RESUMO
The aim of the study was to identify the features of the genetic structure of myocardial infarction (MI) susceptibility depending on age ("early MI" denoting individuals who had the first MI before the age of 60 years, and "late MI" the group of patients with the first "MI after 60 years"). A total of 355 patients were examined (n = 121 early MI and n = 234 late MI) and 285 residents of the Siberian region (as a control group). Genotyping of 58 single nucleotide variants (SNPs) was performed using mass spectrometry using the Agena (ex Sequenom) MassARRAY® System. Statistical analysis was performed using Statistica 8.0 ("StatSoft Inc.", USA), as well as the "stats" and "genetics" packages in the R environment. The regulatory potential of SNPs was evaluated using the rSNPBase online service (http://rsnp.psych.ac.cn/). eQTL loci were identified using data from the Genotype-Tissue Expression (GTEx) project (http://www.gtexportal.org/) and the Blood eQTL online service (https://genenetwork.nl/bloodeqtlbrowser/). The GG genotype of ITGA4 rs1143674, the CC genotype of CDKN2B-AS1 rs1333049, and the CC genotype of KIAA1462 rs3739998, are generally associated with MI. The AA genotype of ADAMDEC1 rs3765124 (OR = 2.03; 95% CI 1.23-3.33; p = 0.004) and the GG genotype of AQP2 rs2878771 (OR = 2.24; 95% CI 1.23-4.09; p = 0.006) are associated with the development of MI at an early age, and the TT genotype of TAS2R38 rs1726866 (OR = 1.82; 95% CI 1.11-2.89; p = 0.009) was the high-risk genotype for the late MI. Genetic variants associated with MI are regulatory SNP (rSNP) and affect the affinity of DNA binding to transcription factors, carry out post-transcriptional control of gene activity and change the level of gene expression in various tissues. Thus, early and late MI are based on both common genetic variants of ITGA4, CDKN2B-AS1, KIAA1462 genes and specific ones (ADAMDEC1 and AQP2 for early MI and TAS2R38 for late MI).
Assuntos
Predisposição Genética para Doença , Infarto do Miocárdio/genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
OBJECTIVES: To study associations between genes of different functional classes, including fibrogenesis genes, with coronary atherosclerosis and specific features of its course. METHODS: We included in this study 404 patients with confirmed chronic ischemic heart disease (IHD) who had undergone coronary artery bypass grafting. Two groups of participants were distinguished - those with (n=188) and without (n=216) history of myocardial infarction (MI). Control group consisted of inhabitants of the Siberia region (n=285). Associations were analyzed using 48 single nucleotide polymorphisms (SNP) located in genes earlier determined as associated with diseases of the cardiovascular continuum (diabetes mellitus, MI, atherosclerosis). Multiplex genotyping was performed using mass spectrometry. For statistical analyses we used Statistica v8.0 and R-language with "stats" and "genetics" packages. RESULTS: We identified several genetic markers contributing to susceptibility to development of atherosclerosis. Same markers were identified as determinants of the character of the course of atherosclerotic disease. Risk of development of atherosclerosis was higher in carriers of the following genotypes: TT of ITGB5 gene (rs1007856) - by 1.6 times (OR=1.59; Ñ=0.0153); GG of ITGA4 gene - by 1.85 times (OR=1.85; Ñ=0.0016); GG of IGFBP7 gene (rs11133482) - by 2.4 times (OR=2.36; Ñ=0.0031). The following genotypes were identified as protective against MI and determining stable course of the disease: AA of TLR4 gene (rs4986790) (OR=0.47; Ñ=0.0104).; CC of LDLR gene (rs2738446) (OR=0,53; Ñ=0.0041); GG of OAS1 gene (rs1131454) (OR=0.50; Ñ=0.0274). CONCLUSION: Susceptibility to coronary atherosclerosis and prognosis of disease progression were found to be associated with polymorphism of certain genes, involved in metabolism of the extracellular matrix and processes of fibrogenesis (ADAMDEC1, ITGA4, ITGB5, CDKN2B-AS1, IGFBP7), lipid metabolism (LDLR), immune system functioning (TLR4, OAS1) and DNA repair (LIG1).
Assuntos
Aterosclerose , Doença da Artéria Coronariana , Infarto do Miocárdio , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , SibériaRESUMO
A group of patients with ischemic heart disease and myocardial infarction (N = 156) and a reference population sample (N = 300) were genotyped for 58 single nucleotide polymorphisms (SNPs) in the genes involved in extracellular matrix function and collagen metabolism or associated with cardiovascular diseases and atherosclerotic plaque stability. Genotyping was performed by mass-spectrometry with two multiplex sets of 27 and 31 SNPs. The study revealed different genetic composition of predisposition to cardiovascular disease continuum (CVDC) syntropy (patients with concomitant conditions: hypercholesterolemia, hypertension, and type-II diabetes mellitus, N = 96) and to isolated myocardial infarction (without these conditions, N = 60). Only the KIAA1462 gene (rs3739998) showed associations with both CVDC syntropy (OR = 1.71; 95% CI 1.19-2.45; Ñ = 0.003) and isolated infarction (OR = 1.58; 95% CI 1.05-2.40; Ñ = 0.028). Isolated myocardial infarction was also associated with LIG1 (rs20579) (OR = 2.08; 95% CI 1.06-4.17; Ñ = 0.028) and ADAMDEC1 (rs3765124) (OR = 1.63; 95% CI 1.07-2.50; Ñ = 0.020). CVDC syntropy was associated with CDKN2BAS1 (rs1333049) (OR = 1.48; 95% CI 1.03-2.12; Ñ = 0.029) and APOA2 (rs5082) (OR = 1.47; 95% CI 1.02-2.11; Ñ = 0.035). So, genes involved in fibrogenesis contribute to predisposition to the myocardial infarction as well. Isolated myocardial infarction and CVDC syntropy can be considered as pathogenetically different cardiovascular conditions, with different genes that contribute to the susceptibility.
Assuntos
Predisposição Genética para Doença , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
For identification of somatic mitochondrial DNA (mtDNA) mutations, the mtDNA major noncoding region (D-loop) sequence in blood samples and carotid atherosclerosis plaques from patients with atherosclerosis was analyzed. Five point heteroplasmic positions were observed in 4 of 23 individuals (17%). Only in two cases could heteroplasmy have resulted from somatic mutation, whereas three heteroplasmic positions were found in both vascular tissue and blood. In addition, length heteroplasmy in a polycytosine stretches was registered at nucleotide positions 303-315 in 16 individuals, and also in the 16184-16193 region--in four patients. The results suggest that somatic mtDNA mutations can occur during atherosclerosis, but some heteroplasmic mutations may appear in all tissues, possibly being inherited.
Assuntos
Aterosclerose/genética , Artérias Carótidas/patologia , DNA Mitocondrial/genética , Placa Aterosclerótica/genética , Idoso , DNA Mitocondrial/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/genética , Placa Aterosclerótica/sangue , Placa Aterosclerótica/patologia , Mutação Puntual/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
AIM: to study associations of polymorphic genetic variants of inflammatory response, endothelial function, lipid metabolism, and blood coagulation with impaired renal function in patients with ST elevation myocardial infarction (STEMI). MATERIAL AND METHODS: We enrolled in the study 171 patients admitted to the Kemerovo Cardiology Dispensary within 24 hours after onset of STEMI. All patients underwent genotype identification of 25 polymorphic variants of 18 major candidate genes for cardiovascular disease. Genotyping was performed with DNA chip SINKAR-1 (Institute of Medical Genetics and LLC "Genomic Diagnosis"). Glomerular filtration rate (GFR) was estimated using serum creatinine level measured at admission. RESULTS: Comparison of allelic and genotype frequencies of the studied polymorphisms revealed that angiotensin-converting enzyme (ACE) gene rs4291 was associated with decreased GFR: odds ratio (OR) for carriers of rare TT genotype was 2.31 [1.01-5.25], =0.043. Analysis of genotype combinations of ACE rs4343 polymorphism and hepatic lipase gene (LIPC) rs1800588 showed that AA genotype of rs4343 polymorphism in combination with CC genotype of rs1800588 polymorphism was associated with lowest risk of renal dysfunction, whereas GG and AG genotypes of ACE rs4343 in combination with TT and CT genotypes of LIPC rs1800588.
Assuntos
Taxa de Filtração Glomerular , Infarto do Miocárdio com Supradesnível do Segmento ST , Alelos , Doenças Cardiovasculares , Genótipo , Taxa de Filtração Glomerular/genética , Humanos , Razão de Chances , Polimorfismo Genético , Infarto do Miocárdio com Supradesnível do Segmento ST/genética , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologiaRESUMO
We have performed association analysis for mtDNA most common variants and haplogroups with myocardial infarction and some prognostic characteristics in patients. Comparison of patients (N=406) and controls (N=183) has shown higher frequency of HV0 haplogroup in patients (6.9% vs. 2.2%; p=0.033). Patients with early infarction (before age 55), comparing to patiens older than 55 and the first infarction, had higher frequency of 16189C variant (24.1 vs. 12.5%; p=0.008); also, haplogroup U2e was registered only in the subgroup with early infarction (4.4%; p=0.004). On the other side, haplogroup U5 was less frequent in the patients with early infarction (5.1% vs. 15.4%; p=0.002). The patients with recurring cardiovascular incidents during one year follow-up had higher frequency of haplogroup H1 (20% versus 4.5% in the patients without complications, p=0.002) and variant 16189C (30% versus 13.5%; p=0.018). Haplogroup U5 was more frequent in the group of patients with left ventricular ejection fraction less than 40%: 17.1% comparing to 8.2% in the group with ejection fraction>40%; p=0.034. The results suggest that mtDNA polymorphism contributes to coronary atherosclerosis. The associations could be explained by the polymorphism effect on oxidative phosphorylation and reactive oxygen production in mitochondria.
Assuntos
Aterosclerose/genética , DNA Mitocondrial/genética , Infarto do Miocárdio/genética , Polimorfismo Genético , Idoso , Estudos de Casos e Controles , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
In this review, the development of ideas focused on the phenomenon of disease combination (comorbidity) in humans is discussed. The genetic bases of the three forms of the phenomenon, comorbidity (syntropias), inverse comorbidity (dystropias), and comorbidity of Mendelian and multifactorial diseases, are analyzed. The results of personal genome-wide association studies of the genetic risk profile that may predispose an individual to cardiovascular disease continuum (CDC), including coronary heart disease, type 2 diabetes, hypertension, and hypercholesterolemia (CDC syntropy), as well as the results of bioinformatic analysis of common genes and the networks of molecular interactions for two (bronchial asthma and pulmonary tuberculosis) diseases rarely found in one patient (dystropy), are presented. The importance of the diseasome and network medicine concepts in the study of comorbidity is emphasized. Promising areas in genomic studies of comorbidities for disease classification and the development of personalized medicine are designated.
Assuntos
Doença das Coronárias/genética , Complicações do Diabetes/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Hipercolesterolemia/genética , Hipertensão/genética , Comorbidade , HumanosRESUMO
The variability of potentially important functional polymorphic variants rs2069705 (5'UTR of the IFNG gene), rs17880053 (near 5'UTR of the IFNGR2), rs11126176 (LOC100287361 pseudogene), and rs804271 (near 5'UTR of the NEIL2 gene) was characterized in representatives of four ethnic groups living in the Siberian region. These ethnic groups included three indigenous Mongoloid ethnic groups (Yakuts, the residents of the Republic of Sakha (Yakutia), Tuvinians from the Republic of Tuva, and Buryats from the Republic Buryatia) and the alien Russian population. All of the examined variants were polymorphic. The frequency of the rs2069705 allele C in Russians was 0.5833, while it was in a range from 0.7842 to 0.8967 in representatives of the indigenous populations. The frequency of rs17880053 deletion was 0.8073 in Russians and from 0.4474 to 0.5521 in the indigenous ethnic groups. The frequency of the rs11126176 allele A was equal to 0.5398 in Russians but was recorded with lower frequencies in indigenous ethnic groups (from 0.2722 to 0.4551). The frequency of the rs804271 allele Gwas 0.5215 in Russians and from 0.2527 to 0.4022 indigenous ethnic groups. With respect to the genotype structure, the alien Russian population was considerably distanced from indigenous Mongoloid populations. Specifically, the genetic distance was 0.0742 between Russians and Yakuts, 0.1365 between Russians and Tuvinians, and 0.1433 between Russians and Buryats. Among the Mongoloid indigenous ethnic groups of Siberia, Tuvinians and Yakuts were the most distant from each other (0.0262). The genetic distance was equal to 0.0151 between Yakuts and Buryats and 0.0127 between Buryats and Tuvinians.
Assuntos
DNA Glicosilases/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Etnicidade/genética , Interferon gama/genética , Receptores de Interferon/genética , Alelos , Povo Asiático , Variação Genética , Genética Populacional , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Pseudogenes/genética , SibériaRESUMO
The first data on the existence of multiple genomic rearrangements, such as copy number variation (CNV) and copy neutral loss of heterozygosity, in vascular tissues and peripheral blood leukocytes from patients with atherosclerosis, are presented. Compared to internal mammary arteries and peripheral blood leukocytes, right coronary arteries in the atherosclerotic plaque area presented with a higher CNV length and number of genes located in their vicinity. In each of the patients, 6-16% of CNVs were common to the three types of tissues examined. Therefore, most of the copy number variations in the tissues affected by atherosclerosis (from 68 to 91% in each of the patients) were of somatic origin. The gains in 3p21.31 (CACNA2D2), 7q32.1 (FLNC), 19p13.3 (C19orf29, PIP5K1C), and 21q22.3 (COL6A1) were detected in vascular tissues but not in peripheral blood leukocytes. Moreover, the gain in 7p15.2 (SKAP2), detected in the patients with atherosclerosis, did not overlap with any CNV regions currently reported in The Database of Genomic Variants. The loss of heterozygosity in 12 out of 13 chromosomal regions was copy neutral and covered tumor suppressor genes (SFRP1, CEBPD, RB1CC1, DIRAS3, TUSC3, and ZDHHC2).
Assuntos
Aterosclerose/genética , Cromossomos Humanos/genética , Variação Genética , Leucócitos , Artéria Torácica Interna , Idoso , Bases de Dados Genéticas , Dosagem de Genes , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The distribution of the allele and genotype frequency for the TOMM40 gene polymorphic variants rs741780, rs157580, rs1160985, rs2075650, and rs8106922 was analyzed in a sampling of ethnic Russians from the city of Kemerovo. The study of the structure of linkage disequilibrium in terms of five studied polymorphic variants showed the presence ofa haplotype block 2 Kb in length, which includes three polymorphic variants, i.e., rs741780, rs1160985, and rs8106922. The differences in the frequencies of alleles and genotypes in terms of the polymorphic rs2075650 and rs157580 variants between ethnic Russians from the city of Kemerovo and other European populations were detected. It was discovered that polymorphic variants of TOMM40 rs741780, rs1160985, and rs8106922 are associated with serum triglyceride concentrations. In men, the polymorphic variant rs2075650 is associated with low-density lipoprotein cholesterol levels. In women, the polymorphic variant rs741780 is associated with diastolic blood pressure levels.
Assuntos
Estudos de Associação Genética , Metabolismo dos Lipídeos/genética , Proteínas de Membrana Transportadoras/genética , Triglicerídeos/sangue , Adulto , LDL-Colesterol/sangue , Etnicidade/genética , Feminino , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Polimorfismo de Nucleotídeo Único , Federação RussaRESUMO
BACKGROUND: Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. OBJECTIVE: To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. METHODS: In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. RESULTS: We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms(SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P < 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1BSNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. CONCLUSIONS AND CLINICAL RELEVANCE: DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.
Assuntos
Índice de Massa Corporal , Estudo de Associação Genômica Ampla , Adolescente , Adulto , Idoso , Alelos , Asma/complicações , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
To date the question of epigenetic mechanisms of gene regulation in the context of cardiovascular diseases is of a considerable interest. Here, for the first time DNA methylation profiles of vascular tissues of atherosclerotic patients have been analyzed with using the microarray Infinium HumanMethylation27 BeadChip ("Illumina", USA). As the result, within 286 genes 314 CpG-sites that varied significantly in the DNA methylation level between the tissue samples of carotid (in the area of atherosclerotic plaques and nearby macroscopically intact tissues of the vascular wall) and mammary arteries as well saphenous veins have been identified. The most pronounced differences in the methylation level were registered for CpG-sites of homeobox genes HOXA2 and HOXD4 as well as imprinted gene MEST. In particular, these genes were found to be hypomethylated in the carotid atherosclerotic plaques compared to their methylation patterns in intact tissues of internal mammary arteries and saphenous veins.
Assuntos
Aterosclerose/metabolismo , Ilhas de CpG , Metilação de DNA , Artéria Torácica Interna/metabolismo , Veia Safena/metabolismo , Aterosclerose/genética , Aterosclerose/patologia , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Artéria Torácica Interna/patologia , Pessoa de Meia-Idade , Proteínas/genética , Proteínas/metabolismo , Veia Safena/patologiaRESUMO
Calcineurin pathway plays the critical role in the cardiac remodeling of various origin, development of chambers dilatation and progression of heart failure. Components of calcineurin pathway are involved in myocardium hypertrophy regulation, angiogenesis and apoptosis. Results of quantitative expression profiling study of main calcineurin pathway genes PPP3CA, PPP3R1, PPP3CB, GATA4 and NFATC4 in myocardium of right atrium auricle of patients with a coronary heart disease, exposed to various types of surgical treatments depending on weight of a clinical finding (surgical reconstruction of the geometry of left ventricle (LV) (postinfarction aneurysm) or coronary artery bypass grafting in case of unaltered morphology of LV) are presented. In patients with sizable postinfarction LV dilatation (n = 21) expression level of calcineurin catalytic subunit genes PPP3CA and PPP3CB was 1.3 and 1.6 times lower (p = 0.018 and 0.023, accordingly) compared to patients with unaltered shape of the heart (n = 34). Expression level of PPP3R1 gene encoding calcineurin regulatory subunit B and GATA4 and NFATC4 genes for transcription factors did not differ in studied subgroups of patients. Thus, lower expression of PPP3CA and PPP3CB genes in atrium myocardium can be related to expressed postinfarction LV remodeling. Further studies of relation quantitative expression profiling of calcineurin pathway genes with the level of damage of myocardium is essential what may have important outcome for the prevention of adverse events of cardiosurgical treatments in patients with postinfarction remodeling.
Assuntos
Calcineurina/biossíntese , Regulação da Expressão Gênica , Proteínas Musculares/biossíntese , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Transdução de Sinais , Remodelação Ventricular , Idoso , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/patologia , Isquemia Miocárdica/cirurgia , Miocárdio/patologiaRESUMO
The frequency of the polymorphic variant T196C (Leu33Pro, rs5918) of ITGB3 gene was studied in several groups of inhabitants of Siberia, including pregnant women with reproductive disorders (n = 186), patients with acute coronary syndrome (n = 330), and population control (n = 858). The frequency of the rare PLA2 allele among residents of Tomsk and Kemerovo was 14.7 and 15.0% respectively. There were no differences in the allele and genotype frequencies of polymorphic variant between patients with acute coronary syndrome and the control group (p = 0.925, p = 0.622). The highest frequency of abnormal PLA2 allele (22.1%) and the PLA2/PLA2 genotype (8.8%) was observed among women, who had miscarried, which was significantly different from the frequency of this allele and genotype in the control group (14.7%, p = 0.017; 2.1%, p = 0.0009). Sequencing showed that all samples with the nonspecific band had the polymorphic rs5918 variant and rs36080296 mutations (T216G, Leu66Arg). The frequency of the rs36080296 mutation among the residents of Siberia was 0.51%. Among the women with reproductive disorders, the frequency of rs36080296 was 2.7%, while in the group who suffered from miscarriages, it was 4.4%; this was different from the frequency in the control group (0.08%, p = 0.2 x 10(-6)). The accumulation of mutations was also observed among men with acute coronary syndrome (0.6%), but the differences from the control group (0%) had no statistical significance.
Assuntos
Síndrome Coronariana Aguda/genética , Infertilidade Feminina/genética , Integrina beta3/genética , Aborto Espontâneo/genética , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Humanos , Masculino , Polimorfismo Genético , Gravidez , SibériaRESUMO
Analysis of association of allergic rhinitis with the KCNE4 gene rs12621643 variant was conducted in Russian residents of Western Siberia (taking into account comorbidity with bronchial asthma). It was found that, among individuals without bronchial asthma, the frequencies of the KCNE4*G allele and KCNE4*G/G genotype are significantly higher in patients with rhinitis compared to individuals without it. At the same time, no association of rs12621643 with rhinitis was detected in the group of individuals with bronchial asthma. The data obtained indicate the association of the KCNE4 gene variability with allergic rhinitis, although the effect of this gene relative to the development of the disease can be leveled against a background of the manifestation of another atopic disease.
Assuntos
Asma/epidemiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Rinite Alérgica Perene/epidemiologia , Rinite Alérgica Perene/genética , Adulto , Asma/genética , Comorbidade , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Rinite Alérgica , Sibéria/epidemiologiaRESUMO
AIM: To investigate the role of polymorphic variants of immune-response modifying genes in predisposition to asthma. PATIENTS AND METHODS: The analysis of restriction fragments length polymorphism was used to investigate 10 single-nucleotide polymorphisms: IFNG rs2069705, IFNGR2 rs17880053, IL4 rs 2070874, IL4RA rs 1805010, GATA3 rs10905277, TBX21 rs11652969, PIASY rs3760903, PIAS3 rs12756687, STATS rs16967593, and SOCS5 rs6737848 in 106 asthma patients and 115 healthy people. RESULTS: The rs6737848 SOCS5 polymorphism was significantly associated with asthma in additive model (p = 0.05, OR = 0.338, 95% CI 0.158-0.723) and in dominant model (p = 0.02, OR = 0.284, CI 0.126-0.638). None of the polymorphisms of the studied genes was associated with total IgE levels. CONCLUSIONS: This is the first report on the association of rs6737848 SOCS5 with asthma.
Assuntos
Asma/genética , DNA/genética , Predisposição Genética para Doença , Polimorfismo Genético , Proteínas Supressoras da Sinalização de Citocina/genética , Adolescente , Adulto , Idoso , Asma/metabolismo , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Adulto JovemRESUMO
A sample of 165 patients with myocardial infarction (MI) with ST segment elevation has been studied to construct a prediction model for one-year period complications (recurrent nonfatal IM or cardiac death). Polymorphic genetic markers (n = 32) with confirmed role in pathogenesis of cardiovascular disease were analyzed. The best model to stratify patients by risk of post-IM complications included variants rs4291 (A-240T) in the ACE gene, rs6025 (G1691A, Leiden mutation) in the F5, and rs5918 (Leu59Pro) in the IGTB3. C statistics for the genetic model was 0.75 (0.64; 0.86), p = 0.001, which is comparable with characteristics of the GRACE scale for the same patients' population: 0.73 (0.61; 0.85). Thereby, analysis of a limited number of genetic markers was sufficient to create risk prediction model for post-MI complications with comparable effectiveness to the model, which is currently in use in clinical practice. To confirm the clinical validity, the predictive model obtained in the study should be evaluated in independent samples of MI patients. Association analysis of individual genetic markers with patients' outcomes has revealed that T allele carrier status (AT and TT genotypes) rs4291 of the ACE and CG genotype rs328 of the LPL gene are risk factors for cardiac death during one year after MI; Leiden mutation (rs6025) of the F5 gene is related to the higher risk of recurrent non-fatal MI or death during one year; CC genotype of the rs10811661, located in 9p21 locus has a protective effect against recurrent MI or death within one year after acute event.
Assuntos
Marcadores Genéticos/genética , Predisposição Genética para Doença , Infarto do Miocárdio/genética , Polimorfismo Genético , Medição de Risco/métodos , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade/tendências , Infarto do Miocárdio/epidemiologia , Prognóstico , Fatores de Risco , Sibéria/epidemiologia , Fatores de TempoRESUMO
The structure of diseases in humans is heterogeneous, which is manifested by various combinations of diseases, including comorbidities associated with a common pathogenetic mechanism, as well as diseases that rarely manifest together. Recently, there has been a growing interest in studying the patterns of development of not individual diseases, but entire families associated with common pathogenetic mechanisms and common genes involved in their development. Studies of this problem make it possible to isolate an essential genetic component that controls the formation of disease conglomerates in a complex way through functionally interacting modules of individual genes in gene networks. An analytical review of studies on the problems of various aspects of the combination of diseases is the purpose of this study. The review uses the metaphor of a hermeneutic circle to understand the structure of regular relationships between diseases, and provides a conceptual framework related to the study of multiple diseases in an individual. The existing terminology is considered in relation to them, including multimorbidity, polypathies, comorbidity, conglomerates, families, "second diseases", syntropy and others. Here we summarize the key results that are extremely useful, primarily for describing the genetic architecture of diseases of a multifactorial nature. Summaries of the research problem of the disease connection phenomenon allow us to approach the systematization and natural classification of diseases. From practical healthcare perspective, the description of the disease connection phenomenon is crucial for expanding the clinician's interpretive horizon and moving beyond narrow, disease-specific therapeutic decisions.
RESUMO
In this study we genotyped polymorphism in GPX1 Pro198Leu (C > T) rs 1050450 in four groups: patients with coronary artery disease, long-livers - above 90 years, early died peoples (before 55 years) from cardiovascular diseases and Russian population as control group. We have found significant higher allele T frequency in men with coronary artery disease -34.84% (Chi2 = 5.228, p = 0.022; OR = 1.46) and in early died men from cardiovascular diseases--38.16% (Chi2 = 6.461, p = 0.011; OR = 1.69) compared with control men--26.8%. Moreover, significantly higher genotype TT frequency has been shown in patients with coronary artery disease and myocardial infarction before age 50--19.44% in comparison with control group--7.28% (Chi2 = 9.55, p = 0.002). The TT frequency in long-livers (4.39%) was the lowest and significantly different from coronary artery disease group--12.79% (Chi2 = 8.07, p = 0.0045) and from coronary artery disease subgroup with myocardial infarction before 50--19.44% (Chi2 = 14.49, p = 0.0001). Thus our results indicate that allele T (Leu) of GPX1 Pro198Leu (C > T) polymorphism is unfavorable for successful ageing. It predisposes to coronary heart disease, earlier myocardial infarction (before age 50) and earlier death (before age 55).
Assuntos
Doença da Artéria Coronariana/genética , Glutationa Peroxidase/genética , Longevidade/genética , Infarto do Miocárdio/genética , População Branca , Fatores Etários , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Doença da Artéria Coronariana/mortalidade , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Federação Russa , Glutationa Peroxidase GPX1RESUMO
Analysis of the genome-specific linkage disequilibrium patterns in certain populations is a highly promising approach to the identification of functional variants that underlie susceptibility to complex diseases. In the present study, the linkage disequilibrium patterns of the methylenetetrahydrofolate reductase gene (MTHFR) were examined in a group of patients with coronary atherosclerosis (coronary artery disease, CAD) and in a control sample from the Russian population. It was demonstrated that in the samples from one population, which were differentiated by the presence or absence of CAD, the MTHFR linkage disequilibrium patterns had similar features. Association of the MTHFR rs7533315 and rs2066462 polymorphisms with CAD was demonstrated. In addition, the evolution of the haplotypes and their role in the formation of CAD in the Russian population was reconstructed. The data on the association between genetic variability in the MTHFR locus and pathogenetically important indices of lipid metabolism were obtained. The high informativeness of the haplotype approach in case-control tests for associations with CAD was demonstrated.