Common Single Nucleotide Polymorphisms in Genes Related to Immune Function and Risk of Papillary Thyroid Cancer Alina V. Brenner 1 *, Gila Neta 1 , Erich M. Sturgis 2 , Ruth M. Pfeiffer 3 , Amy Hutchinson 4 , Meredith Yeager 4 , Li Xu 2 , Cindy Zhou 5 , William Wheeler 6 , Margaret A. Tucker 7 , Stephen J. Chanock 8 , Alice J. Sigurdson 1 1 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, 2 Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America, 3 Biostatistics 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, 4 Core Genotyping Facility, SAIC-Frederick Inc., NCI-Frederick, Frederick, Maryland, United States of America, 5 Department of Epidemiology and Biostatistics, George Washington University, Washington D.C., United States of America, 6 Information Management Systems (IMS), Silver Spring, Maryland, United States of America, 7 Genetic 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, 8 Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Gaithersburg, Maryland, United States of America 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 6 10 26 and P SNP-FDR /P SNP-trend = 0.04/2 6 10 25 , respectively). These associations were indepen- dent 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. Citation: Brenner AV, Neta G, Sturgis EM, Pfeiffer RM, Hutchinson A, et al. (2013) Common Single Nucleotide Polymorphisms in Genes Related to Immune Function and Risk of Papillary Thyroid Cancer. PLoS ONE 8(3): e57243. doi:10.1371/journal.pone.0057243 Editor: Xiao-Ping Miao, Huazhong University of Science and Technology, China Received August 7, 2012; Accepted January 18, 2013; Published March 8, 2013 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: This project was supported in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, by federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E, and by a grant from the American Thyroid Association (PI: E. M. Sturgis). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have the following interests: co-authors AH and MY are employed by Core Genotyping Facility, SAIC-Frederick Inc. Co-author WW is employed by Information Management Systems (IMS), Silver Spring. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. * E-mail: brennera@mail.nih.gov Introduction Thyroid carcinoma is the most common endocrine malignancy and its incidence has increased worldwide during the last 40 years [1–3]. Although improved diagnosis and reporting have likely contributed to this trend, additional reasons remain unclear [3]. Thyroid cancer is consistently more common in females, with a female-to-male ratio in incidence rates of about 3 to 1 [4]. One of the best established etiologic factors for thyroid carcinoma and its most common histological type, papillary thyroid cancer (PTC), is exposure to ionizing radiation during childhood [5,6]. Family history studies suggest that thyroid cancer may have a greater familial component than other cancers with relative risk (RR) estimates of 3–4 or higher for a family history in first-degree relatives [7,8]. Recent genome-wide association studies (GWAS) [9,10] and a candidate gene study [11] have clearly implicated the gene FOXE1, formerly known as TTF2 (thyroid transcription factor 2), as a susceptibility locus for PTC both in persons exposed [11] and unexposed to ionizing radiation [9,11]; however, most genetic determinants of risk remain to be discovered. PLOS ONE | www.plosone.org 1 March 2013 | Volume 8 | Issue 3 | e57243