title: Risk allelic load in Th2 and Th3 cytokines genes as biomarker of susceptibility to HPV-16 positive cervical cancer: a case control study.
abstract: Alterations in the host cellular immune response allow persistent infections with High-Risk Human Papillomavirus (HR-HPV) and development of premalignant cervical lesions and cervical cancer (CC). Variations of immunosuppressive cytokine levels in cervix are associated with the natural history of CC. To assess the potential role of genetic host immunity and cytokines serum levels in the risk of developing CC, we conducted a case-control study paired by age.
  
  
  
  Peripheral blood samples from patients with CC (n = 200) and hospital controls (n = 200), were used to evaluate nine biallelic SNPs of six cytokine genes of the adaptive immune system by allelic discrimination and cytokines serum levels by ELISA.
  
  
  
  After analyzing the SNP association by multivariate logistic regression adjusted by age, CC history and smoking history, three Th2 cytokines (IL-4, IL-6 and IL-10) and one Th3 (TGFB1) cytokine were significantly associated with CC. Individuals with at least one copy of the following risk alleles: T of SNP (-590C > T IL-4), C of SNP (-573G > C IL-6), A of SNP (-592C > A IL-10), T of SNP (-819C > T IL-10) and T of SNP (-509C > T TGFB1), had an adjusted odds ratio (OR) of 2.08 (95 % CI 1.475-2.934, p = 0.0001), an OR of 1.70 (95 % CI 1.208-2.404, p = 0.002), an OR of 1.87 (95 % CI 1.332-2.630, p = 0.0001), an OR of 1.67 (95 % CI 1.192-2.353, p = 0.003) and an OR of 1.91 (95 % CI 1.354-2.701, p = 0.0001), respectively, for CC. The burden of carrying two or more of these risk alleles was found to have an additive effect on the risk of CC (p trend = 0.0001). Finally, the serum levels of Th2 and Th3 cytokines were higher in CC cases than the controls; whereas IFNG levels, a Th1 cytokine, were higher in controls than CC cases.
  
  
  
  The significant associations of five SNPs with CC indicate that these polymorphisms are potential candidates for predicting the risk of development of CC, representing a risk allelic load for CC and can be used as a biomarker of susceptibility to this disease.
authors.affiliation: Dirección de Infecciones Crónicas y Cáncer. Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública (INSP), (Chronic Infectious Diseases and Cancer Division. Center for Research on Infectious Diseases. National Institute of Public Health Mexico), Av. Universidad 655, Santa María Ahuacatitlán, Cuernavaca, C.P.62100, Morelos, Mexico.|CONACyT Research Fellow-Instituto Nacional de Salud Pública (INSP), Cuernavaca, Morelos, Mexico.
authors.forename: K
authors.initials: K
authors.lastname: Torres-Poveda
authors.affiliation: Dirección de Infecciones Crónicas y Cáncer. Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública (INSP), (Chronic Infectious Diseases and Cancer Division. Center for Research on Infectious Diseases. National Institute of Public Health Mexico), Av. Universidad 655, Santa María Ahuacatitlán, Cuernavaca, C.P.62100, Morelos, Mexico.
authors.forename: A I
authors.initials: AI
authors.lastname: Burguete-García
authors.affiliation: Dirección de Infecciones Crónicas y Cáncer. Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública (INSP), (Chronic Infectious Diseases and Cancer Division. Center for Research on Infectious Diseases. National Institute of Public Health Mexico), Av. Universidad 655, Santa María Ahuacatitlán, Cuernavaca, C.P.62100, Morelos, Mexico.
authors.forename: M
authors.initials: M
authors.lastname: Bahena-Román
authors.affiliation: Division of Basic Research, Instituto Nacional de Cancerología (INCan), SS. Mexico City, Mexico.
authors.forename: R
authors.initials: R
authors.lastname: Méndez-Martínez
authors.affiliation: Dirección de Infecciones Crónicas y Cáncer. Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública (INSP), (Chronic Infectious Diseases and Cancer Division. Center for Research on Infectious Diseases. National Institute of Public Health Mexico), Av. Universidad 655, Santa María Ahuacatitlán, Cuernavaca, C.P.62100, Morelos, Mexico.
authors.forename: M A
authors.initials: MA
authors.lastname: Zurita-Díaz
authors.affiliation: Private Health Center for Gynecology, Cuernavaca, Morelos, Mexico.
authors.forename: G
authors.initials: G
authors.lastname: López-Estrada
authors.affiliation: Centro de Atención para la Salud de la Mujer (CAPASAM), (Center for Women's Health). Health Services of the State of Morelos, Cuernavaca, Mexico.
authors.forename: K
authors.initials: K
authors.lastname: Delgado-Romero
authors.affiliation: Dirección de Infecciones Crónicas y Cáncer. Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública (INSP), (Chronic Infectious Diseases and Cancer Division. Center for Research on Infectious Diseases. National Institute of Public Health Mexico), Av. Universidad 655, Santa María Ahuacatitlán, Cuernavaca, C.P.62100, Morelos, Mexico.
authors.forename: O
authors.initials: O
authors.lastname: Peralta-Zaragoza
authors.affiliation: Dirección de Infecciones Crónicas y Cáncer. Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública (INSP), (Chronic Infectious Diseases and Cancer Division. Center for Research on Infectious Diseases. National Institute of Public Health Mexico), Av. Universidad 655, Santa María Ahuacatitlán, Cuernavaca, C.P.62100, Morelos, Mexico.
authors.forename: V H
authors.initials: VH
authors.lastname: Bermúdez-Morales
authors.affiliation: Division of Clinical Research, Instituto Nacional de Cancerología (INCan), SS. Mexico City, Mexico.
authors.forename: D
authors.initials: D
authors.lastname: Cantú
authors.affiliation: Division of Basic Research, Instituto Nacional de Cancerología (INCan), SS. Mexico City, Mexico.|Unit of Biomedical Research in Cancer, Instituto Nacional de Cancerología (INCan), SS and Biomedical Research Institute. Universidad Nacional Autónoma de México, Mexico City, Mexico.
authors.forename: A
authors.initials: A
authors.lastname: García-Carrancá
authors.affiliation: Dirección de Infecciones Crónicas y Cáncer. Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública (INSP), (Chronic Infectious Diseases and Cancer Division. Center for Research on Infectious Diseases. National Institute of Public Health Mexico), Av. Universidad 655, Santa María Ahuacatitlán, Cuernavaca, C.P.62100, Morelos, Mexico. vmarina@insp.mx.
authors.forename: V
authors.initials: V
authors.lastname: Madrid-Marina
mesh_terms: D000328:Adult; D000483:Alleles; D015415:Biomarkers; D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000821:virology; D016022:Case-Control Studies; D016207:Cytokines / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D052162:Human papillomavirus 16 / Q000502:physiology; D006801:Humans; D009367:Neoplasm Staging; D030361:Papillomavirus Infections / Q000235:genetics* / Q000473:pathology / Q000821:virology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D018417:Th1 Cells / Q000378:metabolism*; D018418:Th2 Cells / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology
chemical_list: D015415:Biomarkers; D014408:Biomarkers, Tumor; D016207:Cytokines
keywords: Cervical neoplasm; Cytokines; Genetic susceptibility profile; Promoter polymorphisms; Serum levels