TPO genetic variants and risk of differentiated thyroid carcinoma in two European populations.

Thyroid cancer risk involves the interaction of genetic and environmental factors. The thyroperoxidase (TPO) has a key role in the iodine metabolism, being essential for the thyroid function. Mutations in the TPO gene are common in congenital hypothyroidism, and there are also signs of the implication of TPO in thyroid cancer. We performed a case-control association study of genetic variants in TPO and differentiated thyroid carcinoma (DTC) in 1,586 DTC patients and 1,769 controls including two European populations (Italy: 1,190 DTC and 1,290 controls; Spain: 396 DTC and 479 controls). Multivariate logistic regression analyses were performed separately for each population and each single-nucleotide polymorphism (SNP). From the three studied polymorphisms, significant associations were detected between DTC and rs2048722 and rs732609 in both populations (p < 0.05). In the Italian population, both SNPs showed a negative association (rs2048722, odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.63-1.00, p = 0.045; rs732609, OR = 0.72, 95% CI = 0.55-0.94, p = 0.016), whereas in the Spanish population, these SNPs showed a positive association (rs2048722, OR = 1.39, 95% CI = 1.03-1.89, p = 0.033; rs732609, OR = 1.41, 95% CI = 1.06-1.87, p = 0.018). The corresponding associations for papillary or follicular thyroid cancer were similar to those for all DTC, within population. No association was detected for the third TPO polymorphism in the Italian and the Spanish populations. Our results, for the first time, point to TPO as a gene involved in the risk of DTC, and suggest the importance of interactions between TPO variants and other unidentified population-specific factors in determining thyroid cancer risk.

[Outbreak of 18 cases of hepatitis C in a hemodialysis unit]. / Brote de 18 casos de hepatitis C en una unidad de hemodiálisis.

OBJECTIVES: On September 30, 2001 we had notice of a probable outbreak of hepatitis C virus (HCV) infection in a hemodialysis unit in Ciudad Real (Spain). We conducted an investigation of the outbreak to determine its cause and implement control measures. METHODS: We performed a descriptive study and another analytic study (retrospective cohort study). In the descriptive study, the incidence of HCV infection in the unit between 01/01/98 and 09/30/01 was studied. In the cohort study, 86 subjects were included, of which 18 were infected with HCV during the outbreak. Virologic study was performed, including serology of anti-HCV antibodies, specific IgG avidity study, polymerase chain reaction and phylogenetic analysis of the viral subtypes found. RESULTS: In the study period, there were 86 patients under treatment in the hemodialysis unit, of which 27 (31.4%) were HCV-positive before 03/01/01. The epidemic curve suggested a common source with secondary cases. Since 1998 only one seroconversion had been documented (in 1999). Statistically significant differences were found only for the variable of dialysis shift. None of the patients who underwent dialysis on the Tuesday-Saturday-Thursday shift exclusively was infected. All cases were genosubtype 4d, which is uncommon in Spain (accounting for 3%), suggesting a common initial source for all cases. Most of the previous cases of HCV in the hemodialysis unit were 1b; three were 4c/4d and one was 1a. The IgG avidity study suggested that not all the cases were infected at the same time, supporting the hypothesis of a common source with secondary spread. CONCLUSIONS: The outbreak of HCV was confirmed, with 18 cases among dialyzed patients in the central unit. The outbreak was caused by the same viral strain, probably due to a common source with secondary person-to-person transmission among the patients.

Common genetic variants in pituitary-thyroid axis genes and the risk of differentiated thyroid cancer.

Thyroid hormone receptors, THRA and THRB, together with the TSH receptor, TSHR, are key regulators of thyroid function. Alterations in the genes of these receptors (THRA, THRB and TSHR) have been related to thyroid diseases, including thyroid cancer. Moreover, there is evidence suggesting that predisposition to differentiated thyroid cancer (DTC) is related to common genetic variants with low penetrance that interact with each other and with environmental factors. In this study, we investigated the association of single nucleotide polymorphisms (SNPs) in the THRA (one SNP), THRB (three SNPs) and TSHR (two SNPs) genes with DTC risk. A case-control association study was conducted with 398 patients with sporadic DTC and 479 healthy controls from a Spanish population. Among the polymorphisms studied, only THRA-rs939348 was found to be associated with an increased risk of DTC (recessive model, odds ratio=1.80, 95% confidence interval=1.03-3.14, P=0.037). Gene-gene interaction analysis using the genotype data of this study together with our previous genotype data on TG and TRHR indicated a combined effect of the pairwises: THRB-TG (P interaction=0.014, THRB-rs3752874 with TG-rs2076740; P interaction=0.099, THRB-rs844107 with TG-rs2076740) and THRB-TRHR (P interaction=0.0024, THRB-rs3752874 with TRHR-rs4129682) for DTC risk in a Spanish population. Our results confirm that THRA is a risk factor for DTC, and we show for the first time the combined effect of THRB and TG or TRHR on DTC susceptibility, supporting the importance of gene-gene interaction in thyroid cancer risk.

Common variants of the thyroglobulin gene are associated with differentiated thyroid cancer risk.

BACKGROUND: Genetic factors are important in thyroid cancer susceptibility. Recently, it has been reported that there are associations of certain chromosome regions with thyroid cancer. In this case-control study, we sought to determine whether there is an association between differentiated thyroid cancer (DTC) and variants in regions of chromosome 8q. METHODS: We used a case-control association design in a population of 877 individuals (398 patients with sporadic DTC and 479 healthy controls). The iPLEX technology was applied to analyze seven single-nucleotide polymorphisms (SNPs) in chromosome 8q: two SNPs that map at 8q24, previously reported as risk markers in different types of cancer, two SNPs in the thyrotropin-releasing hormone receptor gene (TRHR), and three SNPs in the thyroglobulin gene (TG). Risk assessment was done by unconditional regression analysis. RESULTS: The two SNPs that map at 8q24, rs6983267 and rs1447295, and the two TRHR polymorphisms showed no association with DTC. No association was also found for the exon 33 TG polymorphism. The two TG polymorphisms in the exon 10-12 cluster, however, were associated with an increased risk of DTC (dominant model odds ratio = 1.80, 95% confidence interval = 1.30-2.50, p < 0.001). CONCLUSIONS: In this study, we show for the first time that the TG gene is a susceptibility factor for thyroid cancer. Although these conclusions are based on a large population, additional studies are warranted to support these data.

WDR3 gene haplotype is associated with thyroid cancer risk in a Spanish population.

BACKGROUND: A member of the genes encoding WD-repeat proteins, the WDR3 gene, maps in the 1p12 region. This region was shown to be associated with thyroid cancer susceptibility in a previous work. In this study we aim to evaluate the contribution of WDR3 to thyroid cancer risk. METHODS: A case-control association study was performed in a total of 402 patients and 479 control subjects from a Spanish population. In the initial phase of the study, 10 single-nucleotide polymorphisms covering the WDR3 region were genotyped in a small group (157 patients and 118 control subjects); next, three of the initial single-nucleotide polymorphisms were further genotyped in the overall population. In addition, WDR3 expression was investigated in 10 thyroid cancer cell lines by RT-PCR and Western blot. RESULTS: Haplotype analysis revealed that combination of certain WDR3 variants, such as haplotype CAT, increases the risk of thyroid cancer (odds ratio = 1.85, 95% confidence interval = 0.97-3.55, p = 0.063). Further, both messenger RNA transcription and protein expression of WDR3 were altered in human thyroid cancer cells. CONCLUSION: These results indicate for the first time that WDR3 is a risk factor to thyroid cancer, suggesting its implication in the etiology of thyroid cancer.