The aim of the present study was to investigate, in 152 Spanish patients infected with hepatitis C virus (HCV), the possibility that killer cell immunoglobulin-like receptors (KIRs) influence progression to hepatocellular carcinoma. KIRs are related to the activation and inhibition of natural killer cells and may play an important role in the innate response against infection with such viruses as HCV. We found that the human leukocyte antigen-Bw4I80 epitope and the KIR3DS1 gene were more frequent in HCV carriers than in patients with hepatocellular carcinoma. Moreover, these associations were not independent of each other-the KIR3DS1/Bw4I80 genotype clearly was also more frequent in HCV carriers (odds ratio, 24.22).NK cells provide defense against viral infections by producing cytokines and causing cytotoxicity, and this capacity is dependent on an equilibrium between the inhibitory and activating receptors [1]. The killer cell immunoglobulin-like receptor (KIR) genes encode a group of proteins that are expressed on NK cells and some T cells [2]. These genes are located on chromosome 19q13.4 in the leukocyte receptor complex. KIR proteins act as receptors that recognize major histocompatibility

Objective: The purpose of this study was to determine the global patterns of aberrant DNA methylation in thyroid cancer. Research Design and Methods:We have used DNA methylation arrays to determine, for the first time, the genome-wide promoter methylation status of papillary, follicular, medullary, and anaplastic thyroid tumors. Results:We identified 262 and 352 hypermethylated and 13 and 21 hypomethylated genes in differentiated papillary and follicular tumors, respectively. Interestingly, the other tumor types analyzed displayed more hypomethylated genes (280 in anaplastic and 393 in medullary tumors) than aberrantly hypermethylated genes (86 in anaplastic and 131 in medullary tumors). Among the genes indentified, we show that 4 potential tumor suppressor genes (ADAMTS8, HOXB4, ZIC1, and KISS1R) and 4 potential oncogenes (INSL4, DPPA2, TCL1B, and NOTCH4) are frequently regulated by aberrant methylation in primary thyroid tumors. In addition, we show that aberrant promoter hypomethylation-associated overexpression of MAP17 might promote tumor growth in thyroid cancer. Conclusions:Thyroid cancer subtypes present differential promoter methylation signatures, and nondifferentiated subtypes are characterized by aberrant promoter hypomethylation rather than hypermethylation. Additional studies are needed to determine the potential clinical interest of the tumor subtype-specific DNA methylation signatures described herein and the role of aberrant promoter hypomethylation in nondifferentiated thyroid tumors. (J Clin Endocrinol Metab 98: 2811-2821, 2013)

MHC class I-related genes A/B (MICA/B) are ligands of the NKG2D receptor expressed on T and NK cells. Their expression is highly restricted in normal tissues, but is upregulated in tumoral and infected cells. We show that the minimal promoter of both genes contains a CCAAT box, which binds to NF-Y, and a GC box, which binds to Sp1, Sp3 and Sp4. We also demonstrate that MICB promoter is polymorphic, showing three single nucleotide polymorphisms (C>G at +16, -341, -408) and a deletion of two base pairs at -66 (AG>-) that is located close to the CCAAT box (-70) and the GC box (-86). Transcriptional activity associated with MICB promoter variants carrying this deletion, present in the 45.3% of Spanish population, showed a remarkable decrease (18-fold, p <0.01). By functional analysis, we show that the deletion plays a critical role in MICB promoter activity by diminishing Sp1 transcriptional activation. These important variations in MICB expression among normal individuals could imply a significant difference in the natural immune response against infections or tumor transformation, and might thereby contribute to an increased aberrant immune response against self cells, providing the molecular basis for the associations of the MICB gene to different autoimmune diseases.

Background: Altered DNA methylation has been associated with various diseases.Objective: We evaluated the association between levels of methylation in leukocyte DNA at long interspersed nuclear element 1 (LINE-1) and genetic and non-genetic characteristics of 892 control participants from the Spanish Bladder Cancer/EPICURO study.Methods: We determined LINE-1 methylation levels by pyrosequencing. Individual data included demographics, smoking status, nutrient intake, toenail concentrations of 12 trace elements, xenobiotic metabolism gene variants, and 515 polymorphisms among 24 genes in the one-carbon metabolism pathway. To assess the association between LINE-1 methylation levels (percentage of methylated cytosines) and potential determinants, we estimated beta coefficients (βs) by robust linear regression.Results: Women had lower levels of LINE-1 methylation than men (β = –0.7, p = 0.02). Persons who smoked blond tobacco showed lower methylation than nonsmokers (β = –0.7, p = 0.03). Arsenic toenail concentration was inversely associated with LINE-1 methylation (β = –3.6, p = 0.003). By contrast, iron (β = 0.002, p = 0.009) and nickel (β = 0.02, p = 0.004) were positively associated with LINE-1 methylation. Single nucleotide polymorphisms (SNPs) in DNMT3A (rs7581217-per allele, β = 0.3, p = 0.002), TCN2 (rs9606756-GG, β = 1.9, p = 0.008; rs4820887-AA, β = 4.0, p = 4.8 × 10–7; rs9621049-TT, β = 4.2, p = 4.7 × 10–9), AS3MT (rs7085104-GG, β = 0.7, p = 0.001), SLC19A1 (rs914238, TC vs. TT: β = 0.5 and CC vs. TT: β = –0.3, global p = 0.0007) and MTHFS (rs1380642, CT vs. CC: β = 0.3 and TT vs. CC; β = –0.8, global p = 0.05) were associated with LINE-1 methylation.Conclusions: We identified several characteristics, environmental factors, and common genetic variants that predicted DNA methylation among study participants.

Gestational diabetes mellitus (GDM) is defined as the glucose intolerance that is not present or recognized prior to pregnancy. Several risk factors of GDM depend on environmental factors that are thought to regulate the genome through epigenetic mechanisms. Thus, epigenetic regulation could be involved in the development of GDM. In addition, the adverse intrauterine environment in patients with GDM could also have a negative impact on the establishment of the epigenomes of the offspring.