Tel/fax +86 395 296 9417, Email songjiayu1986@21cn.com2018 25 7 2018 11 4339 4344 © 2018 Zhang et al. This work is published and licensed by Dove Medical Press Limited2018The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Purpose In this paper, the association between polymorphisms of IFN-γ +874T/A (rs2430561), IFN-γR1 −56 T/C (rs2234711), IFN-γR1 +95 C/T (rs7749390), and IFN-γR1 −611A/G (rs 1327474) and human papillomavirus (HPV) susceptibility was investigated in rural women from Luohe, Henan, China. Patients and methods A total of 520 rural women were enrolled from Luohe, including 260 with HPV infection and mild dysplasia or less and 260 without HPV infection. Single-nucleotide polymorphisms (SNPs) of IFN-γ +874T/A, IFN-γR1 −56 T/C, IFN-γR1 +95 C/T and IFN-γR1 −611A/G were genotyped using TaqMan Pre-Designed SNP Genotyping Assays. Serum IFN-γ levels were measured using Human IFN-γ Quantikine ELISA Kit. Multivariate logistic regression analysis was performed to identify the SNPs associated with HPV susceptibility. Serum IFN-γ levels were compared between different genotypes. Results The polymorphism of IFN-γ +874T/A was associated with HPV susceptibility and +874A carriers had an increased risk. Moreover, the odds ratio was higher in +874 AA carriers than in +874 AT carriers (1.672 vs 2.874). Serum IFN-γ levels were highest in IFN-γ +874 TT carriers, intermediate in AT carriers, and lowest in AA carriers (2.86±1.14 vs 1.57±0.79 vs 0.41±0.22 pg/mL, all P<0.05). Conclusion The polymorphism of IFN-γ +874T/A was associated with HPV susceptibility in rural women from Luohe, Henan, China, and +874A carriers had an increased risk. The possible mechanism was that +874A carriers had a low production of IFN-γ. Keywords single-nucleotide polymorphismsIFN-γIFN-γR1human papillomavirussusceptibility ==== Body Introduction As one of the most common cancers in women around the world,1,2 cervical cancer led to >266,000 deaths in 2012 alone.3 In China, cervical cancer is the second most common gynecologic cancer among women, with an increasing incidence and mortality.4,5 Human papillomavirus (HPV) is a typical risk factor for cervical cancer as the only confirmed cancer-inducing virus so far.6 Cervical HPV infection is common,7,8 with a lifetime risk of 80%–90%.9 Although most HPV infections are transitory,10 5%–10% of women with persistent infections remain at an increased risk for the development of cervical intraepithelial neoplasia (CIN) 3 and, less commonly, cervical cancer.11 The immune system of hosts has an important role in controlling HPV infection. Immunosuppressed women have an increased incidence of HPV infection.12,13 The imbalance of local inflammatory cytokines, including interferon-gamma (IFN-γ), interleukin (IL)-12 and tumor necrosis factor-alpha, is associated with persistent HPV infection.14–16 INF-γ has a role in both innate and adaptive immunity,17 and can induce cellular resistance to HPV infection.18 Both IFN-γ and its receptor (IFN-γR1) genes are key immune response genes.19 The IFN-γ gene is located on chromosome 12q24.1 and encodes IFN-γ.20 The polymorphism of IFN-γ +874T/A (rs2430561) may affect the production of IFN-γ.21 The IFN-γR1 gene locates on chromosome 13q31.3–32.1 and encodes the ligand-binding chain of the IFN-γ receptor.22 In this paper, the association between the polymorphisms of IFN-γ +874T/A (rs2430561), IFN-γR1 −56 T/C (rs2234711), IFN-γR1 +95 C/T (rs7749390) and IFN-γR1 −611A/G (rs 1327474) and HPV susceptibility was investigated in rural women from Luohe, Henan, China. The aim was to identify susceptible genotypes to HPV infection and, thus, provide useful information for vaccination. Patients and methods Sampling and randomization strategy This case–control study employed a multistage randomized sampling strategy. One district was selected from five districts in Luohe using computer-generated random selection, and five villages were selected from this selected district. All women meeting the inclusion criteria in these selected villages were detected for HPV infection. The inclusion criteria included: 1) voluntary participation, 2) age ranging from 22 to 70 years and 3) a sexual history of >3 years. The exclusion criteria included having a medical history of CIN, or cervical cancer, or hysterectomy. Participants A total of 260 women were randomly selected and allocated to the case group from the screened women with HPV infection and mild dysplasia or less. The case group was matched by the control group (n=260) according to age and village at a ratio of 1:1. This study was permitted by the ethics committee of Luohe Central Hospital (201402016), and all participants provided written informed consent. HPV infection testing Cervical tissue cells were collected >3 days after menstruation and 72 hours after sexual life or vaginal medication from all participants. The sampling brush was rotated softly in the cervical canals to take specimens, and specimens were then stored in a refrigerator at a temperature of 4°C. The HPV infection status in the cervical tissue was tested with Hybrid Capture 2 (HC-2) detector developed by QIAGEN (Hilden, Germany). Single-nucleotide polymorphism genotyping DNA for single-nucleotide polymorphism (SNP) genotyping was extracted from the peripheral blood of participants using salting out method according to Hashemi et al.23 SNPs of IFN-γ +874T/A, IFN-γR1 −56 T/C, IFN-γR1 +95 C/T and IFN-γR1 −611A/G were genotyped with TaqMan Pre-Designed SNP Genotyping Assays (Applied Biosystems, Carlsbad, CA, USA). Polymerase chain reaction amplification and allelic discrimination were performed according to product specifications using the ABI 7500 Fast real-time polymerase chain reaction system (Applied Biosystems). Measurement of serum IFN-γ levels Serum IFN-γ levels were measured with Human IFN-γ Quantikine ELISA Kit (R&D Systems Europe, Ltd., Abingdon, UK) in all participants, according to the instructions of the manufacturer. Statistical analysis For all SNPs, Hardy–Weinberg equilibrium test, allele frequencies and genotype frequencies were computed with the SNPstats software (a web tool for the analysis of association studies: net/SNPstats).24 All factors, including general data and all SNPs, were compared with a chi-squared test between the case group and the control group. The factors with a P-value <0.10 in univariate analysis were included in the multivariate analysis with a backward stepwise logistic regression model. Multivariate logistic regression analysis was then performed to identify the SNPs associated with HPV susceptibility. Serum IFN-γ levels were compared with analysis of variance between different genotypes. The SPSS version 22.0 for Windows (IBM Corporation, Armonk, NY, USA) was employed to perform all statistical analyses. Significance was set at P<0.05. Results General data The average age of all participants was 41.58±9.46 years. According to the results of univariate analysis, annual family income, education level and occupation were statistically different between the case group and the control group, and race, and marital, drinking and smoking status were not statistically different (Table 1). SNP analysis The success rates of genotyping of all SNPs were 100% in both the control group and the case group. The genotype frequencies of all SNPs did not deviate significantly from those expected under Hardy–Weinberg equilibrium (Table 2). According to the results of univariate analysis, the genotype frequencies of IFN-γ +874T/A and IFN-γR1 −56 T/C were statistically different between the case group and the control group (P<0.05), and those of IFN-γR1 +95 C/T and IFN-γR1 −611A/G were not statistically different (P>0.05). Multivariate analysis Multivariate logistic regression analysis was performed to determine the association between different genotypes of IFN-γ +874T/A and IFN-γR1 −56 T/C and HPV susceptibility, adjusting for age, annual family income, education level, occupation and smoking status (Table 3). According to the results of multivariate analysis, the polymorphism of IFN-γ +874T/A was associated with HPV susceptibility, and +874A carriers had an increased risk of HPV infection. Moreover, the odds ratio (OR) was higher in +874 AA carriers than in +874 AT carriers (Figure 1). Serum IFN-γ levels The results of analysis of variance showed that serum IFN-γ levels were highest in IFN-γ +874 TT carriers, intermediate in AT carriers and lowest in AA carriers (Table 4). Discussion Cytokines have a pivotal role in establishing and maintaining immune responses against virus infection.25 Polymorphisms of regulating regions of cytokine genes, including IFN-γ, IL-6, IL-10, transforming growth factor beta 1 (TGF-β1) and TNF genes, have been associated with their production, which lead to difference in susceptibility to virus infection.26–30 HPV infection is very common among women. However, the virus is eliminated in most infected women (70%–90%) 12–24 months after the initial diagnosis without any intervention.31,32 The exact mechanism associated with the clearance of HPV infection remains uncertain. Both the innate and adaptive immune responses are involved in the clearance, persistence or progression of HPV infection.33 The innate immune response is thought to be critical in early control of HPV infection as the first line of defense against invading pathogens.34 It can coordinate the host responses to prevent or reduce viral replication and spread, until the adaptive immune system is established.35 Most cervical HPV infections are eliminated or suppressed through cell-mediated immunity with CD4+ and CD8+ T cells as the major effector cells,36 and the Th1 response is associated with clearance of the HPV infection.37 As a T-helper 1 proinflammatory cytokine, IFN-γ is produced during virus infection. IFN-γ has a pivotal role in defense against HPV through inducing cell-mediated inflammatory responses.38,39 Telesheva et al found that the outcome of HPV infection is correlated with the interferon component of the immune response.40 A persistent HPV infection is characterized by decreased levels of IFN-α, and transient infection is associated with increased levels of IFN-γ and IFN-α. Song et al investigated 57 women with high-risk HPV (HR-HPV) infection and untreated mild dysplasia or less. After a follow-up period of 12 months, HPV was not detectable in 93.3% (28/30) of women who were IFN-γ positive and in 66.7% (18/27) of women who were IFN-γ negative. Multivariate analysis showed that IFN-γ-positive status was significantly associated with clearance of HR-HPV (OR: 8.26; 95% CI: 1.24–54.94). Therefore, they concluded that IFN-γ may be a prognostic marker for clearance of HR-HPV.15 As the encoding gene of IFN-γ, IFN-γ gene may affect the production of IFN-γ through an SNP located in the first intron at the 5′ end adjacent to a CA repeat region (+874T/A polymorphism).21 IFN-γ +874 TT genotype produces a high level of IFN-γ and helps the host’s defense against viral infection. Conversely, the genotypes AA and AT cause low IFN-γ production, which may increase the risk of viral infection.41–45 According to our results, the polymorphism of IFN-γ +874T/A was associated with HPV susceptibility, and +874A carriers had an increased risk of HPV infection. Moreover, the OR was higher in +874 AA carriers than in +874 AT carriers. The serum levels of IFN-γ were +874 TT carriers>AT carriers>AA carriers. Therefore, the polymorphism of IFN-γ +874T/A affected HPV susceptibility through modulating the production of IFN-γ. Meanwhile, the polymorphisms of IFN-γR1 −56 T/C, IFN-γR1 +95 C/T and IFN-γR1 −611A/G were not associated with HPV susceptibility, and the serum levels of IFN-γ were not statistically different between different genotypes. Conclusion The polymorphism of IFN-γ +874T/A was associated with HPV susceptibility in rural women from Luohe, Henan, China, and +874A carriers had an increased risk of HPV infection. The possible mechanism was that +874A carriers had a low production of IFN-γ. Acknowledgments This work was supported by the Project for Outstanding Young Scholars of Luohe, Key Project of Colleges and Universities in Henan Province (contract number: 17B320011), Project of Luohe Medical College (contract number: 2016-S-LMC-11) and Huimin Project of Science and Technology in Henan Province (contract number: 142207310008). Disclosure The authors report no conflicts of interest in this work. Figure 1 Association between IFN-γ +874T/A polymorphism and human papilloma-virus susceptibility. Note: IFN-γ +874 TT was used as Ref. Abbreviations: IFN, interferon; OR, odds ratio; Ref, reference. Table 1 General data of the case group and the control group Variables Case group (n=260) Control group (n=260) χ2 P-value Race  Han 251 (96.54%) 250 (96.15%) 0.055 >0.05  Hui/Mongol/Manchu 9 (3.46%) 10 (3.85%) Educational level  Primary school and below 79 (30.38%) 56 (21.54%) 28.626 <0.001  Junior high school 144 (55.38%) 115 (44.23%)  Senior high school and above 37 (14.24%) 89 (34.23%) Occupation  Farmer 218 (83.85%) 177 (68.08%) 18.001 <0.001  Worker 29 (11.15%) 53 (20.38%)  Civil servant/teacher/doctor 13 (5.00%) 30 (11.54%) Annual family income (RMB)  <10,000 199 (76.54%) 148 (56.92%) 26.01 <0.001  10,000–20,000 42 (16.15%) 60 (23.08%)  >20,000 19 (7.31%) 52 (20.00%) Marital status  Married 245 (94.23%) 249 (95.77%) 0.648 >0.05  Unmarried/divorced 15 (5.77%) 11 (4.23%) Drinking status  Yes 234 (90.00%) 239 (91.92%) 0.585 >0.05  No 26 (10.00%) 21 (8.08%) Smoking status  Yes 228 (87.69%) 238 (91.54%) 2.066 >0.05  No 32 (12.31%) 22 (8.46%) Note: Case group, women with HPV infection and mild dysplasia or less; control group, women without HPV infection. Abbreviations: HPV, human papillomavirus; RMB, Renminbi. Table 2 Allele and genotype frequencies of the case group and the control group Single-nucleotide polymorphisms Allele frequency Genotype frequency HWE P-value IFN-γ +874T/A T A TT AT AA  Case group* 224 296 72 80 108 >0.05  Control group 302 218 119 79 62 >0.05 IFN-γR1 −56 T/C T C TT CT CC  Case group* 251 269 64 123 73 >0.05  Control group 225 295 41 143 76 >0.05 IFN-γR1 +95 C/T C T CC CT TT  Case group 252 268 67 118 75 >0.05  Control group 249 271 62 125 73 >0.05 IFN-γR1 −611A/G A G AA AG GG  Case group 467 53 218 31 11 >0.05  Control group 458 62 213 32 15 >0.05 Notes: * P<0.05, vs genotype frequency of the control group. Abbreviations: HWE, Hardy–Weinberg equilibrium; IFN, interferon. Table 3 Association between polymorphism of IFN-γ +874T/A, IFN-γR1 −56 T/C, IFN-γR1 +95 C/T, IFN-γR1 −611A/G and HPV susceptibility Genotypes Regression coefficient Standard error Wald OR 95% CI P-value IFN-γ +874 10.668 0.003  TT – – Ref=1  AT 0.316 0.167 8.639 1.672 1.0912–2.563 0.014  AA 0.425 0.226 12.639 2.874 1.872–4.414 <0.001 IFN-γR1 −56 1.217 0.203  TT – – Ref=1  CT 0.249 0.136 1.329 0.551 0.232–1.157 0.187  CC 0.273 0.148 1.208 0.615 0.396–1.398 0.209 IFN-γR1 +95 1.054 0.264  CC – – Ref=1  CT 0.357 0.192 1.145 0.874 0.491–1.586 0.241  TT 0.282 0.159 0.967 0.951 0.619–1.835 0.318 IFN-γR1 −611 0.987 0.296  AA – – Ref=1  AG 0.174 0.126 0.871 0.946 0.608–1.826 0.349  GG 0.225 0.137 1.238 0.717 0.401–1.479 0.195 Abbreviations: HPV, human papillomavirus; IFN, interferon; OR, odds ratio; Ref, reference. Table 4 Serum IFN-γ levels in different genotypes of IFN-γ +874T/A Genotypes Different genotypes (n) Serum IFN-γ levels (pg/mL) IFN-γ +874 TT 72 2.86±1.14 IFN-γ +874 AT 80 1.57±0.79* IFN-γ +874 AA 108 0.41±0.22*,‡ F 8.947 P-value <0.001 Notes: * P<0.05, vs IFN-γ +874 TT. ‡ P<0.05, vs IFN-γ +874 AT. Abbreviation: IFN, interferon. ==== Refs References 1 Bailey HH Chuang LT Dupont NC American society of clinical oncology statement: human papillomavirus vaccination for cancer prevention J Clin Oncol 2016 34 15 1803 1812 27069078 2 Lavigne AW Triedman SA Randall TC Trimble EL Viswanathan AN Cervical cancer in low and middle income countries: Addressing barriers to radiotherapy delivery Gynecol Oncol Rep 2017 22 16 20 28948205 3 Ferlay J Soerjomataram I Dikshit R Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012 Int J Cancer 2015 136 5 E359 E386 25220842 4 Kim K Zang R Choi SC Ryu SY Kim JW Current status of gynecological cancer in China J Gynecol Oncol 2009 20 2 72 76 19590717 5 Wu C Zhu X Kang Y Epidemiology of Humanpapilloma virus infection among women in Fujian, China BMC Public Health 2017 18 1 95 28774274 6 Dickson EL Vogel RI Luo X Downs LS Recent trends in type-specific HPV infection rates in the United States Epidemiol Infect 2015 143 5 1042 1047 25744667 7 Doorbar J Quint W Banks L The biology and life-cycle of human papillomaviruses Vaccine 2012 30 Suppl 5 F55 F70 23199966 8 Ortiz AP Romaguera J Pérez CM Prevalence, genotyping, and correlates of anogenital HPV infection in a population-based sample of women in Puerto Rico Papillomavirus Res 2016 2 89 96 29074191 9 Einstein MH Schiller JT Viscidi RP Clinician’s guide to human papillomavirus immunology: knowns and unknowns Lancet Infect Dis 2009 9 6 347 356 19467474 10 Goodman MT Shvetsov YB Mcduffie K Prevalence, acquisition, and clearance of cervical human papillomavirus infection among women with normal cytology: Hawaii Human Papillomavirus Cohort Study Cancer Res 2008 68 21 8813 8824 18974124 11 Schiffman M Castle PE Jeronimo J Rodriguez AC Wacholder S Human papillomavirus and cervical cancer Lancet 2007 370 9590 890 907 17826171 12 Grulich AE van Leeuwen MT Falster MO Vajdic CM Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis Lancet 2007 370 9581 59 67 17617273 13 Palefsky J Human papillomavirus infection among HIV-infected individuals. Implications for development of malignant tumors Hematol Oncol Clin North Am 1991 5 2 357 370 1850727 14 Kobayashi A Weinberg V Darragh T Smith-Mccune K Evolving immunosuppressive microenvironment during human cervical carcinogenesis Mucosal Immunol 2008 1 5 412 420 19079205 15 Song SH Lee JK Lee NW Interferon-gamma (IFN-gamma): a possible prognostic marker for clearance of high-risk human papillomavirus (HPV) Gynecol Oncol 2008 108 3 543 548 18164379 16 Yang W Song Y Lu YL Sun JZ Wang HW Yl L Increased expression of programmed death (PD)-1 and its ligand PD-L1 correlates with impaired cell-mediated immunity in high-risk human papillomavirus-related cervical intraepithelial neoplasia Immunology 2013 139 4 513 522 23521696 17 Critchley-Thorne RJ Simons DL Yan N Impaired interferon signaling is a common immune defect in human cancer Proc Natl Acad Sci U S A 2009 106 22 9010 9015 19451644 18 Day PM Thompson CD Lowy DR Schiller JT Interferon Gamma Prevents Infectious Entry of Human Papillomavirus 16 via an L2- Dependent Mechanism J Virol 2017 91 10 e00168 17 28250129 19 Naderi M Hashemi M Rezaei M Safdari A Association of Genetic Polymorphisms of IFNGR1 with the Risk of Pulmonary Tuberculosis in Zahedan, Southeast Iran Tuberc Res Treat 2015 2015 292505 5 26649196 20 He J Wang J Lei D Ding S Analysis of functional SNP in ifng/ ifngr1 in Chinese Han population with tuberculosis Scand J Immunol 2010 71 6 452 458 20500698 21 Pravica V Perrey C Stevens A Lee JH Hutchinson IV A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production Hum Immunol 2000 61 9 863 866 11053629 22 Bach EA Aguet M Schreiber RD The IFN gamma receptor: a paradigm for cytokine receptor signaling Annu Rev Immunol 1997 15 563 591 9143700 23 Hashemi M Moazeni-Roodi AK Fazaeli A Lack of association between paraoxonase-1 Q192R polymorphism and rheumatoid arthritis in southeast Iran Genet Mol Res 2010 9 1 333 339 20198589 24 Solé X Guinó E Valls J Iniesta R Moreno V SNPStats: a web tool for the analysis of association studies Bioinformatics 2006 22 15 1928 1929 16720584 25 Hardikar S Johnson LG Malkki M A population-based case-control study of genetic variation in cytokine genes associated with risk of cervical and vulvar cancers Gynecol Oncol 2015 139 1 90 96 26241630 26 Turner DM Williams DM Sankaran D An investigation of polymorphism in the interleukin-10 gene promoter Eur J Immunogenet 1997 24 1 1 8 27 Kroeger KM Carville KS Abraham LJ The −308 tumor necrosis factor-alpha promoter polymorphism effects transcription Mol Immunol 1997 34 5 391 399 9293772 28 Fishman D Faulds G Jeffery R The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis J Clin Invest 1998 102 7 1369 1376 9769329 29 Pravica V Asderakis A Perrey C In vitro production of IFN-gamma correlates with CA repeat polymorphism in the human IFN-gamma gene Eur J Immunogenet 1999 26 1 1 3 10068907 30 Marangon AV Guelsin GA Visentainer JE The association of the immune response genes to human papillomavirus-related cervical disease in a Brazilian population Biomed Res Int 2013 2013 146079 11 23936772 31 Zur Hausen H Papillomaviruses and cancer: from basic studies to clinical application Nat Rev Cancer 2002 2 5 342 350 12044010 32 Ho GY Bierman R Beardsley L Chang CJ Burk RD Natural history of cervicovaginal papillomavirus infection in young women N Engl J Med 1998 338 7 423 428 9459645 33 Chen X Jiang J Shen H Hu Z Genetic susceptibility of cervical cancer J Biomed Res 2011 25 3 155 164 23554684 34 Daud II Scott ME Ma Y Association between toll-like receptor expression and human papillomavirus type 16 persistence Int J Cancer 2011 128 4 879 886 20473890 35 Haralambieva IH Ovsyannikova IG Umlauf BJ Genetic polymorphisms in host antiviral genes: associations with humoral and cellular immunity to measles vaccine Vaccine 2011 29 48 8988 8997 21939710 36 Hibma MH The immune response to papillomavirus during infection persistence and regression Open Virol J 2012 6 241 248 23341859 37 Sasagawa T Takagi H Makinoda S Immune responses against human papillomavirus (HPV) infection and evasion of host defense in cervical cancer J Infect Chemother 2012 18 6 807 815 23117294 38 Feng Q Wei H Morihara J Th2 type inflammation promotes the gradual progression of HPV-infected cervical cells to cervical carcinoma Gynecol Oncol 2012 127 2 412 419 22828962 39 Billiau A Heremans H Vermeire K Matthys P Immunomodulatory properties of interferon-gamma. An update Ann N Y Acad Sci 1998 856 22 32 9917861 40 Telesheva LF Dolgushina VF Abramovskikh OS Cytokine status of cervical mucus in women with transitory and persistent course of papillomavirus infection Zh Mikrobiol Epidemiol Immunobiol 2012 4 4 118 121 41 Sun Y Lu Y Xie L Interferon gamma polymorphisms and hepatitis B virus-related liver cirrhosis risk in a Chinese population Cancer Cell Int 2015 15 35 25861244 42 Schena FP Cerullo G Torres DD Role of interferon-gamma gene polymorphisms in susceptibility to IgA nephropathy: a family-based association study Eur J Hum Genet 2006 14 4 488 496 16493441 43 Mehta AM Mooij M Branković I Cervical Carcinogenesis and Immune Response Gene Polymorphisms: A Review J Immunol Res 2017 2017 8913860 12 28280748 44 Holla LI Hrdlickova B Linhartova P Fassmann A Interferon-γ +874A/T polymorphism in relation to generalized chronic periodontitis and the presence of periodontopathic bacteria Arch Oral Biol 2011 56 2 153 158 20932510 45 Sun Y Lu Y Li T Interferon Gamma +874T/A Polymorphism Increases the Risk of Hepatitis Virus-Related Diseases: Evidence from a Meta-Analysis PLoS One 2015 10 5 e0121168 25939029