RESUMEN
Pneumonia is a common and severe infectious lung disease. Host genetics, together with underlying medical and lifestyle conditions, determine pneumonia susceptibility. We performed a secondary analysis of the results of two genome-wide studies for pneumonia in 23andMe participants (40 600 cases/90 039 controls) (Tian et al., 2017) and UK Biobank (BB) participants (12 614 cases/324 585 controls) (via the Global Biobank Engine) and used the GTEx database to correlate the results with expression quantitative trait loci (eQTLs) data in lung and whole blood. In the 23andMe pneumonia single nucleotide polymorphism (SNP) set, 177 genotyped SNPs in the human leukocyte antigen (HLA) region satisfied the genome-wide significance level, P ≤ 5·0E-08. Several target genes (e.g. C4A, VARS2, SFTA2, HLA-C, HLA-DQA2) were unidirectionally regulated by many HLA eSNPs associated with a higher risk of pneumonia. In lung, C4A transcript was up-regulated by 291 pneumonia risk alleles spanning the half the HLA region. Among SNPs correlated with the expression levels of SFTA2 and VARS2, approximately 75% overlapped: all risk alleles were associated with VARS2 up-regulation and SFTA2 down-regulation. To find shared gene loci between pneumonia and pulmonary function (PF), we used data from the Global Biobank Engine and literature on genome-wide association studies (GWAS) of PF in general populations. Numerous gene loci overlapped between pneumonia and PF: 28·8% in the BB data set and 49·2% in the 23andMe data set. Enrichment analysis within the database of Genotypes and Phenotypes (dbGaP) and National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) Catalog of pneumonia and pneumonia/PF gene sets identified significant overlap between these gene sets and genes related to inflammatory, developmental, neuropsychiatric and cardiovascular and obesity-related traits.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Pulmón/metabolismo , Neumonía/genética , Polimorfismo de Nucleótido Simple , Adulto , Expresión Génica , Estudios de Asociación Genética , Genotipo , Antígenos HLA/genética , Humanos , Pulmón/patología , Fenotipo , Sitios de Carácter Cuantitativo/genética , Valina-ARNt Ligasa/genéticaRESUMEN
Oncologists have pointed out an urgent need for biomarkers that can be useful for clinical application to predict the susceptibility of patients to preoperative therapy. This review collects, evaluates and combines data on the influence of reported somatic and germline genetic variations on histological tumor regression in neoadjuvant settings of rectal and esophageal cancers. Five hundred and twenty-seven articles were identified, 204 retrieved and 61 studies included. Among 24 and 14 genetic markers reported for rectal and esophageal cancers, respectively, significant associations in meta-analyses were demonstrated for the following markers. In rectal cancer, major response was more frequent in carriers of the TYMS genotype 2 R/2 R-2 R/3 R (rs34743033), MTHFR genotype 677C/C (rs1801133), wild-type TP53 and KRAS genes. In esophageal cancer, successful therapy appeared to correlate with wild-type TP53. These results may be useful for future research directions to translate reported data into practical clinical use.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Mutación de Línea Germinal , Terapia Neoadyuvante , Variantes Farmacogenómicas , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/genética , Quimioterapia Adyuvante , Distribución de Chi-Cuadrado , Neoplasias Esofágicas/patología , Estudios de Asociación Genética , Genotipo , Humanos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Oportunidad Relativa , Fenotipo , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias del Recto/patología , Factores de Riesgo , Timidilato Sintasa/genética , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Host genetic variations may influence a changing profile of biochemical markers and outcome in patients with trauma/injury. The objective of this study was to assess clinical associations of single nucleotide polymorphisms (SNPs) in the genes of cytokines in critically ill patients. A total of 430 patients were genotyped for SNPs in the genes of pro- (IL1B, IL6, IL8) and anti-inflammatory (IL4, IL10, IL13) cytokines. The main end-points were sepsis, mortality and adult respiratory distress syndrome (ARDS). We evaluated the dynamic levels of bilirubin, blood urea nitrogen, creatine kinase, creatinine and lactate dehydrogenase in five points of measurements (between 1 and 14 days after admission) and correlated them with SNPs. High-producing alleles of proinflammatory cytokines protected patients against sepsis (IL1B -511A and IL8 -251A) and mortality (IL1B -511A). High-producing alleles of anti-inflammatory cytokines IL4 -589T and IL13 431A (144Gln) were less frequent in ARDS patients. The carriers of IL6 -174C/C genotypes were prone to the increased levels of biochemical markers and acute kidney and liver insufficiency. Genotype-dependent differences in the levels of biochemical indicators gradually increased to a maximal value on the 14th day after admission. These findings suggest that genetic variability in pro- and anti-inflammatory cytokines may contribute to different clinical phenotypes in patients at high risk of critical illness.
Asunto(s)
Enfermedad Crítica , Citocinas/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Adulto , Biomarcadores , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Pronóstico , Síndrome de Dificultad Respiratoria/genética , Síndrome de Dificultad Respiratoria/mortalidad , Sepsis/genética , Sepsis/mortalidad , Adulto JovenRESUMEN
Pelvic organ prolapse (POP) represents a urologic and gynecological disease, the development of which is governed both by environmental and genetic factors. We describe the results of our association study of polymorphic variants of genes involved in the assembly of elastic fibrils, namely, the lysyl oxidase protein 1 (LOXL1) and fibulin-3 (FBLN3) genes. We revealed an association of the rs2304719-T allele and rs2165241 (C)-rs2304719(T)-rs893821(T) haplotype of the LOXL1 gene with an increased risk of POP development, as well as a weak association with the disease of the rs3791660-C allele and the rs3791679(T)- rs1367228(A)-rs3791660(C)-rs2033316(A) haplotype of the FBLN3 gene.
Asunto(s)
Alelos , Haplotipos , Prolapso de Órgano Pélvico/genética , Polimorfismo Genético , Anciano , Tejido Elástico , Femenino , Humanos , Persona de Mediana EdadRESUMEN
Oxidative stress may play a role in the recurrent miscarriage (RM) with no known etiology. This study was conducted to investigate the association of polymorphisms in oxidative stress-related genes with idiopathic RM. A total of 331 idiopathic RM patients and 197 controls were genotyped for ABCB1 rs1045642, CYP1A1 rs1048943 and rs4646903, COMT rs4680, CAT rs17880664, GCLC rs17883901, GPX4 rs713041, NRF2 rs6721961, SOD2 rs4880, and OGG1 rs1052133. A protective effect of COMT rs4680-G allele on RM was shown in individual SNP analysis: P = 0.0016, OR = 0.47, 95% CI 0.29-0.75. The multi-factor dimensionality reduction (MDR) approach revealed gene-gene interactions for ABCB1, COMT, GPX4, and OGG1 genes. Cumulative gene risk score analysis demonstrated that more than three risk alleles in the genes ABCB1 (rs1045642-T), COMT (rs4680-A), GPX4 (rs713041-T), and OGG1 (rs1052133-G) were associated with idiopathic RM P = 1.2 × 10(-3), OR = 1.97, 95% CI 1.31-2.97. In silico data interpreting by GeneMANIA analysis revealed genetic, physical, pathway, and coexpression networks for these four genes.
Asunto(s)
Aborto Habitual/etiología , Estrés Oxidativo/genética , Aborto Habitual/genética , Adulto , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , EmbarazoRESUMEN
The study included 243 patients with acute community-acquired pneumonia and 173 healthy subjects. The following candidate loci were used to investigate genetic variability: 3 sites of CYP1A1, GSTM1, GSTT1, GSTP1, ACE gene of the rennin-angiotensin system, chemokine receptor gene CCR5. Enhanced predisposition to pneumonia was shown to be characteristic of homozygotes in deletion at the ACE locus (OR = 1.8; p = 0.013), carriers of normal alleles of the GSTM1 locus (OR = 1.7; p = 0.010), and homozygotes in allele 606T of the CYP1A1 gene (OR = 1.6; p = 0.020).
Asunto(s)
Infecciones Comunitarias Adquiridas/genética , Predisposición Genética a la Enfermedad , Neumonía/genética , Adulto , Infecciones Comunitarias Adquiridas/fisiopatología , Citocromo P-450 CYP1A1/genética , Femenino , Interacción Gen-Ambiente , Estudios de Asociación Genética , Pruebas Genéticas , Glutatión Transferasa/genética , Humanos , Masculino , Peptidil-Dipeptidasa A/genética , Neumonía/fisiopatología , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo de Nucleótido Simple , Receptores CCR5/genética , Índice de Severidad de la EnfermedadRESUMEN
This study presents the results of research on DNA polymorphism in children with malignant brain tumors (172 patients, 183 in the control group). Genotyping was performed using an allele-specific tetraprimer reaction for the genes of the first (CYP1A1 (2 sites)) and second phases of xenobiotic detoxication (GSTM1, GSTT1, GSTP1, GSTM3), DNA repair genesXRCC1, XPD(2 sites),OGG1, as well asNOS1andMTHFR.The increased risk of disease is associated with a minor variant ofCYP1A1(606G) (p = 0.009; OR = 1.50) and a deletion variant ofGSTT1, (p = 0.013, OR = 1.96). Maximum disease risk was observed in carriers of double deletions inGSTT1-GSTM1(p = 0.017, OR = 2.42). The obtained results are discussed in reference to literary data on the risk of malignant brain tumor formation in children and adults.