RESUMEN
Alpha-subunit of the IL-2 receptor (IL-2Rα) encoded by the IL2RA/CD25 gene binds IL-2 that plays a pivotal role in the regulation of T cell function. Levels of a soluble form of IL-2Rα (sIL-2Rα) lacking the transmembrane and cytoplasmic domains were shown to be increased in several autoimmune diseases including Graves' disease (GD). Recent studies showed association between the IL2RA/CD25 gene variants and several autoimmune diseases including GD. In this study, we analyzed whether polymorphic markers rs2104286, rs41295061, and rs11594656 located at the IL2RA/CD25 locus confer susceptibility to GD and are related to increased concentrations of sIL-2Rα. A total of 1474 Russian GD patients and 1609 control subjects were genotyped for rs2104286, rs41295061, and rs11594656 using a Taqman assay. Concentrations of sIL-2Rα in sera of affected and non-affected individuals were measured using an ELISA test. A minor allele A of rs41295061 showed significant association with increased risk of GD [odds ratio (OR) = 1.43, P(c) = 0.00102]. The allele A of rs41295061 and allele A of rs11594656 constitute a higher risk haplotype AA (OR = 1.47, P(c) = 0.0477). Compared to carriers of the protective haplogenotype GT/GT, the carriage of two copies of the haplogenotype AA/AA was associated with elevated levels of sIL-2Rα in both GD patients (AA/AA versus GT/GT: 1.35 ± 0.47 ng/ml versus 1.12 ± 0.45 ng/ml, P = 0.0065) and healthy controls (AA/AA versus GT/GT: 0.67 ± 0.28 ng/ml versus 0.51 ± 0.33 ng/ml, P = 0.0098). This is the first report presenting correlation between the carriage of disease-associated variants of IL2RA/CD25 with increased levels of sIL-2Rα in GD.
Asunto(s)
Enfermedad de Graves/genética , Enfermedad de Graves/inmunología , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Adolescente , Adulto , Estudios de Casos y Controles , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Enfermedad de Graves/sangre , Enfermedad de Graves/epidemiología , Humanos , Subunidad alfa del Receptor de Interleucina-2/genética , Subunidad alfa del Receptor de Interleucina-2/inmunología , Masculino , Polimorfismo Genético , Federación de RusiaRESUMEN
Investigated within the case study are parameters of disbalance of lineage (HC) for 4 micro-satellite locuses of human genome: LPL, CD4, vWA and vWFII. The above locuses are widely used, both in Russia and abroad, in molecular-genetic applications for personality identification. Meanwhile, according to cytogenetics criteria, CD4, vWA and vWFII, are located close to each other in the telomeric region 12pter-12p12 in the short chromosome 12 arm, therefore their potential genetic interdependence is still a topical issue. We found a reliable HC between locuses vWA and vWFII. Locus CD4 did not display HC with locuses vWA and vWFII or with locus LPL. The latter, which is located in chromosome 8 and which must have been negative control for HC, was shown to have no HC with any of the studied markers. Such results correlate well with data on the relative physical localization of CD4, vWA, vWFII and LPL. Multiplication of frequency of alleles (genotypes) is not acceptable in typing locuses vWA and vWFII within one multi-locus panel due to the genetic linkage of these markers demonstrated within the present case study, which is an important practical conclusion.
Asunto(s)
Cromosomas Humanos/genética , ADN/análisis , Medicina Legal , Ligamiento Genético , Repeticiones de Microsatélite/genética , Polimorfismo Genético , Alelos , Secuencia de Bases , Mapeo Cromosómico , Genética de Población , Humanos , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Federación de RusiaRESUMEN
Graves' disease (GD) is a complex autoimmune thyroid disorder with a strong genetic component. Genome-wide screens resolved several susceptibility loci that contribute to the development of GD. One of the susceptibility loci (GD-1 locus) was mapped on chromosome 14q31. However, a susceptibility gene located within the GD-1 locus remains undefined. Here we screen eighteen single nucleotide polymorphisms (SNPs), each is situated at a corresponding positional candidate gene, located within the GD-1 susceptibility locus on chromosome 14q23-q32, for predisposition to GD using the transmission disequilibrium test in 126 simplex Russian families affected with GD. Among SNPs tested, a significant preferential transmission of the Ala allele (41 transmissions vs. 17 nontransmissions, corrected P=0.031) of the Thr92Ala SNP within the DIO2 gene, encoding type II iodothyronine deiodinase, from parents to affected children was found in a Russian family data set. The Thr92Ala SNP of the DIO2 gene and the D727E substitution of the thyrotropin receptor (TSHR) gene have been found to be in pair-wise linkage disequilibrium. The A92/E727 haplotype showed significant preferential transmission from parents to affected sibling (17 transmissions vs. 8 nontransmissions, P=0.039) in simplex families. This suggests that the Thr92Ala variant of the DIO2 gene is associated or may be in linkage disequilibrium with a functional DIO2 polymorphism which involves in the development of GD in a Russian population.
Asunto(s)
Cromosomas Humanos Par 14/genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Enfermedad de Graves/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Mapeo Cromosómico , Cartilla de ADN , Femenino , Haplotipos/genética , Humanos , Yoduro Peroxidasa/genética , Desequilibrio de Ligamiento , Masculino , Receptores de Tirotropina/genética , Federación de Rusia , Yodotironina Deyodinasa Tipo IIRESUMEN
BACKGROUND: Oxidative stress is involved in the origin of type 1 diabetes. Low efficiency of the scavenging antioxidant system has been shown to be related to the pathogenesis of the disease. This, therefore suggests that genes encoding catalase and other antioxidant enzymes may implicate in the development of type 1 diabetes. METHODS: Nine microsatellite markers that cover about 10 megabases around the catalase (CAT) gene on chromosome 11p13 were analyzed using polymerase chain reaction (PCR) and fluorescence-based genotyping on an automatic DNA sequencer. We also evaluated three single-nucleotide polymorphisms (SNP) within genes encoding catalase (T1667T and C(-262)T dimorphism) and ETS homologous factor (EHF) (C255T SNP) using a PCR-restriction fragment-length polymorphism approach. Multipont linkage analysis in 37 affected sibling pairs was performed using GENEHUNTER 2.1. We examined the markers for association with the disease by transmission disequilibrium tests in 57 discordant sibling pairs and by a case-control study in 258 unrelated healthy donors and 247 affected patients. RESULTS: We obtained close-to-suggestive evidence of linkage to type I diabetes, with the maximum linkage peak between markers D11S907 and D11S2008. Analysis of three SNPs at the CAT and EHF gene located within the region of maximum linkage showed that T1667T and C(-262)T markers of the CAT gene are strongly associated with the disease. CONCLUSION: Our findings support evidence of a new putative type 1 diabetes susceptibility locus on chromosome 11p13 and suggest that the CAT gene may play a role in conferring susceptibility to the disorder in Russian patients.
Asunto(s)
Catalasa/genética , Cromosomas Humanos Par 11 , Diabetes Mellitus Tipo 1/genética , Predisposición Genética a la Enfermedad , Adulto , Alelos , ADN/sangre , Femenino , Ligamiento Genético , Humanos , Masculino , Estrés Oxidativo , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Federación de RusiaRESUMEN
BACKGROUND: Previous research has found that depression is a major cause of memory complaints. However, there is evidence that memory complaints also weakly predict cognitive decline and dementia. The present study examined a range of possible determinants of memory complaints, covering psychiatric and personality factors, medical history, cognitive test performance, and biological risk factors for dementia (APOE genotype, hippocampus and amygdala volumes, and white-matter hyperintensities). METHOD: A community survey was carried out with 2546 persons aged 60-64 years living in Canberra and Queanbeyan, Australia. Participants were asked about memory problems which interfered with daily life and whether medical help had been sought. A randomly selected subsample of 476 persons was given a brain MRI scan. RESULTS: Participants with memory complaints were found to have poorer memory test performance, more depression and anxiety symptoms, have higher scores on personality traits involving negative affect, and to have worse physical health. Multivariate analyses showed that measures of cognitive performance did not make a unique contribution to the prediction of memory complaints above that of the other categories of predictors. Those with memory complaints did not differ on any of the biological risk factors for dementia. CONCLUSION: In a community sample aged 60-64 years, memory complaints were most closely related to psychiatric symptoms, personality characteristics and poor physical health. There was no evidence of brain changes indicating early dementia.
Asunto(s)
Trastornos de la Memoria/genética , Trastornos de la Memoria/fisiopatología , Trastornos Mentales/complicaciones , Personalidad , Amígdala del Cerebelo/anatomía & histología , Amígdala del Cerebelo/patología , Apolipoproteínas E/genética , Trastornos del Conocimiento/complicaciones , Estudios Transversales , Demencia/complicaciones , Femenino , Estado de Salud , Hipocampo/anatomía & histología , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos de la Memoria/etiología , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Autoimmune thyroid disease (AITD) occurs in two common forms: Graves' disease and Hashimoto thyroiditis. On the basis of functional and experimental data, it has been suggested that the gene encoding cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a candidate gene for conferring susceptibility to thyroid autoimmunity. In this review, we critically evaluate the evidence for pathogenetic involvement of CTLA-4 in the various forms of AITD and focus on the possible role of genetic variation of the CTLA4 locus. Population genetics data strongly suggest a role for the CTLA4 region in susceptibility to AITD. However, further functional studies are required to understand the significance of CTLA4 polymorphisms in the pathogenic mechanism of AITD.
Asunto(s)
Antígenos de Diferenciación/genética , Linfocitos T/inmunología , Tiroiditis Autoinmune/genética , Tiroiditis Autoinmune/inmunología , Antígenos CD , Antígeno CTLA-4 , Predisposición Genética a la Enfermedad/genética , Variación Genética , Enfermedad de Graves/inmunología , Humanos , Fragmentos Fc de Inmunoglobulinas/inmunología , Polimorfismo GenéticoRESUMEN
Basedow-Graves disease is an autoimmune thyroid syndrome. Genetic factors contribute to the pathogenesis of Graves disease, and current findings confirm that a number of genes may be involved in the development of autoimmune thyrotoxicosis. At present three loci, namely human leukocyte antigen (HLA, 6p21.3), cytotoxic T-lymphocyte-associated esterase-4 (CTLA4, 2q33), and thyroid-stimulating hormone receptor (TSHR, 14q31), are the only well-known genetic determinants for Graves disease. It is difficult to determine clearly the contribution of large multifunctional proteasome genes and transporter genes associated with antigen processing in the disorder, because of strong linkage disequilibrium between these genes and certain HLA alleles. Two recently discovered suspectibility loci, 20q11.2 and Xq21.33-q22, should be studied to find specific genes linked to Graves disease.
Asunto(s)
Enfermedad de Graves/genética , Inmunoconjugados , Abatacept , Antígenos CD , Antígenos de Diferenciación/genética , Antígeno CTLA-4 , Enfermedad de Graves/inmunología , Antígenos HLA/genética , Humanos , Desequilibrio de Ligamiento , Repeticiones de Minisatélite , Mutación , Receptores de Tirotropina/genéticaRESUMEN
Graves disease is complex autoimmune thyrotoxicosis. A number of genes may contribute to the development of the disorder. Some of them may be genes that encode cytotoxic T-lymphocyte-associated serine esterase-4 (CTLA4), subunit 2 of large multifunctional protease (LMP2), thyroid-stimulating hormone receptor (TSHR), and interleukin 1 receptor antagonist (IL1RN). We studied polymorphism of Ala17Thr CTLA4, H60R LMP2, Pro52Thr TSHR, and IL1RN-VNTR in healthy controls (n = 93) and patients with Graves disease (n = 78) using PCR. To study CTLA4, H60R, and TSHR polymorphism, PCR products were digested with MboI, Hin6I and PsyI, respectively. Comparative analysis using chi(2) test showed significant differences in allele and genotype frequency of Ala17Thr polymorphic marker between the two groups studied. Thus, the CTLA4 gene may be involved in the pathogenesis of Graves disease in a Moscow population.
Asunto(s)
Antígenos de Diferenciación/genética , Enfermedad de Graves/genética , Inmunoconjugados , Polimorfismo Genético/genética , Receptores de Tirotropina/genética , Sialoglicoproteínas/genética , Proteínas de la Matriz Viral/genética , Abatacept , Adulto , Alelos , Sustitución de Aminoácidos , Antígenos CD , Antígeno CTLA-4 , ADN/análisis , Femenino , Frecuencia de los Genes , Marcadores Genéticos , Genotipo , Humanos , Proteína Antagonista del Receptor de Interleucina 1 , Masculino , Mutación , Reacción en Cadena de la Polimerasa , Mapeo RestrictivoRESUMEN
The allele and genotype frequency distributions of the D11S2008 tetranucleotide microsatellite linked with the catalase (CAT) gene were compared between patients with insulin-dependent diabetes mellitus (IDDM) with (N = 72) and without (N = 82) coronary heart disease (CHD), and between IDDM patients with normal arterial tension (N = 82) and with arterial hypertension (N = 42). In total, eight alleles were found. The alleles varied in length from 120 to 148 bp and included from 15 to 22 tetranucleotide repeats. The groups did not differ in D11S2008 allele and genotype frequencies; the only exception was that the frequency of genotype 18/19 in patients with CHD (31.9%) was significantly higher than in the controls (18.3%). Thus, the D11S2008 polymorphic locus located in proximity to the catalase gene proved to be weakly associated with CHD, but not associated with arterial hypertension, in IDDM patients. Genotype 18/19 was associated with a higher risk of CHD.
Asunto(s)
Catalasa/genética , Mapeo Cromosómico , Diabetes Mellitus Tipo 2/genética , Hipertensión/genética , Isquemia Miocárdica/genética , Polimorfismo Genético , Secuencia de Bases , Cartilla de ADN , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/enzimología , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Hipertensión/complicaciones , Hipertensión/metabolismo , Moscú , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/enzimología , Reacción en Cadena de la PolimerasaRESUMEN
The groups of patients with myocardial infarction (MI) and hypertrophy of the left ventricle (HLV) (n = 45 and n = 53, respectively) and a sample of healthy individuals from the Moscow population (n = 60) were examined for T174M polymorphism of AGT gene (replacement of methionine for threonine at position 174 of the correspondent amino acid sequence). In MI patients the content of TT genotypes and T allele was significantly lower than in the control group (57.8% against 80% and 67.9 against 89.2%, respectively), whereas the proportion of M allele and TM heterozygotes was increased (32.1 against 10.8% and 37.8 against 18.3%, respectively). In patients with HLV, the proportion of TT genotype (64.2%) and T allele (77.4%) was also lower than in the control group, whereas the frequency of M allele was increased (22.6%). Our results suggest that the T174M polymorphism of AGT gene is associated with MI and HLV in the Moscow population.
Asunto(s)
Angiotensinógeno/genética , Hipertrofia Ventricular Izquierda/genética , Infarto del Miocardio/genética , Polimorfismo Genético , Adulto , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , MoscúRESUMEN
Essential hypertension is a widespread multifactorial pathology which is probably controlled by numerous genes. Twenty to forty percent of hypertension may be genetically determined. In this review, polymorphism of three group of candidate genes is analyzed. Products of these genes are most likely involved in hypertension development. These are the genes controlling the renin-angiotensin system, ionic channels, and nitric oxide system and NO-synthase.
Asunto(s)
Marcadores Genéticos , Hipertensión/genética , Humanos , Hipertensión/fisiopatología , Minerales/metabolismo , Óxido Nítrico/fisiología , Óxido Nítrico Sintasa/genética , Polimorfismo Genético , Sistema Renina-Angiotensina/genética , Factores de RiesgoRESUMEN
In samples from populations of the cities of Moscow and Tomsk, analysis of allelic polymorphism of microsatellite loci HUMF13A01 and HUMCD4 was performed by polymerase chain reaction (PCR). Eight HUMCD4 alleles (115-165 bp) and nine alleles (180-230 bp) of locus HUMF13A01 were identified. In both populations, the distributions of allelic frequencies for these loci did not differ significantly. The distribution of observed genotype frequencies fitted Hardy-Weinberg equilibrium in both populations. Mendelian inheritance of these tandem repeats was demonstrated by analysis of two large families. Parameters of polymorphism information content (PIC) for the loci studied were detected; comparative analysis of allelic frequencies with similar data on several populations was performed. These short tandem repeats (STR) were proposed for use in personal identification and paternity tests.