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1.
Materials (Basel) ; 16(12)2023 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-37374461

RESUMO

Metasurface coatings on a free-standing SiN thin film membrane are fabricated on a Si substrate using masked lithography and CMOS-compatible surface micromachining. The result is a band-limited absorber for the mid-IR, which is part of a microstructure that is attached to the substrate by long and slender suspension beams to provide thermal isolation. As a residual of the fabrication, the regular pattern of sub-wavelength unit cells of 2.6 µm side length, which defines the metasurface, is interrupted by an equally regular array of sub-wavelength holes of 1-2 µm diameter and at 7.8-15.6 µm of pitch. This array of holes is essential for enabling access of the etchant and attack of the underlying layer during fabrication, which ultimately results in the sacrificial release of the membrane from the underlying substrate. As the plasmonic responses of the two patterns interfere, a maximum is imposed on the hole diameter and a minimum on the hole-to-hole pitch. However, the hole diameter should be sufficiently large to allow access of the etchant, while the maximum spacing between holes is set by the limited selectivity of the different materials to the etchant during sacrificial release. The effect of the parasitic hole pattern on the spectral absorption of a metasurface design is analyzed by simulations of the responses of combined holes-metasurface structures. Arrays of 300 × 180 µm2 Al-Al2O3-Al MIM structures are mask-fabricated on suspended SiN beams. The results show that the effect of the array of holes can be disregarded for a hole-to-hole pitch larger than 6 times the side length of the metamaterial until cell, while the diameter of the hole should remain smaller than about 1.5 µm, and their alignment is critical.

2.
Gynecol Oncol ; 165(2): 230-238, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35277281

RESUMO

OBJECTIVE: Despite its generally favorable prognosis at primary diagnosis, recurrence of endometrial cancer remains an important clinical challenge. The aim of this study was to analyze the value of molecular classification in recurrent endometrial cancer. METHODS: This study included patients with recurrent endometrial cancer who underwent primary surgical treatment between 2004 and 2015 at the Karolinska University Hospital, Sweden and the Bern University Hospital, Switzerland (KImBer cohort) with molecular classification of the primary tumor. RESULTS: Out of 594 molecularly classified endometrial cancer patients, 101 patients experienced recurrence, consisting of 2 POLEmut, 33 MMRd, 30 p53abn, and 36 NSMP tumors. Mean age at recurrence was 71 years and mean follow-up was 54 months. Overall, median time to first recurrence was 16 months (95% CI 12-20); with the shortest median time in MMRd patients, with 13 months (95% CI 5-21). The pattern of recurrence was distinct among molecular subgroups: MMRd tumors experienced more locoregional, while p53abn cases showed more abdominal recurrences (P = .042). Median survival after recurrence was best for MMRd cases (43 months, 95% CI 11-76), compared to 39 months (95% CI 21-57) and 10 months (95% CI 7-13) for the NSMP and p53abn cases respectively (log-rank, P = .001). CONCLUSION: Molecular classification is a significant indicator of survival after recurrence in endometrial cancer patients, and patterns of recurrence differ by molecular subgroups. While MMRd endometrial cancer show more locoregional recurrence and the best survival rates after recurrence, p53abn patients experience abdominal recurrence more often and had the worst prognosis of all recurrent patients.


Assuntos
Neoplasias do Endométrio , Proteína Supressora de Tumor p53 , Estudos de Coortes , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Recidiva Local de Neoplasia/genética , Prognóstico , Estudos Retrospectivos , Proteína Supressora de Tumor p53/genética
3.
Br J Cancer ; 111(11): 2091-102, 2014 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-25349971

RESUMO

BACKGROUND: Gastrointestinal stromal tumour (GIST) is mainly initialised by receptor tyrosine kinase gene mutations. Although the tyrosine kinase inhibitor imatinib mesylate considerably improved the outcome of patients, imatinib resistance still remains a major therapeutic challenge in GIST therapy. Herein we evaluated the clinical impact of microRNAs in imatinib-treated GISTs. METHODS: The expression levels of microRNAs were quantified using microarray and RT-qPCR in GIST specimens from patients treated with neoadjuvant imatinib. The functional roles of miR-125a-5p and PTPN18 were evaluated in GIST cells. PTPN18 expression was quantified by western blotting in GIST samples. RESULTS: We showed that overexpression levels of miR-125a-5p and miR-107 were associated with imatinib resistance in GIST specimens. Functionally, miR-125a-5p expression modulated imatinib sensitivity in GIST882 cells with a homozygous KIT mutation but not in GIST48 cells with double KIT mutations. Overexpression of miR-125a-5p suppressed PTPN18 expression, and silencing of PTPN18 expression increased cell viability in GIST882 cells upon imatinib treatment. PTPN18 protein levels were significantly lower in the imatinib-resistant GISTs and inversely correlated with miR-125a-5p. Furthermore, several microRNAs were significantly associated with metastasis, KIT mutational status and survival. CONCLUSIONS: Our findings highlight a novel functional role of miR-125a-5p on imatinib response through PTPN18 regulation in GIST.


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , MicroRNAs/fisiologia , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/mortalidade , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Mesilato de Imatinib , Mutação , Proteínas Tirosina Fosfatases não Receptoras/genética , Proteínas Tirosina Fosfatases não Receptoras/fisiologia , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética
5.
Int J Lab Hematol ; 32(1 Pt 2): 122-6, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19016916

RESUMO

Clinical diagnosis of the myeloproliferative disorders (MPD) has previously been based on clinical data and bone marrow morphology due to lack of specific molecular markers. The discovery of JAK2 V617F mutation has shed light on understanding of the molecular pathways involved in the pathogenesis of the myeloproliferative disorders. The thrombopoietin receptor gene (MPL) is expressed in megakaryocytes and exhibits the gain of function point mutation in approximately 5% of MPDs. Several research groups have used real-time PCR to detect and quantify the presence of JAK2 V617F mutation. We report here a highly specific real-time assay based on the TaqMan((R)) technology to detect the MPL W515L mutation with high sensitivity from the patient's blood. This assay can be easily performed together with the JAK2 V617F mutation assay on the same real-time PCR reaction plate.


Assuntos
Mutação/genética , Transtornos Mieloproliferativos/genética , Reação em Cadeia da Polimerase/métodos , Receptores de Trombopoetina/genética , Humanos , Janus Quinase 2/genética , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/fisiopatologia , Sensibilidade e Especificidade , Transdução de Sinais , Fatores de Tempo
6.
Ann N Y Acad Sci ; 1110: 92-8, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17911424

RESUMO

Type 1 diabetes mellitus (T1DM) is a typical autoimmune disease and results from the destruction of insulin-producing beta cells of the pancreas. It develops in the presence of genetic susceptibility, even though more than 85% of patients with T1DM do not have a close relative with the disorder. The etiology of T1DM is complex, and both genetic and environmental factors play important roles. A permissive genetic background is required for the development of the islet autoimmune process. The strongest genetic association idengified is that with HLA class II genes located on the short arm of chromosome 6. It is well known that both HLA DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8) and DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) are positively, and DRB1*15-DQA1*0102-DQB1*0602 is negatively, associated with T1DM. However, only a minority of the subjects carrying the high-risk haplotypes/genotypes develops the disease, which suggests that additional genes play a crucial role in conferring either protection or susceptibility to T1DM. Major histocompatibility complex (MHC) class I chain-related A (MICA) is located in a candidate susceptibility region and activates natural killer (NK) cells, T cells and gammadelta CD8 T cells by its receptor NKG2D. The polymorphism of the MICA gene is associated with T1DM in different populations as demonstrated in several papers published in the last 7 years.


Assuntos
Diabetes Mellitus Tipo 1/genética , Antígenos de Histocompatibilidade Classe I/genética , Polimorfismo Genético/genética , Adolescente , Adulto , Idade de Início , Idoso , Autoimunidade/genética , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Haplótipos/genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade
7.
Rheumatology (Oxford) ; 44(3): 287-92, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15522921

RESUMO

OBJECTIVE: To evaluate the contribution of the MHC class I chain-related A (MICA) gene polymorphism to the genetic risk of systemic lupus erythematosus (SLE). METHODS: HLA-DRB1-DQA1-DQB1 genotyping, MICA exon 5 microsatellite genotyping and HLA-B8 genotyping were performed in 48 Italian SLE patients and in 158 healthy control subjects. RESULTS: Of HLA class II haplotypes, only DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) was significantly more frequent among SLE patients than among healthy control subjects [odds ratio (OR) = 6.5, corrected P < 0.0026]. HLA-B8 was detected in 31% SLE patients and 13% healthy control subjects (OR = 3.0, P = 0.005). The allele-wise comparison between patients and controls showed that both MICA5 (OR = 2.5, corrected P < 0.0005) and MICA5.1 (OR = 2.4, corrected P < 0.0005) were positively and MICA9 (OR = 0.2, corrected P < 0.0005) was negatively associated with the disease. The MICA5/5.1 genotype was positively associated with SLE (OR = 28.9, corrected P < 0.0015) also in subjects negative for DR3-DQ2 (OR > 22.6, corrected P < 0.011). The simultaneous presence of DR3-DQ2 and MICA5.1 was detected in 15/48 (31%) SLE and in 10/158 (6%) healthy control subjects (OR = 6.7, corrected P < 0.011). The simultaneous combination of DR3-DQ2 and MICA5 was found in 10/48 (21%) SLE patients and in only 1/158 healthy control subjects (OR = 41.3, corrected P < 0.011). Logistic regression analysis showed the independent positive associations of MICA5 and MICA5.1 and negative association of MICA9 with the disease, and revealed that the interaction of the three major markers (DR3-DQ2, MICA5 and MICA5.1) was associated with increasing genetic risk, which was highest (OR > 30.3) in DR3-DQ2-positive subjects carrying the MICA5-5.1 genotype. CONCLUSIONS: Our study provides the first demonstration of the independent association of the MICA gene polymorphism with genetic risk of SLE.


Assuntos
Antígenos de Histocompatibilidade Classe I/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético/genética , Adulto , Idoso , Alelos , Feminino , Marcadores Genéticos/genética , Predisposição Genética para Doença/genética , Genótipo , Antígeno HLA-B8/genética , Antígenos HLA-DQ/genética , Antígeno HLA-DR3/genética , Haplótipos , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade
8.
Eur J Immunogenet ; 31(2): 73-6, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15086346

RESUMO

The attraction of leukocytes to tissues is essential for inflammation and the initiation of the autoimmune reaction. The process is controlled by chemokines, which are chemotactic cytokines. We investigated whether human chemokine receptor gene polymorphisms, namely CCR5-Delta32 and CCR2-64I, are associated with susceptibility to autoimmune Addison's disease. Genotyping was performed in 56 patients and 127 healthy controls by a new method using pyrosequencing for CCR2-64I and by polymerase chain reaction and detecting gel for CCR5-Delta32. None of the CCR2 or CCR5 alleles was found to be associated, either positively or negatively, with disease risk. Our results indicate that the CCR2-64I and CCR5-Delta32 gene polymorphisms do not play a major role in conferring genetic risk for, and/or protection against, autoimmune Addison's disease.


Assuntos
Doença de Addison/genética , Polimorfismo Genético , Receptores CCR5/química , Receptores de Quimiocinas/genética , Adulto , Idoso , Alelos , Criança , Feminino , Frequência do Gene , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Receptores CCR2
9.
Ann N Y Acad Sci ; 958: 309-11, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12021130

RESUMO

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by autoimmune destruction of pancreatic beta cells. Genetic and environmental factors contribute in this disease. There is evidence that MHC class I chain-related gene (MIC-A) plays a role in the susceptibility to this and other autoimmune diseases. There are five alleles of the MIC-A gene, which consist of different repetitions of GCT. In particular, MIC-A alleles 5 and 5.1 (the former with five repetitions of GCT, the latter with five repetitions and one additional insertion of nucleotide G) have been found to be associated with susceptibility to and age at onset of T1DM. The aim of our study was to analyze the transmission of these MIC-A alleles to T1DM-affected offsprings in HBDI families. These are multiplex families with affected offsprings and unaffected parents. DNA samples were amplified for MIC-A using fluorescence-labeled primers and analyzed on an ABI prism DNA sequencer. The transmission of alleles was then analyzed using pedigrees of families also obtained from HBDI. We analyzed 78 families and found that MIC-A alleles 5 and 5.1 are present and transmitted more frequently than expected. Heterozygotic parents for MIC-A alleles 5 and 5.1 were excluded from the study. Our results suggest that MIC-A alleles 5 and 5.1 are associated with susceptibility to T1DM in family studies.


Assuntos
Alelos , Diabetes Mellitus Tipo 1/genética , Frequência do Gene/genética , Genes MHC Classe I/genética , Antígenos de Histocompatibilidade Classe I/genética , Linhagem Celular , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Núcleo Familiar , Linhagem , Reação em Cadeia da Polimerase
10.
Ann N Y Acad Sci ; 958: 349-52, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12021140

RESUMO

Insulin-dependent diabetes mellitus (IDDM) is one of the most common chronic diseases. It is an autoimmune, polygenic disease, associated with several genes on different chromosomes. The most important gene is human leukocyte antigen (HLA), also known as major histocompatibility complex (MHC), which is located on chromosome 6p21.3. HLA-DQ8/DR4 and DQ2/DR3 are positively associated with IDDM and DQ6 is negatively associated with IDDM in most Caucasian populations. The MICA gene is located in the MHC class I region and is expressed by monocytes, keratinocytes, and endothelial cells. Sequence determination of the MICA gene identifies 5 alleles with 4, 5, 6, and 9 repetitions of GCT or 5 repetitions of GCT with 1 additional insertion (GGCT), and the alleles are referred to as A4, A5, A5.1, A6, and A9. Analysis of allele distribution among 93 Latvian IDDM patients and 108 healthy controls showed that allele A5 of MICA is significantly increased in IDDM patients [33/93 (35%)] compared to healthy controls [22/108 (20%)] (OR = 2.15; P = 0.016). In conclusion, we believe that MICA may play an important role in the etiopathogenesis of IDDM.


Assuntos
Alelos , Diabetes Mellitus Tipo 1/genética , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Antígenos de Histocompatibilidade Classe I/genética , Adolescente , Criança , Pré-Escolar , Feminino , Antígenos HLA-DQ/genética , Humanos , Lactente , Recém-Nascido , Letônia , Masculino , Repetições de Microssatélites/genética
11.
Ann N Y Acad Sci ; 958: 341-4, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12021138

RESUMO

Insulin-dependent diabetes mellitus (IDDM) is a polygenic disorder with an autoimmune basis for disease development. In addition to HLA, a second susceptibility locus for IDDM has been identified to lie in the major histocompatibility class III region. MIC-A is located in the MHC class III region and is expressed by monocytes, keratinocytes, and endothelial cells. Sequence determination of the MIC-A gene identifies trinucleotide repeat (GCT) microsatellite polymorphism in exon 5. Five alleles with 4, 5, 6, and 9 repetitions of GCT or 5 repetitions of GCT with 1 additional nucleotide insertion (GGCT) are identified. The alleles are A4, A5, A5.1, A6, and A9. The aim of our study was to find the association of MIC-A alleles with IDDM, malnutrition-modulated diabetes mellitus (MMDM), and non-insulin-dependent diabetes mellitus (NIDDM) patients. IDDM (n = 52), MMDM (n = 41), NIDDM (n = 212), and healthy controls (n = 73) from Cuttack, in eastern India, were studied. Of the 212 NIDDM patients analyzed, 96 of them were found to be positive for either GAD65 or IA-2 antibodies. Autoantibodies to GAD65 and IA-2 were measured by radioligand binding assay using (35)S-labeled recombinant human GAD65 and IA-2 in an in vitro transcription/translation system. Autoantibody-positive NIDDM patients (n = 96) and adult healthy controls for NIDDM (n = 113) were also compared. These autoantibody-positive NIDDM patients are considered as slow-onset IDDM or latent autoimmune diabetes in adults (LADA) patients. The samples were analyzed for MIC-A by PCR amplification, and fragment sizes were determined in an ABI prism DNA sequencer. The results of the MIC-A typing are: allele 9 of MIC-A is positively associated (OR 3.62; P < 0.001), and allele 4 is negatively associated (OR 0.31; P < 0.05) with MMDM patients compared to controls. Allele 5 is positively associated with IDDM (OR 2.64; P < 0.05) when compared to controls. Allele 5.1 is positively associated in the autoantibody-positive NIDDM patients compared to adult controls. Our findings of a significant increase of allele A9 in MMDM patients compared to healthy controls suggest that MMDM is immunogenetically different from IDDM in eastern India. MIC-A is important in the pathogenesis of MMDM patients from Cuttack. MIC-A alleles distinguish acute-onset IDDM from slow-onset IDDM, indicating that this molecule may be important for delaying the onset of IDDM with the result that these patients are diagnosed clinically as NIDDM.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Antígenos de Histocompatibilidade Classe I/genética , Distúrbios Nutricionais/complicações , Frequência do Gene/genética , Predisposição Genética para Doença , Humanos , Índia , Distúrbios Nutricionais/genética , Reação em Cadeia da Polimerase
12.
Hum Immunol ; 62(10): 1153-8, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11600224

RESUMO

Human papillomaviruses type 16 and 18 are the major cause of cervical cancer. However, genetic factors contribute to the propensity of persistent HPV infection and cervical carcinoma. Allelic variants of the human leukocyte genes have shown to be associated with cervical neoplasia. The strongest associations have been found with the genes in the HLA class II region. The aim of this study was to analyze the association of two non-HLA class II markers with invasive cervical cancer. Microsatellite polymorphism of the TNFA gene located in the class III region and a short tandem repeat polymorphism of the MICA gene located in the centromeric end of the HLA class I region were analyzed. Eighty-five patients and 120 matched control individuals from a population-based cohort from Northern Sweden participated in this nested case-control study. MICA was not associated with cervical carcinoma. TNFa-11 frequency was increased in the HPV18 DNA positive patients (OR = 2.84, p = 0.0481, CI = 1.04-7.78, pc = NS). TNFa-11 was not associated with susceptibility to HPV16 infection, but it increased the risk for cervical cancer with the HLA DQ6 (DQA 1*0102-DQB 1*0602) haplotype. Our findings indicate that the association of TNFA with cervical cancer is different with CIN. The extended HLA DQ6-TNFa-11 haplotype is increasing the risk for development of cervical cancer significantly (OR = 3.08, p = 0.0104, CI = 1.30-7.31).


Assuntos
Genes MHC Classe I , Antígenos de Histocompatibilidade Classe I/genética , Polimorfismo Genético/imunologia , Fator de Necrose Tumoral alfa/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/imunologia , Adulto , Idoso , Alelos , Feminino , Genes MHC da Classe II , Genótipo , Antígenos HLA-DQ/genética , Cadeias alfa de HLA-DQ , Cadeias beta de HLA-DQ , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , Pessoa de Meia-Idade , Papillomaviridae/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/imunologia , Infecções Tumorais por Vírus/genética , Infecções Tumorais por Vírus/imunologia , Neoplasias do Colo do Útero/virologia
13.
J Clin Endocrinol Metab ; 86(8): 3754-60, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11502807

RESUMO

The polymorphism of the major histocompatibility complex class I chain-related A gene is associated with type 1 diabetes mellitus. The major histocompatibility complex class I chain-related A gene 5 allele is significantly more frequent in Caucasian type 1 diabetes mellitus children than in healthy subjects, but no information is available on the association with adult-onset type 1 diabetes mellitus or with the so-called slowly progressive latent autoimmune diabetes of the adult in the same ethnic group. In this study we estimated the frequency of major histocompatibility complex class I chain- related A gene alleles and human leukocyte antigen-DRB1*03-DQA1*0501-DQB1*0201 and human leukocyte antigen-DRB1*04- DQA1*0301-DQB1*0302 in 195 type 1 diabetes mellitus subjects, in 80 latent autoimmune diabetes of the adult subjects, and in 158 healthy subjects from central Italy. Major histocompatibility complex class I chain-related A gene 5 was significantly associated with type 1 diabetes mellitus only in the 1-25 yr age group at diagnosis, and the odds ratio of the simultaneous presence of both major histocompatibility complex class I chain-related A gene 5 and human leukocyte antigen-DRB1*03- DQA1*0501-DQB1*0201 and/or human leukocyte antigen-DRB1*04-DQA1*0301-DQB1*0302 was as high as 54 and higher than 388 when compared with double negative individuals. Adult-onset type 1 diabetes mellitus (age at diagnosis, >25 yr) and latent autoimmune diabetes of the adult were significantly associated with major histocompatibility complex class I chain-related A gene 5.1, which was not significantly increased among diabetic children. Only the combination of major histocompatibility complex class I chain-related A gene 5.1 and human leukocyte antigen-DRB1*03-DQA1*0501-DQB1*0201 and/or human leukocyte antigen-DRB1*04-DQA1*0301-DQB1*0302 conferred increased risk for adult-onset type 1 diabetes mellitus or for latent autoimmune diabetes of the adult. Our study provides demonstration of the existence of distinct genetic markers for childhood/young-onset type 1 diabetes mellitus and for adult-onset type 1 diabetes mellitus/latent autoimmune diabetes of the adult, namely major histocompatibility complex class I chain-related A gene 5 and major histocompatibility complex class I chain-related A gene 5.1, respectively.


Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Antígenos de Histocompatibilidade Classe I/genética , Adolescente , Adulto , Idade de Início , Idoso , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Marcadores Genéticos , Genótipo , Haplótipos , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Sistema de Registros , Fatores de Risco , Suécia/epidemiologia
14.
Cancer Epidemiol Biomarkers Prev ; 9(10): 1067-70, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11045789

RESUMO

HLA genes have been shown to be associated with cervical intraepithelial neoplasia (CIN), a precursor of cervical cancer. The human papillomaviruses (HPV) types 16 and 18 are the major environmental cause of this disease. Because the immune system plays an important role in the control of HPV infection, the association of polymorphic HLA could lead to a different immune response to control the development of cervical cancer. The aim of this study was to analyze the association between CIN and a microsatellite polymorphism of tumor necrosis factor (TNFa) taking HPV exposure and CIN-associated HLA haplotypes into account. In a nested case-control study in northern Sweden, 64 patients and 147 controls matched for age and sex and derived from the same population-based cohort were typed for TNFA, HLA-DR, and DQ and assayed for antibodies to HPV types 16 and 18. TNFa polymorphism was not associated with CIN per se. However, there was a significant increase in the frequency of TNFa-11 among HPV16-positive and HLA DR15-DQ6 (B*0602) patients compared with HPV16- and HLA-DQ6-negative patients (odds ratios, 5.4 and 9.3, respectively). The relative risk for CIN conferred by the combination of TNFa-11, HLA-DQ6, and HPV 16 positivity was 15. Our study suggests that the TNFa-11 allele is associated with HPV16 infection and associated with CIN in combination with HLA-DQ6 but not by itself.


Assuntos
Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/complicações , Polimorfismo Genético , Fator de Necrose Tumoral alfa/genética , Infecções Tumorais por Vírus/complicações , Displasia do Colo do Útero/genética , Displasia do Colo do Útero/virologia , Neoplasias do Colo do Útero/genética , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Humanos , Repetições de Microssatélites/genética , Medição de Risco , Suécia/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/virologia , Displasia do Colo do Útero/epidemiologia
15.
Diabetologia ; 43(4): 507-14, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10819246

RESUMO

AIMS/HYPOTHESIS: A distinct family of MHC genes has been identified in the class III region and denominated MHC Class I chain-related genes (MIC). The MIC-A gene is located between the TNFA and the HLA-B genes. The aim of our study was to test the association of the polymorphism of the MIC-A gene with Type I (insulin-dependent) diabetes mellitus and evaluate the interaction between MIC-A and TNFA, HLA-B, HLA-DR and HLA-DQ gene polymorphism. METHODS: Type I diabetic (n =95) and healthy (n = 98) Italian subjects were typed for exon 5 of MIC-A and for HLA-DRB1, HLA-DQA1, HLA-DQB1 and TNFA alleles. All subjects were also typed for the presence of HLA-B8 or HLA-B15. RESULTS: The frequency of MIC-A5 was increased in diabetic subjects (53 % vs 15 %) (OR = 6.1) (corrected p, p(c) < 0.0005). Among HLA class II haplotypes, both HLA-DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) and DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8) ("at-risk class II haplotypes") were positively associated with diabetes (OR = 6.7 and 6.0, respectively) (p(c) < 0.003). Also HLA-B8 was more frequent among Type I diabetic subjects than among healthy control subjects (OR = 2.8, p = 0.01). None of the TNFA alleles were statistically significantly associated with Type I diabetes. The MIC-A5 exon was negatively associated with age at clinical onset of diabetes (p = 0.012). Thus, 68 % diabetic subjects younger than 25 years and 29 % older than 25 years were carrying this allele. Both MIC-A5 and the at-risk class II haplotypes were independently associated with Type I diabetes and the combined association of the two markers had the highest relative risk (OR = 172). In subjects younger than 25 years, the OR of MIC-A5 was as high as 21.7 and was more than twofold that of at-risk class II haplotypes (OR = 9.5). The MIC-A5 exon was not in linkage disequilibrium with any of the HLA-class I, class II or TNFA alleles studied. CONCLUSIONS/INTERPRETATION: The MIC-A gene polymorphism is associated with genetic risk for Type I diabetes and the combination of MIC-A5 and at-risk class II haplotypes is now to be seen as the strongest genetic marker for this disease.


Assuntos
Diabetes Mellitus Tipo 1/genética , Antígenos de Histocompatibilidade Classe I/genética , Polimorfismo Genético , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Antígenos HLA-B/genética , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Haplótipos , Humanos , Itália , Masculino , Pessoa de Meia-Idade
16.
Hum Immunol ; 60(10): 970-3, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10566597

RESUMO

Cervical intraepithelial neoplasia (CIN) is associated with human papillomaviruses (HPV) and the HLA genes. The MICA (MHC class I chain-related gene A) is expressed by keratinocytes and epithelial cells and interacts with gamma delta T cells. It is therefore possible that MICA might influence the pathogenesis of CIN and cervical cancer through presentation of viral or tumor antigens. To investigate this, we determined the MICA transmembrane allele frequencies in a prospective population-based cohort study from the Västerbotten County in northern Sweden. 74 women developed CIN. 153 control women who remained healthy during follow up were matched for age. Five polymorphic microsatellite alleles of MICA were identified by a polymerase chain reaction-based (PCR) technique using fluorescent-labeled primers. MICA A5 and A5.1 were the most common alleles in this population. None of the alleles of MICA were associated with disease. The frequency of MICA allele A5 was higher among HPV 18 seropositive than HPV 18 seronegative patients but this difference was not significant after the correction of p value. In conclusion, microsatellite allele polymorphism of MICA transmembrane part is not associated with cervical intraepithelial neoplasia.


Assuntos
Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe I/genética , Polimorfismo Genético , Displasia do Colo do Útero/genética , Éxons , Feminino , Frequência do Gene , Antígenos HLA-DQ/isolamento & purificação , Humanos , Repetições de Microssatélites , Papillomaviridae/isolamento & purificação , Estudos Prospectivos , Suécia/epidemiologia , Repetições de Trinucleotídeos , Displasia do Colo do Útero/epidemiologia , Displasia do Colo do Útero/etiologia
17.
J Clin Endocrinol Metab ; 84(10): 3701-7, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10523017

RESUMO

The major histocompatibility complex class I chain-related MIC-A and MIC-B genes are located on chromosome 6 between the histocompatibility leucocyte antigen (HLA)-B and the B-associated transcript genes. The presence of 21-hydroxylase autoantibodies is a sensitive and specific marker of autoimmune Addison's disease. We studied the polymorphism of exon 5 of the MIC-A gene, of intron 1 of the MIC-B gene, and of HLA-DRB1, -DQA1, and -DQB1 genes in 28 autoimmune (21-hydroxylase autoantibody positive) Addison's disease patients and in 75 healthy subjects from central Italy. The MIC-A5.1 allele was significantly more frequent in Addison's disease patients (79%) than in healthy subjects (36%) [odds ratio (OR) = 6.52, corrected P (Pc) = 0.0015], whereas MIC-A6 was significantly reduced in affected subjects (15% vs. 56%, OR = 0.13, Pc = 0.002). The A5.1/A5.1 genotype had an OR for autoimmune Addison's disease as high as 18.0 and an absolute risk of 1 per 1131. In the presence of MIC-A5.1, MICB-CA-25 was significantly increased in Addison's disease patients (25% vs. 4%, OR = 8.0, P = 0.0039, Pc = 0.047). The MICB-CA-17 allele was absent in Addison's disease patients, but present in more than 25% healthy individuals (OR = 0.10, P = 0.0025, Pc = 0.03). Among HLA-DR and -DQ haplotypes, only DRB1*03-DQA1*0501-DQB1*0201 (DR3/DQ2) was significantly more frequent in Addison's disease patients than in healthy subjects, but only in the presence of MIC-A5.1. The frequency of MIC-A5.1 was significantly increased in Addison's disease patients only in the presence of HLA-DR3-DQ2. Our study demonstrates that susceptibility to autoimmune Addison's disease is linked to the MIC-A microsatellite allele 5.1 and that both MIC-A5.1 and HLA-DR3/DQ2 are necessary to confer increased genetic risk for Addison's disease.


Assuntos
Doença de Addison/genética , Doenças Autoimunes/genética , Genes MHC Classe I/genética , Antígenos de Histocompatibilidade Classe I/genética , Polimorfismo Genético/genética , Adolescente , Adulto , Idoso , Criança , Feminino , Genótipo , Antígenos HLA-DQ/genética , Cadeias alfa de HLA-DQ , Cadeias beta de HLA-DQ , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Fatores de Risco
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