title: A population-based case-control study of genetic variation in cytokine genes associated with risk of cervical and vulvar cancers.
abstract: OBJECTIVE
  Persistent infection with oncogenic human papillomavirus (HPV) is known to be the necessary cause of cervical cancer and a majority of vulvar cancers. Persistent HPV infections must evade host immune responses, including cytokines released by activated T-helper (Th) cells. In this study, we investigated the risk of cervical and vulvar cancers associated with common genetic variations in 560 tagging single-nucleotide polymorphisms (SNPs) in candidate cytokine genes.
  
  
  METHODS
  The study included 399 invasive squamous cell carcinomas (SCCs) and 502 in situ or invasive adenocarcinomas (AC) of the cervix; 357 in situ or invasive vulvar SCC; and 1109 controls from the Seattle-area case-control studies of HPV-related cancers. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) using a log additive model, with adjustment for multiple testing.
  
  
  RESULTS
  Statistically significant risks were observed for HPV16-containing SCC of the cervix with the variant allele rs879576 in IL17RA and rs2229094 in TNF [OR, 95% CI and multiple-testing corrected p: 1.91 (1.30-2.79), p=0.018 and 0.61 (0.45-0.83), p=0.02, respectively]. We also observed significantly increased risk of HPV-positive vulvar cancers associated with variant alleles in CSF2 (rs25882 and rs27438, 26-28% increased risk) and IL-12B (rs2569254 and rs3181225, 40-41% increased risk) genes.
  
  
  CONCLUSIONS
  We found that variation in several Th-cytokine genes is significantly associated with cervical and vulvar cancer risk. The strong association between these HPV-related cancers and common variation in cytokine genes in the Th1 and Th17 pathways may be important for development of new therapies.
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA.
authors.forename: Sheetal
authors.initials: S
authors.lastname: Hardikar
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Johnson
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Malkki
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Effie W
authors.initials: EW
authors.lastname: Petersdorf
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Denise A
authors.initials: DA
authors.lastname: Galloway
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Schwartz
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA. Electronic address: mmadelei@fredhutch.org.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Madeleine
mesh_terms: D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000276:immunology / Q000821:virology; D016022:Case-Control Studies; D016207:Cytokines / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000235:genetics / Q000276:immunology / Q000821:virology; D020641:Polymorphism, Single Nucleotide; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000276:immunology / Q000821:virology; D014846:Vulvar Neoplasms / Q000235:genetics* / Q000276:immunology / Q000821:virology
chemical_list: D016207:Cytokines
keywords: Cervical cancer; Genetic variation; T-helper 1 pathways; T-helper 17 pathway; T-helper 2 pathway; Vulvar cancer