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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.

SUBMITTER: Brenner AV

PROVIDER: S-EPMC3592848 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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

Brenner Alina V AV Neta Gila G Sturgis Erich M EM Pfeiffer Ruth M RM Hutchinson Amy A Yeager Meredith M Xu Li L Zhou Cindy C Wheeler William W Tucker Margaret A MA Chanock Stephen J SJ Sigurdson Alice J AJ

PloS one 20130308 3

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 ...[more]

PMID: 23520464

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Project description:Thyroid cancer (TC) is the most common endocrine malignancy and its incidence continues to rise worldwide. Ionizing radiation exposure is the best established etiological factor. Heritability is high; however, despite valuable contribution from recent genome-wide association studies, the current understanding of genetic susceptibility to TC remains limited. Several studies suggest that altered function or expression of the DNA mismatch repair (MMR) system may contribute to TC pathogenesis. Therefore, the present study aimed to evaluate the potential role of a panel of MMR single nucleotide polymorphisms (SNPs) on the individual susceptibility to well-differentiated TC (DTC). A case-control study was performed involving 106 DTC patients and 212 age- and gender-matched controls, who were all Caucasian Portuguese. Six SNPs present in distinct MMR genes (MLH1 rs1799977, MSH3 rs26279, MSH4 rs5745325, PMS1 rs5742933, MLH3 rs175080 and MSH6 rs1042821) were genotyped through TaqMan® assays and genotype-associated risk estimates were calculated. An increased risk was observed in MSH6 rs1042821 variant homozygotes [adjusted odds ratio (OR)=3.42, 95% CI: 1.04-11.24, P=0.04, under the co-dominant model; adjusted OR=3.84, 95% CI: 1.18-12.44, P=0.03, under the recessive model]. The association was especially evident for the follicular histotype and female sex. The association was also apparent when MSH6 was analysed in combination with other MMR SNPs such as MSH3 rs26279. Interestingly, two other SNP combinations, both containing the MSH6 heterozygous genotype, were associated with a risk reduction, suggesting a protective effect for these genotype combinations. These data support the idea that MMR SNPs such as MSH6 rs1042821, alone or in combination, may contribute to DTC susceptibility. This is coherent with the limited evidence available. Nevertheless, further studies are needed to validate these findings and to establish the usefulness of these SNPs as genetic susceptibility biomarkers for DTC so that, in the near future, cancer prevention policies may be optimized under a personalized medicine perspective.

Project description:Numerous studies have investigated the relationship between various candidate gene polymorphisms and gallbladder stone disease (GSD) across ethnic populations; however, the results are often inconsistent. This meta-analysis aims to comprehensively evaluate the influence of common ABCG8 T400K, ABCG8 D19H, ABCG8 C54Y, ApoB100 EcoRI, ApoB100 XbaI, ApoE HhaI, CETP TaqI, CYP7A1 Bsa, LRPAP1 I/D and TNF-α A308G polymorphisms on the risk of gallbladder stone disease. 33 Full-text articles with 9250 cases and 12,029 healthy controls (total 21,279 subjects) were analyzed using the RevMan software (V5.1) and the Comprehensive Meta-analysis software (Version 2.0, BIOSTAT, Englewood, NJ) a Random-effects model was applied. Begg's funnel plots, Fail-safe number, Egger's regression intercept and Begg and Mazumdar rank correlation tests were performed for the potential publication bias and sensitivity analysis. The studies were also sub-grouped into European and non-European groups to find out role of ethnicity, if any, on GSD risk. Studies included in quantitative synthesis were ABCG8 T400K rs4148217 (cases/controls, n = 671/1416) (4 studies), ABCG8 D19H rs11887534 (n = 1633/2306) (8 studies), ABCG8 C54Y rs4148211 (n = 445/1194) (3 studies), ApoB100 EcoRI rs1042031 (n = 503/390) (4 studies), ApoB100 XbaI rs693 (n = 1214/1389) (9 studies), ApoE HhaI rs429358 (n = 1335/1482) (12 studies), CETP TaqI rs708272 (n = 1038/1025) (5 studies), CYP7A1 Bsa rs3808607 (n = 565/514) (3 studies), LRPAP1 I/D rs11267919 (n = 849/900) (3 studies), TNF-α A308G rs1800629 (n = 997/1413) (3 studies). The combined results displayed significant association of ABCG8 D19H (GC + CC) [OR with 95%CI = 2.2(1.7-2.8); p < 0.00001], ABCG8 Y54C (GA + GG) [OR with 95%CI = 0.65(0.5-0.9); p = 0.01]. APOB100 EcoRI (GG vs. AA) [OR with 95%CI = 0.51(0.3-0.9); p = 0.05], (GG vs. GA) [OR with 95%CI = 0.6(0.4-0.9); p = 0.04], (GA + AA) [OR with 95%CI = 0.6(0.4-0.9); p = 0.006]. APOB Xba I (X- vs. X+) [OR with 95%CI = 0.53(0.3-0.8); p = 0.006. APOE Hha I (E4/E4 vs. E3/E3) [OR with 95%CI = 3.5(1.1-14.9); p = 0.04] and LRPAP1 I/D (ID + II) [OR with 95%CI = 1.27(1.0-1.6); p = 0.03] with the GSD risk. It was found that ABCG D19H was significantly associated with GSD in both European and Non-European populations. While APOB XbaI and LRPAP1 I/D markers were associated with gallstone disease only in Non- European population. Additionally, APOE HhaI and APOB 100 ECoRI were found to be associated with GSD only in European population. The results of quantitative synthesis suggest that the ABCG8 D19H polymorphism was associated with the increased risk of GSD in both European and Non-European populations, APOE Hha I and LRPAP1 I/D polymorphisms were associated with the increased risk of GSD in European and Non-European population respectively. However, no association was found in ABCG8 T400K, CETP Taq1, CYP7A1 Bsa and TNF-A308G polymorphisms with Gallstone Disease.

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

Publications

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

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