title: Nucleotide variation in IL-10 and IL-12 and their receptors and cervical and vulvar cancer risk: a hybrid case-parent triad and case-control study.
abstract: Given the important role of cell mediated immunity in viral clearance and control of premalignant lesions, we hypothesize that variation in the IL-12/IL-10 cytokine and cytokine receptor genes may influence cervical and vulvar cancer risk. We evaluated 76 tagSNPs from seven candidate genes (IL-10, IL-12A, IL-12B, IL-10RA, IL-10RB, IL-12RB1, and IL12RB2) in case-parent sets (n=43 cervical squamous cell carcinoma (SCC), n=96 cervical adenocarcinoma, n=53 vulvar SCC), additional cases (n=356 cervical SCC, n=406 cervical adenocarcinoma, and n=473 vulvar SCC) and population based controls (1,111). We calculated log-additive odds ratios (ORs) and 95% confidence intervals (CIs) for the association between tagSNP and cancer risk using a pseudo-likelihood based method which combined genotype information on cases, parents, and population controls. After correction for multiple comparisons, we identified several statistically significant SNP associations. Cervical SCC risk was associated with the minor alleles of the IL10RA rs9610 3' UTR SNP (OR=1.76, 95% CI=1.15-2.68) and two synonymous IL12RB2 SNPs (rs4297265, OR=0.46, 95% CI=0.26-0.82; rs2229546, OR=0.43, 95% CI=0.21-0.87). Cervical adenocarcinoma risk was associated with the minor alleles of the IL10RA rs4252314 intronic SNP (OR=2.23, 95% CI=1.26-3.96) and IL12RB1 rs11575934 non-synonymous SNP (OR=1.51, 95% CI=1.12-2.05). Finally, the minor allele of the IL12B rs3181224 3' UTR SNP was associated with a reduced risk of vulvar SCC (OR=0.30, 95% CI=0.12-0.74). These results raise the possibility that a shift in the balance of the immune response due to genetic variants in key cytokine genes could influence the development of cervical and vulvar cancer.
authors.affiliation: Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA, USA. skhussain@ucla.edu
authors.forename: Shehnaz K
authors.initials: SK
authors.lastname: Hussain
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Madeleine
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Johnson
authors.forename: Qin
authors.initials: Q
authors.lastname: Du
authors.forename: Denise A
authors.initials: DA
authors.lastname: Galloway
authors.forename: Janet R
authors.initials: JR
authors.lastname: Daling
authors.forename: Mari
authors.initials: M
authors.lastname: Malkki
authors.forename: Effie W
authors.initials: EW
authors.lastname: Petersdorf
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Schwartz
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics*; D053710:Interleukin-10 Receptor beta Subunit / Q000235:genetics; D018664:Interleukin-12 / Q000235:genetics*; D053765:Interleukin-12 Subunit p35 / Q000235:genetics; D053762:Interleukin-12 Subunit p40 / Q000235:genetics; D008875:Middle Aged; D009711:Nucleotides / Q000235:genetics*; D016017:Odds Ratio; D010290:Parents; D020641:Polymorphism, Single Nucleotide; D053701:Receptors, Interleukin-10 / Q000235:genetics*; D053707:Receptors, Interleukin-12 / Q000235:genetics*; D012107:Research Design; D018570:Risk Assessment; D012307:Risk Factors; D002583:Uterine Cervical Neoplasms / Q000235:genetics*; D014846:Vulvar Neoplasms / Q000235:genetics*
chemical_list: C508609:IL10 protein, human; C081846:IL10RB protein, human; C508858:IL12A protein, human; C500879:IL12B protein, human; C508438:IL12RB1 protein, human; C508439:IL12RB2 protein, human; D053710:Interleukin-10 Receptor beta Subunit; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D009711:Nucleotides; D053701:Receptors, Interleukin-10; D053707:Receptors, Interleukin-12; D016753:Interleukin-10; D018664:Interleukin-12