RESUMEN
BACKGROUND: Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. METHODS: Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. RESULTS: Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 × 10-2) and IL4 (rs2070874; HR 1.22; p-value = 1.1 × 10-3) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 × 10-2). CONCLUSIONS: This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.
Asunto(s)
Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Mutación de Línea Germinal , Interleucina-4/genética , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/mortalidad , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Ensayos Clínicos como Asunto , Estudios de Cohortes , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias de la Próstata/patología , Tasa de SupervivenciaRESUMEN
BACKGROUND: Recent genome-wide studies identified several genetic variants associated with blood lipid level alterations. Because affected lipid metabolism can confer risk to the development of ischaemic stroke, we studied three polymorphisms reportedly associated with triglyceride-level changes, rs17145738 and rs3812316 of the MLXIPL locus, and rs4846914 variant of GALNT2 gene in biobanked samples of patients with stroke. This pool of samples was previously investigated for haplotype tagging minor alleles of apolipoprotein A5 gene (T-1131C, T1259C, IVS3+G476A and C56G), and an association was found between the minor allele carriage and the triglyceride levels, and also these variants were found to confer risk to the development of stroke. METHODS: Here, a total of 467 patients with stroke, stratified as large vessel, small vessel and mixed stroke groups, and 156 control subjects were genotyped using PCR-RFLP methods. RESULTS: In the current study, we could not verify association of the variants analyzed either with triglyceride and total cholesterol levels or with the risk of ischaemic stroke susceptibility. CONCLUSIONS: The data presented here revealed differentiated risk nature of the triglyceride level modifying natural gene variants.
Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Isquemia Encefálica/metabolismo , N-Acetilgalactosaminiltransferasas/metabolismo , Accidente Cerebrovascular/metabolismo , Triglicéridos/sangre , Anciano , Alelos , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Isquemia Encefálica/genética , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , N-Acetilgalactosaminiltransferasas/genética , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple , Estadísticas no Paramétricas , Accidente Cerebrovascular/genética , Polipéptido N-AcetilgalactosaminiltransferasaRESUMEN
Recently, associations were found between several autoimmune diseases and functional variants of interleukin-23 receptor (IL23R) gene; here, we studied the possible association of nine polymorphisms of IL23R with ankylosing spondylitis (AS) and with Sjögren syndrome (SS). In our study, we genotyped groups of patients with AS (n = 206), SS (n = 156) and healthy controls (n = 235) for rs11805303, rs10889677, rs1004819, rs2201841, rs11209032, rs11209026, rs10489629, rs7517847 and rs7530511 variants using PCR-RFLP methods. We observed significant increase in the carriage of the T allele of rs11805303 and the A allele of rs1004189 in the AS group compared with the controls. For the rs10889677 variant, the prevalence of the AA genotype and for the rs2201841, the CC genotype showed a more than two-fold increase in the AS group compared with the controls. By contrast, the GA heterozygous genotype of rs11209026 variant showed a significant decrease in AS patients compared with controls. Haplotype analysis revealed association of four IL23R haplotypes with AS. There was no difference in the distribution of any of the examined IL23R variants between controls and SS patients. In conclusion, we confirmed the susceptibility or protective associations of IL23R polymorphisms with AS in a Hungarian population and first demonstrated the involvement of the rs11805303 intronic single nucleotide polymorphisms, which was tested so far only for other autoimmune diseases.
Asunto(s)
Predisposición Genética a la Enfermedad , Receptores de Interleucina/genética , Síndrome de Sjögren/genética , Espondilitis Anquilosante/genética , Genotipo , Humanos , Hungría , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVES: Recently, an association was found between Crohn's disease and the interleukin-23 receptor (IL-23R) gene. Since the IL-23/IL-17 pathway is known to associate with other autoimmune diseases, including rheumatoid arthritis (RA) and systemic sclerosis (SSc), we hypothesised that IL-23R could be a shared susceptibility gene. METHODS: Groups of patients with rheumatoid arthritis (n = 412), systemic sclerosis (n = 224), Crohn's disease (n = 190) and healthy controls (n = 220) were genotyped for rs10889677 (exon-3'UTR C2370A), rs2201841, and rs1884444 variants; the first two have been shown to confer risk for Crohn's disease. RESULTS: We observed an increased prevalence of the homozygous rs10889677 AA and homozygous rs2201841 CC genotypes both in the Crohn's disease and in the RA groups as compared to the controls (12.1%, 11.9% vs 5.91%, p<0.05; and 13.2%, 13.1% vs 5.91%, p<0.05), but not in the SSc patients. Logistic regression analysis revealed that bearing these alleles represent risk for the development of rheumatoid arthritis (chi(2) = 5.58, p = 0.018, OR = 2.15, 95% CI 1.14-4.06 for rs10889677; and chi(2) = 7.45, p = 0.006, OR = 2.40, 95% CI 1.28-4.51 for rs2201841). The rs1884444 allele, which has been previously reported as neutral for development of Crohn's disease, was also found neutral for all studied groups in the present study. CONCLUSIONS: The data reported here provide direct evidence that some allelic variants or haplogroups of IL-23R represent independent risk factors for rheumatoid arthritis as well as Crohn's disease, but not for scleroderma.
