Genetic Polymorphisms in Host Innate Immune Sensor Genes and the Risk of Nasopharyngeal Carcinoma in North Africa

Nasopharyngeal carcinoma (NPC) is a rare malignancy in most parts of the world. It is an Epstein-Barr virus−associated malignancy with an unusual racial and geographical distribution. The host innate immune sensor genes play an important role in infection recognition and immune response against viruses. Therefore, we examined the association between polymorphisms in genes within a group of pattern recognition receptors (including families of Toll-like receptors, C-type lectin receptors, and retinoic acid−inducible gene I−like receptors) and NPC susceptibility. Twenty-six single-nucleotide polymorphisms (SNPs) in five pattern-recognition genes were genotyped in 492 North African NPC cases and 373 frequency-matched controls. TLR3_rs3775291 was the most significantly associated SNP (odds ratio [OR] 1.49; 95% confidence interval [95% CI] 1.11−2.00; P = 0.008; dominant model). The analysis showed also that CD209_rs7248637 (OR 0.69; 95% CI 0.52−0.93; P = 0.02; dominant model) and DDX58_rs56309110 (OR 0.70; 95% CI 0.51−0.98; P = 0.04) were associated with the risk of NPC. An 18% increased risk per allele was observed for the five most significantly associated SNPs, TLR3_rs3775291, CD209_rs7248637, DDX58_rs56309110, CD209_rs4804800, and MBL2_rs10824792, (ptrend = 8.2 × 10−4). Our results suggest that genetic variation in pattern-recognition genes is associated with the risk of NPC. These preliminary findings require replication in larger studies.

[1]  E. Coccia,et al.  EBV stimulates TLR‐ and autophagy‐dependent pathways and impairs maturation in plasmacytoid dendritic cells: Implications for viral immune escape , 2013, European journal of immunology.

[2]  M. Raftery,et al.  Association of TLR3-hyporesponsiveness and functional TLR3 L412F polymorphism with recurrent herpes labialis. , 2012, Human immunology.

[3]  Zhijian J. Chen,et al.  Differential Roles for RIG-I–like Receptors and Nucleic Acid-Sensing TLR Pathways in Controlling a Chronic Viral Infection , 2012, The Journal of Immunology.

[4]  H. Qin,et al.  Non-viral environmental risk factors for nasopharyngeal carcinoma: a systematic review. , 2012, Seminars in cancer biology.

[5]  R. Vierkant,et al.  Genetic polymorphisms in host antiviral genes: Associations with humoral and cellular immunity to measles vaccine , 2011, Vaccine.

[6]  H. Caron,et al.  Mannose‐binding lectin (MBL) and the risk for febrile neutropenia and infection in pediatric oncology patients with chemotherapy , 2011, Pediatric blood & cancer.

[7]  C. Rabourdin-Combe,et al.  Innate immunity modulation in virus entry , 2011, Current Opinion in Virology.

[8]  Kuender D Yang,et al.  DC-SIGN (CD209) Promoter −336 A/G Polymorphism Is Associated with Dengue Hemorrhagic Fever and Correlated to DC-SIGN Expression and Immune Augmentation , 2011, PLoS neglected tropical diseases.

[9]  F. Vizoso,et al.  Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis , 2010, BMC Cancer.

[10]  W. Jia,et al.  Sequencing of DC-SIGN promoter indicates an association between promoter variation and risk of nasopharyngeal carcinoma in cantonese , 2010, BMC Medical Genetics.

[11]  J. Crowe,et al.  Variant in CD209 promoter is associated with severity of liver disease in chronic hepatitis C virus infection. , 2010, Human immunology.

[12]  A. García-Sastre,et al.  A Common Polymorphism in the Caspase Recruitment Domain of RIG-I Modifies the Innate Immune Response of Human Dendritic Cells , 2010, The Journal of Immunology.

[13]  J. Towbin,et al.  A Role for Toll-like Receptor 3 Variants in Host Susceptibility to Enteroviral Myocarditis and Dilated Cardiomyopathy* , 2010, The Journal of Biological Chemistry.

[14]  M. McElrath,et al.  Polymorphisms in toll-like receptor 4 and toll-like receptor 9 influence viral load in a seroincident cohort of HIV-1-infected individuals , 2009, AIDS.

[15]  K. Kawa,et al.  Epstein-Barr virus (EBV)–encoded small RNA is released from EBV-infected cells and activates signaling from toll-like receptor 3 , 2009, The Journal of experimental medicine.

[16]  A. Benider,et al.  Cannabis, tobacco and domestic fumes intake are associated with nasopharyngeal carcinoma in North Africa , 2009, British Journal of Cancer.

[17]  J. Hiscott,et al.  RIG-I-like receptors: sensing and responding to RNA virus infection. , 2009, Seminars in immunology.

[18]  G. Goulielmos,et al.  Mannose-binding Lectin MBL2 Gene Polymorphisms and Outcome of Hepatitis C Virus-infected Patients , 2008, Journal of Clinical Immunology.

[19]  A. Iwasaki,et al.  Toll-like receptors regulation of viral infection and disease. , 2008, Advanced drug delivery reviews.

[20]  R. Vierkant,et al.  Associations between SNPs in toll-like receptors and related intracellular signaling molecules and immune responses to measles vaccine: preliminary results. , 2008, Vaccine.

[21]  T. Wienker,et al.  Investigation of promoter variations in dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN) (CD209) and their relevance for human cytomegalovirus reactivation and disease after allogeneic stem-cell transplantation. , 2008, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[22]  U. Braga-Neto,et al.  MBL2 gene polymorphisms protect against development of thrombocytopenia associated with severe dengue phenotype. , 2008, Human immunology.

[23]  E. El-Omar,et al.  Polymorphisms in Toll-like receptor genes and risk of cancer , 2008, Oncogene.

[24]  G. Sirugo,et al.  CD209 Genetic Polymorphism and Tuberculosis Disease , 2008, PloS one.

[25]  H. Qin,et al.  Genetic polymorphisms of TLR3 are associated with Nasopharyngeal carcinoma risk in Cantonese population , 2007, BMC Cancer.

[26]  A. Benider,et al.  Dietary risk factors for nasopharyngeal carcinoma in Maghrebian countries , 2007, International journal of cancer.

[27]  P. Romero,et al.  Toll-like Receptor 3 Expressed by Melanoma Cells as a Target for Therapy? , 2007, Clinical Cancer Research.

[28]  W. Miller,et al.  Effects of Single Nucleotide Polymorphisms on Toll-like Receptor 3 Activity and Expression in Cultured Cells* , 2007, Journal of Biological Chemistry.

[29]  K. Ogino,et al.  RANTES -28G delays and DC-SIGN - 139C enhances AIDS progression in HIV type 1-infected Japanese hemophiliacs. , 2007, AIDS research and human retroviruses.

[30]  H. Adami,et al.  The Enigmatic Epidemiology of Nasopharyngeal Carcinoma , 2006, Cancer Epidemiology Biomarkers & Prevention.

[31]  T. Kanda,et al.  EB virus‐encoded RNAs are recognized by RIG‐I and activate signaling to induce type I IFN , 2006, The EMBO journal.

[32]  A. Hajjej,et al.  The contribution of HLA class I and II alleles and haplotypes to the investigation of the evolutionary history of Tunisians. , 2006, Tissue antigens.

[33]  Li Hao,et al.  DC-SIGN and immunoregulation. , 2006, Cellular & molecular immunology.

[34]  C. Kao,et al.  Structural and Functional Analyses of the Human Toll-like Receptor 3 , 2006, Journal of Biological Chemistry.

[35]  S. Lebecque,et al.  TLR3 Can Directly Trigger Apoptosis in Human Cancer Cells1 , 2006, The Journal of Immunology.

[36]  Shizuo Akira,et al.  Innate immune recognition of viral infection , 2006, Nature Immunology.

[37]  D. Davies,et al.  The molecular structure of the Toll-like receptor 3 ligand-binding domain. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Anavaj Sakuntabhai,et al.  A variant in the CD209 promoter is associated with severity of dengue disease , 2005, Nature Genetics.

[39]  P. Busson,et al.  EBV-associated nasopharyngeal carcinomas: from epidemiology to virus-targeting strategies. , 2004, Trends in microbiology.

[40]  C. Sousa.  Faculty Opinions recommendation of TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction. , 2003 .

[41]  T. Akazawa,et al.  TICAM-1, an adaptor molecule that participates in Toll-like receptor 3–mediated interferon-β induction , 2003, Nature Immunology.

[42]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[43]  V. Levitsky,et al.  Epstein-Barr virus inhibits the development of dendritic cells by promoting apoptosis of their monocyte precursors in the presence of granulocyte macrophage-colony-stimulating factor and interleukin-4. , 2002, Blood.

[44]  J. H. Moore,et al.  Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. , 2001, American journal of human genetics.

[45]  P. Underhill,et al.  High-resolution analysis of human Y-chromosome variation shows a sharp discontinuity and limited gene flow between northwestern Africa and the Iberian Peninsula. , 2001, American journal of human genetics.

[46]  T. Delozier,et al.  Polyadenylic–Polyuridylic Acid Plus Locoregional Radiotherapy Versus Chemotherapy with CMF in Operable Breast Cancer: a 14 Year Follow-up Analysis of a Randomized Trial of the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) , 2000, Breast Cancer Research and Treatment.

[47]  J. Gilbert,et al.  Variants in toll-like receptors 2 and 9 influence susceptibility to pulmonary tuberculosis in Caucasians, African-Americans, and West Africans , 2009, Human Genetics.

[48]  N. Sobol,et al.  Preliminary results , 2020, Asymptotic Analysis of Random Walks: Light-Tailed Distributions.

[49]  J. Crowe,et al.  A variant in the CD 209 promoter is associated with the severity of liver disease in chronic Hepatitis C virus infection , 2022 .