title: Common single nucleotide polymorphisms in genes related to immune function and risk of papillary thyroid cancer.
abstract: Accumulating evidence suggests that alterations in immune function may be important in the etiology of papillary thyroid cancer (PTC). To identify genetic markers in immune-related pathways, we evaluated 3,985 tag single nucleotide polymorphisms (SNPs) in 230 candidate gene regions (adhesion-extravasation-migration, arachidonic acid metabolism/eicosanoid signaling, complement and coagulation cascade, cytokine signaling, innate pathogen detection and antimicrobials, leukocyte signaling, TNF/NF-kB pathway or other) in a case-control study of 344 PTC cases and 452 controls. We used logistic regression models to estimate odds ratios (OR) and calculate one degree of freedom P values of linear trend (P(SNP-trend) ) for the association between genotype (common homozygous, heterozygous, variant homozygous) and risk of PTC. To correct for multiple comparisons, we applied the false discovery rate method (FDR). Gene region- and pathway-level associations (P(Region) and P(Pathway)) were assessed by combining individual P(SNP-trend) values using the adaptive rank truncated product method. Two SNPs (rs6115, rs6112) in the SERPINA5 gene were significantly associated with risk of PTC (P(SNP-FDR)/P(SNP-trend)= 0.02/6×10(-6) and P(SNP-FDR)/P(SNP-trend)= 0.04/2×10(-5), respectively). These associations were independent of a history of autoimmune thyroiditis (OR = 6.4; 95% confidence interval: 3.0-13.4). At the gene region level, SERPINA5 was suggestively associated with risk of PTC (P(Region-FDR)/P(Region)= 0.07/0.0003). Overall, the complement and coagulation cascade pathway was the most significant pathway (P(Pathway)= 0.02) associated with PTC risk largely due to the strong effect of SERPINA5. Our results require replication but suggest that the SERPINA5 gene, which codes for the protein C inhibitor involved in many biological processes including inflammation, may be a new susceptibility locus for PTC.
authors.affiliation: Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, United States of America. brennera@mail.nih.gov
authors.forename: Alina V
authors.initials: AV
authors.lastname: Brenner
authors.forename: Gila
authors.initials: G
authors.lastname: Neta
authors.forename: Erich M
authors.initials: EM
authors.lastname: Sturgis
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Pfeiffer
authors.forename: Amy
authors.initials: A
authors.lastname: Hutchinson
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.forename: Cindy
authors.initials: C
authors.lastname: Zhou
authors.forename: William
authors.initials: W
authors.lastname: Wheeler
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Tucker
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Alice J
authors.initials: AJ
authors.lastname: Sigurdson
mesh_terms: D000328:Adult; D000368:Aged; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism; D001777:Blood Coagulation / Q000235:genetics; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018046:Protein C Inhibitor / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D018046:Protein C Inhibitor; C534934:SERPINA5 protein, human