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Clinical Trial
. 2013;8(3):e57243.
doi: 10.1371/journal.pone.0057243. Epub 2013 Mar 8.

Common single nucleotide polymorphisms in genes related to immune function and risk of papillary thyroid cancer

Alina V Brenner  1 , Gila Neta, Erich M Sturgis, Ruth M Pfeiffer, Amy Hutchinson, Meredith Yeager, Li Xu, Cindy Zhou, William Wheeler, Margaret A Tucker, Stephen J Chanock, Alice J Sigurdson
Affiliations
Clinical Trial

Common single nucleotide polymorphisms in genes related to immune function and risk of papillary thyroid cancer

Alina V Brenner et al. PLoS One. 2013.

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.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1. Observed and expected distributions for the P values of linear trend for 3,985 tag-SNPs in 230 gene regions related to immune function in a case-control study of PTC risk.
Figure 2
Figure 2. Linkage disequlibrium (LD) representation of the SERPINA5 gene.
The figure represents LD based on the genotyping data from the study controls with European ancestry. LD is measured by D′ parameters (top panel) and the r2 correlation coefficient (bottom panel). D′ and r2 values of one are interpreted as complete LD.
See this image and copyright information in PMC

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