ABSTRACT
INTRODUCTION: Despite continuous glucose monitoring having been proven useful in patients with type 1 diabetes mellitus, A1C remains the gold standard for assessing disease management. MATERIAL AND METHODS: Descriptive, retrospective study which included 252 patients, 40.5% male, mean age 44.91±14.57 years, mean duration of diabetes 22.21±13.12 years, 88.1% on basal-bolus insulin therapy and 11.9% users of continuous subcutaneous insulin infusion. Glucose measurement, analytical and anthropometric data were obtained. RESULTS: The mean time in range was 60.18±15.60% and was associated with A1C after adjusting for age, gender, duration of diabetes, BMI, insulin regimen, %CV and time below range (ß: -0.548; p<0.01). The glucose management indicator (GMI) was 7.19±0.69% and was also associated with A1C (ß: 0.957; p<0.01) regardless of age, gender, duration of diabetes, BMI, insulin treatment, %CV and time in range. The average difference between A1C and GMI was 0.17±0.65% (-2.70-3.40%), being higher as A1C increased, in a linear and significant manner, without being influenced by the duration of diabetes or CV. CONCLUSIONS: Although we found a positive correlation between continuous glucose monitoring glucose measurement parameters and A1C, there is still not enough evidence to replace one parameter with another.
Subject(s)
Blood Glucose Self-Monitoring , Hypoglycemic Agents , Adult , Blood Glucose , Female , Glucose , Glycated Hemoglobin/analysis , Humans , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Male , Middle Aged , Retrospective StudiesABSTRACT
Objective: The minimally invasive fine-needle aspiration cytology (FNAC) is the current gold standard for the diagnosis of thyroid nodule malignancy. However, the correct discrimination of follicular neoplasia often requires more invasive diagnostic techniques. The lack of suitable immunohistochemical markers to distinguish between follicular thyroid carcinoma and other types of follicular-derived lesions complicates diagnosis, and despite most of these tumours being surgically resected, only a small number will test positive for malignancy. As such, the development of new orthogonal diagnostic approaches may improve the accuracy of diagnosing thyroid nodules. Design: This study includes a retrospective, multi-centre training cohort including 54 fresh-frozen follicular-patterned thyroid samples and two independent, multi-centre validation cohorts of 103 snap-frozen biopsies and 33 FNAC samples, respectively. Methods: We performed a genome-wide genetic and epigenetic profiling of 54 fresh-frozen follicular-patterned thyroid samples using exome sequencing and the Illumina Human DNA Methylation EPIC platform. An extensive validation was performed using the bisulfite pyrosequencing technique. Results: Using a random forest approach, we developed a three-CpG marker-based diagnostic model that was subsequently validated using bisulfite pyrosequencing experiments. According to the validation cohort, this cost-effective method discriminates between benign and malignant nodules with a sensitivity and specificity of 97 and 88%, respectively (positive predictive value (PPV): 0.85, negative predictive value (NPV): 0.98). Conclusions: Our classification system based on a minimal set of epigenetic biomarkers can complement the potential of the diagnostic techniques currently available and would prioritize a considerable number of surgical interventions that are often performed due to uncertain cytology. Significance statement: In recent years, there has been a significant increase in the number of people diagnosed with thyroid nodules. The current challenge is their etiological diagnosis to discount malignancy without resorting to thyroidectomy. The method proposed here, based on DNA pyrosequencing assays, has high sensitivity (0.97) and specificity (0.88) for the identification of malignant thyroid nodules. This simple and cost-effective approach can complement expert pathologist evaluation to prioritize the classification of difficult-to-diagnose follicular-patterned thyroid lesions and track tumor evolution, including real-time monitoring of treatment efficacy, thereby stimulating adherence to health promotion programs.
Subject(s)
Thyroid Neoplasms , Thyroid Nodule , Biomarkers , Epigenesis, Genetic , Humans , Retrospective Studies , Sensitivity and Specificity , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/genetics , Thyroid Neoplasms/pathology , Thyroid Nodule/diagnosis , Thyroid Nodule/genetics , Thyroid Nodule/pathologyABSTRACT
OBJETIVO: Investigar la influencia del sexo en la mortalidad según la presencia o ausencia de diabetes mellitus tipo 2 (DM2) y otros factores de riesgo cardiovascular en la cohorte del Estudio Asturias. MÉTODO: El Estudio Asturias (iniciado en 1998) es un estudio de cohortes observacional, prospectivo, de una muestra representativa de la población asturiana de entre 30 y 75 años. Se dividió la población en grupos según la presencia o ausencia de DM2 y el sexo para valorar el control de los factores de riesgo cardiovascular. Además, conociendo el estatus vital de la cohorte 18 años después del inicio del estudio, se analizaron las diferencias en causas de mortalidad según las categorías anteriores. RESULTADOS: En 1998 iniciaron el estudio 1034 personas, de las cuales 561 eran mujeres (54,25%) y 473 eran hombres (45,75%). Padecían diabetes 131 (12,66%; 75 varones y 56 mujeres). Las mujeres con DM2 presentaron una hazard ratio (HR) para mortalidad total de 1,64 (intervalo de confianza del 95% [IC95%]: 0,97-2,77), y los hombres de 1,63 (IC95%: 1,07-2,50); para mortalidad cardiovascular, la HR fue de 3,06 (IC95%: 1,44-6,47) en las mujeres y de 1,49 (IC95%: 0,64-3,46) en los hombres. La tasa de mortalidad para las personas con DM2 en ambos sexos fue más alta que para las personas sin DM2. CONCLUSIONES: Las mujeres con DM2 tienen un riesgo de fallecer por causas cardiovasculares tres veces mayor que las mujeres sin DM2. Deberían implementarse estrategias de tratamiento en las mujeres con esta condición
OBJECTIVE: To investigate the influence of gender on mortality according to the presence or absence of type 2 diabetes mellitus (DM2) and other cardiovascular risk factors in the Asturias Study cohort. METHOD: The Asturias Study (started in 1998) is an observational, prospective cohort study of a representative sample of a population of Asturias aged 30-75 years. The population was divided into groups according to the presence or absence of DM2 and according to gender to assess control of cardiovascular risk factors. In addition, aware of the vital status of the cohort 18 years after the beginning of the study, we analyzed differences in causes of mortality according to the previous categories. RESULTS: In 1998, 1034 people started the study, 561 women (54.25%) and 473 men (45.75%). Of these, 131 (12.66%) had diabetes (75 men and 56 women). The women with T2D presented a hazard ratio (HR) for total mortality of 1.64 (95% confidence interval [95%CI]: .97-2.77), which was 1.63 (95%CI: 1.07-2.50) for the men and, for cardiovascular mortality, 3.06 (95%CI: 1.44-6.47) for the females, versus 1.49 (95%CI: 0.64-3.46) for the males. The mortality rate for people with T2D of both sexes was higher than for people without T2D. CONCLUSIONS: Women with T2D have a risk more than three times higher than women without diabetes of dying from cardiovascular causes. We should implement treatment strategies in women with this condition
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Diabetes Mellitus, Type 2/mortality , Cardiovascular Diseases/epidemiology , Hyperglycemia/prevention & control , Sex Distribution , Risk Factors , Indicators of Morbidity and Mortality , Prospective Studies , Case-Control Studies , Health Surveys/statistics & numerical data , Tobacco Use Disorder/epidemiology , Sedentary BehaviorABSTRACT
OBJECTIVE: To investigate the influence of gender on mortality according to the presence or absence of type 2 diabetes mellitus (DM2) and other cardiovascular risk factors in the Asturias Study cohort. METHOD: The Asturias Study (started in 1998) is an observational, prospective cohort study of a representative sample of a population of Asturias aged 30-75 years. The population was divided into groups according to the presence or absence of DM2 and according to gender to assess control of cardiovascular risk factors. In addition, aware of the vital status of the cohort 18 years after the beginning of the study, we analyzed differences in causes of mortality according to the previous categories. RESULTS: In 1998, 1034 people started the study, 561 women (54.25%) and 473 men (45.75%). Of these, 131 (12.66%) had diabetes (75 men and 56 women). The women with T2D presented a hazard ratio (HR) for total mortality of 1.64 (95% confidence interval [95%CI]: .97-2.77), which was 1.63 (95%CI: 1.07-2.50) for the men and, for cardiovascular mortality, 3.06 (95%CI: 1.44-6.47) for the females, versus 1.49 (95%CI: 0.64-3.46) for the males. The mortality rate for people with T2D of both sexes was higher than for people without T2D. CONCLUSIONS: Women with T2D have a risk more than three times higher than women without diabetes of dying from cardiovascular causes. We should implement treatment strategies in women with this condition.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetes Mellitus, Type 2/epidemiology , Female , Humans , Male , Prospective Studies , Risk Factors , Sex Characteristics , Sex FactorsABSTRACT
[This corrects the article DOI: 10.1371/journal.pone.0211070.].
ABSTRACT
People who develop type 2 diabetes (T2D) are known to have a higher mortality risk. We estimated all-cause, cardiovascular, and cancer mortality-risks in our patient cohort according to categories of impaired glucose metabolism. This 18-year retrospective analysis included a region-wide, representative sample of a population aged 30-75 years. Age- and sex-stratified hazard ratios (HRs) were calculated for 48 participants with diagnosed T2D, 83 with undiagnosed T2D (HbA1c ≥6.5%, fasting glycemia ≥126 mg/dL, or glycemia after 75 g glucose load ≥200 mg/dL); 296 with prediabetes (HbA1c 5.7%-6.4%, fasting glycemia 100-125 mg/dL, or glycemia after 75 g glucose load 140-199 mg/dL), and 607 with normoglycemia. Over 18,612 person-years, 32 individuals with undiagnosed T2D, 30 with diagnosed T2D, 62 with prediabetes, and 80 with normoglycemia died. Total sample crude mortality rate (MR) was 10.96 deaths per 1,000 person-years of follow-up. MR of the diagnosed T2D group was more than 3-times higher and that of newly diagnosed T2D was 2-times higher (34.72 and 21.42, respectively) than total sample MR. Adjusted HR for all-cause mortality was 2.02 (95% confidence interval 1.29-3.16) and 1.57 (95% CI 1.00-2.28) in the diagnosed T2D group and the newly diagnosed T2D group, respectively. Adjusted HR for cardiovascular mortality in the T2D group was 2.79 (95% CI 1.35-5.75); this risk was greatly increased in women with T2D: 6.72 (95% CI 2.50-18.07). In Asturias, age- and sex-standardized all-cause mortality is more than 2-times higher for adults with T2D than for adults without T2D. The HR for cardiovascular mortality is considerably higher in T2D women than in normoglycemic women.
Subject(s)
Cardiovascular Diseases/mortality , Diabetes Complications/mortality , Diabetes Mellitus, Type 2/mortality , Prediabetic State/mortality , Adult , Age Factors , Aged , Blood Glucose/metabolism , Cardiovascular Diseases/blood , Cardiovascular Diseases/diagnosis , Diabetes Complications/blood , Diabetes Complications/diagnosis , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/diagnosis , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prediabetic State/blood , Prediabetic State/diagnosis , Retrospective Studies , Risk Factors , Sex Factors , Survival RateABSTRACT
AIMS/HYPOTHESIS: Failure in glucose response to insulin is a common pathology associated with obesity. In this study, we analyzed the genome wide DNA methylation profile of visceral adipose tissue (VAT) samples in a population of individuals with obesity and assessed whether differential methylation profiles are associated with the presence of type 2 diabetes (T2D). METHODS: More than 485,000 CpG genome sites from VAT samples from women with obesity undergoing gastric bypass (n = 18), and classified as suffering from type 2 diabetes (T2D) or not (no type 2 diabetes, NT2D), were analyzed using DNA methylation arrays. RESULTS: We found significant differential methylation between T2D and NT2D samples in 24 CpGs that map with sixteen genes, one of which, HOOK2, demonstrated a significant correlation between differentially hypermethylated regions on the gene body and the presence of type 2 diabetes. This was validated by pyrosequencing in a population of 91 samples from both males and females with obesity. Furthermore, when these results were analyzed by gender, female T2D samples were found hypermethylated at the cg04657146-region and the cg 11738485-region of HOOK2 gene, whilst, interestingly, male samples were found hypomethylated in this latter region. CONCLUSION: The differential methylation profile of the HOOK2 gene in individuals with T2D and obesity might be related to the attendant T2D, but further studies are required to identify the potential role of HOOK2 gene in T2D disease. The finding of gender differences in T2D methylation of HOOK2 also warrants further investigation.
Subject(s)
Adipose Tissue/metabolism , DNA Methylation , Diabetes Mellitus, Type 2/genetics , Microtubule-Associated Proteins/genetics , Obesity/genetics , Cohort Studies , Female , Humans , MaleABSTRACT
There are some well known factors involved in the etiology of thyroid cancer, including iodine deficiency, radiation exposure at early ages, or some genetic changes. However, epigenetic modulators that may contribute to development of these tumors and be helpful to for both their diagnosis and treatment have recently been discovered. The currently known changes in DNA methylation, histone modifications, and non-coding RNAs in each type of thyroid carcinoma are reviewed here.
Subject(s)
Cell Transformation, Neoplastic/genetics , Epigenesis, Genetic , Thyroid Neoplasms/genetics , Adenocarcinoma, Follicular/genetics , Animals , Carcinoma, Medullary/genetics , Carcinoma, Papillary/genetics , Clinical Trials as Topic , CpG Islands/genetics , DNA Methylation , DNA, Neoplasm/genetics , Histone Code , Histone Deacetylase Inhibitors/therapeutic use , Humans , Models, Genetic , Neoplasm Proteins/genetics , Oncogenes , Promoter Regions, Genetic/genetics , RNA, Neoplasm/genetics , RNA, Untranslated/genetics , Thyroid Neoplasms/drug therapyABSTRACT
There are some well known factors involved in the etiology of thyroid cancer, including iodine deficiency, radiation exposure at early ages, or some genetic changes. However, epigenetic modulators that may contribute to development of these tumors and be helpful to for both their diagnosis and treatment have recently been discovered. The currently known changes in DNA methylation, histone modifications, and non-coding RNAs in each type of thyroid carcinoma are reviewed here (AU)
Son conocidos algunos factores implicados en la etiología del cáncer de tiroides como el déficit de yodo o la exposición a radiación en edades tempranas o algunas alteraciones genéticas. Sin embargo, en los últimos años se han descubierto moduladores epigenéticos que puedan contribuir al desarrollo de estos tumores y podrían tener una utilidad tanto en el diagnóstico como en el tratamiento. En esta revisión se repasan las alteraciones conocidas hasta ahora tanto en la metilación del ADN como en las modificaciones de las histonas y los ARN no codificantes en cada uno de los tipos de carcinomas de tiroides (AU)
Subject(s)
Humans , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/genetics , DNA Methylation/genetics , Carcinoma/diagnosis , Carcinoma/genetics , Thyroid Neoplasms/etiology , Histones/analysis , Histones/genetics , MicroRNAs/analysis , MicroRNAs/geneticsABSTRACT
Aberrant epigenetics is a hallmark of cancer, and endocrine-related tumors are no exception. Recent research has been identifying an ever-growing number of epigenetic alterations in both genomic DNA methylation and histone post-translational modification in tumors of the endocrine system. Novel microarray and ultra-deep sequencing technologies have allowed the identification of genome-wide epigenetic patterns in some tumor types such as adrenocortical, parathyroid, and breast carcinomas. However, in other cancer types, such as the multiple endocrine neoplasia syndromes and thyroid cancer, tumor information is limited to candidate genes alone. Future research should fill this gap and deepen our understanding of the functional role of these alterations in cancer, as well as defining their possible clinical uses.
Subject(s)
Endocrine Gland Neoplasms/genetics , Epigenesis, Genetic , Animals , Breast Neoplasms/genetics , HumansABSTRACT
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.
Subject(s)
DNA Methylation , Down-Regulation , Neoplasm Proteins/genetics , Promoter Regions, Genetic , Thyroid Gland/metabolism , Thyroid Neoplasms/metabolism , Up-Regulation , Adenocarcinoma, Follicular/genetics , Adenocarcinoma, Follicular/metabolism , Adenocarcinoma, Follicular/pathology , Carcinoma/genetics , Carcinoma/metabolism , Carcinoma/pathology , Carcinoma, Medullary/genetics , Carcinoma, Medullary/metabolism , Carcinoma, Medullary/pathology , Carcinoma, Neuroendocrine , Carcinoma, Papillary/genetics , Carcinoma, Papillary/metabolism , Carcinoma, Papillary/pathology , Cell Line, Tumor , Cohort Studies , Genome-Wide Association Study , Humans , Neoplasm Proteins/metabolism , Oligonucleotide Array Sequence Analysis , Thyroid Cancer, Papillary , Thyroid Carcinoma, Anaplastic , Thyroid Gland/pathology , Thyroid Neoplasms/genetics , Thyroid Neoplasms/pathology , Tissue Banks , Tumor Cells, CulturedABSTRACT
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 (ßs) by robust linear regression. RESULTS: Women had lower levels of LINE-1 methylation than men (ß = -0.7, p = 0.02). Persons who smoked blond tobacco showed lower methylation than nonsmokers (ß = -0.7, p = 0.03). Arsenic toenail concentration was inversely associated with LINE-1 methylation (ß = -3.6, p = 0.003). By contrast, iron (ß = 0.002, p = 0.009) and nickel (ß = 0.02, p = 0.004) were positively associated with LINE-1 methylation. Single nucleotide polymorphisms (SNPs) in DNMT3A (rs7581217-per allele, ß = 0.3, p = 0.002), TCN2 (rs9606756-GG, ß = 1.9, p = 0.008; rs4820887-AA, ß = 4.0, p = 4.8 × 10-7; rs9621049-TT, ß = 4.2, p = 4.7 × 10-9), AS3MT (rs7085104-GG, ß = 0.7, p = 0.001), SLC19A1 (rs914238, TC vs. TT: ß = 0.5 and CC vs. TT: ß = -0.3, global p = 0.0007) and MTHFS (rs1380642, CT vs. CC: ß = 0.3 and TT vs. CC; ß = -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.
Subject(s)
DNA Methylation , Leukocytes/metabolism , Long Interspersed Nucleotide Elements , Adult , Aged , Aged, 80 and over , Female , Genotype , Humans , Male , Middle Aged , Nutrition Assessment , Polymorphism, Single Nucleotide , Smoking/geneticsABSTRACT
The process of aging refers to the decay of an organism's structure and function, in which molecular and cellular modifications can have various effects at the individual level over the course of a lifetime. The accumulation of molecular errors that compromise adult stem cell functions occurs because of genetic and epigenetic interactions and depends on hereditary, environmental, and stochastic factors. Here we review the known genetic factors involved in aging.
ABSTRACT
Aging is one of the most challenging and unresolved problems in biology owing to its highly complex nature. Public interest in aging has increased not only because all of us can expect to live to a ripe old age but also because we wish to avoid those age-related changes that lead to physical invalidity or other diseases (cancer, depression) and may ultimately cause social isolation. Aging is a process of genetic and epigenetic interactions at all biological levels, where epigenetics has an important function in determining the phenotypic differences that arise. Epigenetics also plays a key role in the development of diseases associated with aging and explains the relationship between an individual's genetic background, the environment, aging, and disease. DNA plasticity is mediated in part by the epigenetic changes that lead the role of a cell, and can be passed on to future generations. Epigenetics establishes the idea that our health can be affected not only by the interplay of our genes and environment but also by the inherited effects of our ancestors' genes and environment.
Subject(s)
Aging/genetics , Epigenesis, Genetic/genetics , Animals , Humans , Models, BiologicalABSTRACT
Recent studies demonstrated that dysregulation of NKG2D and its ligands, leading to activation of autoreactive effector cells, can trigger autoimmune diseases, but soluble forms of these ligands can downmodulate NKG2D expression in T effector cells. We investigated the presence of soluble major histocompatibility complex class I chain-related A or B (MICA or MICB) molecules in sera of multiple sclerosis (MS) patients and whether they play a role in the progression of the disease. Although soluble MICA serum levels did not differ, soluble MICB serum levels were higher in MS patients compared with controls. Moreover, the highest MICB levels were in MS patients during relapses. Using immunohistochemistry techniques, it was possible to locate MIC expression in neurons of MS demyelinating plaques that were intracellularly accumulated. Elevated soluble MICB levels exist in serum of multiple sclerosis patients related with disease activity. This may contribute to the modulation of immune response activity during relapses.
Subject(s)
Histocompatibility Antigens Class I/blood , Multiple Sclerosis, Relapsing-Remitting/immunology , Adult , Astrocytes/immunology , Astrocytes/pathology , Disease Progression , Female , Humans , Immunohistochemistry , Longitudinal Studies , Male , Microscopy, Confocal , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/blood , Multiple Sclerosis, Relapsing-Remitting/pathology , Neurons/immunology , Neurons/pathologyABSTRACT
We report that the allele MICB 0050204(1) allele, present in the majority of the Spanish population (70% of healthy controls) is characterized by the presence of an extra exon found between the sequence corresponding to exon 1 and 2. This is generated by a dinucleotide polymorphism in the first MICB intron that introduces a new splice junction, which can generate, by alternative splicing, transcripts with an additional exon. This new exon contains a premature stop codon and therefore the transcript does not produce a functional protein.
Subject(s)
Codon, Nonsense/genetics , Exons/genetics , Histocompatibility Antigens Class I/genetics , Introns/genetics , Alleles , Alternative Splicing , Base Sequence , Histocompatibility Antigens Class I/chemistry , Humans , Molecular Sequence Data , SpainABSTRACT
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 up-regulated 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.
Subject(s)
Histocompatibility Antigens Class I/genetics , Polymorphism, Genetic , Promoter Regions, Genetic/genetics , Sp1 Transcription Factor/genetics , Transcription, Genetic , Base Sequence , Caco-2 Cells , Electrophoretic Mobility Shift Assay , Flow Cytometry , Gene Expression Regulation , HeLa Cells , Humans , Immunoprecipitation , Molecular Sequence Data , NK Cell Lectin-Like Receptor Subfamily K , Receptors, Immunologic/immunology , Receptors, Natural Killer Cell , Reverse Transcriptase Polymerase Chain Reaction , Sp1 Transcription Factor/metabolism , Transcription Factors/genetics , TransfectionABSTRACT
The possibility that susceptibility to celiac disease (CD) might be influenced by the MHC class I chain-related gene family, MICA and MICB, has been previously reported. In this study, we analyzed the MICB promoter and examined the association of the polymorphisms found within such in a group of CD patients. To study the MICB promoter we sequenced the 5' flanking region of MICB gene in DNA from homozygous B-lymphoblastoid cell lines corresponding to the most frequent MICB alleles found in our population (MICB*00502, MICB*002, MICB*004, and MICB*008). DNA from a MICB*003 homozygous individual was also analyzed. Sequence analysis revealed six single nucleotide polymorphisms located at positions 45860 C/A, 45862 G/C, 45877 C/G, 46113 A/C, 46219 G/C, and 46286 G/C and an insertion of 2 bp --/AG at position 45944 according to the published genomic sequence. Those polymorphisms were found to be associated in four different haplotypes corresponding to different MICB alleles. Subsequently, 126 CD subjects and 117 healthy controls were typed by polymerase chain reaction using sequence-specific primers for these polymorphisms. MICB promoter polymorphism haplotypes were also found in our population and showed strong linkage disequilibrium with MICB alleles. MICB promoter polymorphism Haplotype 3, included in MICB*002 and MICB*008 alleles, was found to be overrepresented in CD patients (79.4% CD patients vs 45.3% healthy controls; p(c) < 0.0001; OR = 4.64; CI 95% = 2.64-8.16). Both MICB*008 and MICB*002 alleles were found as part of the CD susceptibility extended haplotypes B8/DR3/DQ2, B18/DR3/DQ2, and DR4/DQ8.
Subject(s)
Celiac Disease/genetics , Genetic Predisposition to Disease , Histocompatibility Antigens Class I/genetics , Polymorphism, Single Nucleotide , Adult , B-Lymphocytes/metabolism , Cell Line, Tumor , Female , Homozygote , Humans , Male , Promoter Regions, GeneticABSTRACT
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).
Subject(s)
Carcinoma, Hepatocellular/immunology , HLA-B Antigens/genetics , Hepatitis C/immunology , Receptors, Immunologic/genetics , Adult , Aged , Carcinoma, Hepatocellular/genetics , Disease Progression , Epitopes/genetics , Female , Genotype , Hepatitis C/genetics , Humans , Killer Cells, Natural/immunology , Liver Cirrhosis/immunology , Male , Middle Aged , Receptors, KIR , Receptors, KIR3DS1ABSTRACT
BACKGROUND AND AIMS: Celiac disease (CD) is an enteropathic disorder characterized by strong association with HLA-DQ2. Our aim was to investigate whether MICB, a gene located in the MHC class I region, may contribute to CD susceptibility. PATIENTS AND METHODS: Total of 133 CD patients, previously reported to be associated with MICA-A5.1, and 116 controls were initially analyzed. Twenty-eight additional DQ2-negative CD patients were also studied. MICB was typed by PCR using sequence-specific primers. HLA-B, -DRB1, -DQA1, -DQB1, and MICA were also typed. RESULTS: The allele MICB0106 was strongly associated with CD (pc < 0.000001, odds ratio (OR) = 5.6, 95% confidence interval (CI) = 3.1-10.1) and it was overrepresented in atypical patients compared with typical ones (pc = 0.04, OR = 2.9, CI = 1.4-6.1). MICB0106 was part of DR3-DQ2 haplotype (B8-MICA-A5.1-MICB0106-DR3-DQ2), and consequently a strong linkage disequilibrium between MICB0106 with DQ2 (lambdas = 1) and MICA-A5.1 (lambdas = 0.55) was found. To analyze whether the association of MICB is independent of this haplotype, its association was also studied in DQ2-negative patients (n = 46). DQ8 (28%vs 9%, p = 0.0085, pc = NS) and MICB0104 (52%vs 30%, p = 0.01, pc = NS) were increased in DQ2-negative patients. MICA-A5.1 was significantly increased in atypical patients (p(c)= 0.001, OR = 6.4, CI = 2.2-18.4), and this association was independent of DQ2 and DQ8 (pc = 0.02, OR = 2.6, CI = 1.1-6.1). CONCLUSIONS: The expression of MIC genes on enterocytes under stressful conditions and their function as ligands of intraepithelial gammadelta and CD8 T cells, together with the data presented here suggest a potential role of MIC genes in the pathogenesis of CD.