RESUMEN
Our study investigated the underlying mechanism for the 14q24 renal cell carcinoma (RCC) susceptibility risk locus identified by a genome-wide association study (GWAS). The sentinel single-nucleotide polymorphism (SNP), rs4903064, at 14q24 confers an allele-specific effect on expression of the double PHD fingers 3 (DPF3) of the BAF SWI/SNF complex as assessed by massively parallel reporter assay, confirmatory luciferase assays, and eQTL analyses. Overexpression of DPF3 in renal cell lines increases growth rates and alters chromatin accessibility and gene expression, leading to inhibition of apoptosis and activation of oncogenic pathways. siRNA interference of multiple DPF3-deregulated genes reduces growth. Our results indicate that germline variation in DPF3, a component of the BAF complex, part of the SWI/SNF complexes, can lead to reduced apoptosis and activation of the STAT3 pathway, both critical in RCC carcinogenesis. In addition, we show that altered DPF3 expression in the 14q24 RCC locus could influence the effectiveness of immunotherapy treatment for RCC by regulating tumor cytokine secretion and immune cell activation.
Asunto(s)
Carcinoma de Células Renales/genética , Cromosomas Humanos Par 14 , Proteínas de Unión al ADN/genética , Sitios Genéticos , Neoplasias Renales/genética , Factor de Transcripción STAT3/genética , Factores de Transcripción/genética , Carcinogénesis/genética , Carcinogénesis/inmunología , Carcinogénesis/patología , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/terapia , Línea Celular Tumoral , Cromatina/química , Cromatina/inmunología , Ensamble y Desensamble de Cromatina/inmunología , Citocinas/genética , Citocinas/inmunología , Proteínas de Unión al ADN/inmunología , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Genoma Humano , Estudio de Asociación del Genoma Completo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunoterapia/métodos , Neoplasias Renales/inmunología , Neoplasias Renales/patología , Neoplasias Renales/terapia , Polimorfismo de Nucleótido Simple , Factor de Transcripción STAT3/inmunología , Linfocitos T Citotóxicos , Factores de Transcripción/inmunologíaRESUMEN
Polycystic ovary syndrome (PCOS) is one of the most common endocrine-metabolic disorders in women of reproductive age. It is characterized by an increase in the biosynthesis of androgens, anovulation, and infertility. PCOS has been reported as a polygenic entity in which multiple single nucleotide polymorphisms (SNPs) are associated with the clinical features of the pathology. Herein, we describe the common polymorphic variants in genes related to PCOS, their role in its pathogenesis, and etiology. Whole-genome association studies have been focused on women from Asian and European populations. The most common genes associated with PCOS are DENND1A, THADA, FSHR, and LHCGR. However, other genes have been associated with PCOS such as AMH, AMHR2, ADIPOQ, FTO, HNF1A, CYP19, YAP1, HMGA2, RAB5B, SUOX, INSR, and TOX3. Nevertheless, the relationship between the biological functions of these genes and the development of the pathology is unclear. Studies in each gene in different populations do not always comply with a general pattern, so researching these variants is essential for better understanding of this polygenic syndrome. Future population studies should be carried out to evaluate biological processes, incidence rates, allelic and genotypic frequencies, and genetic susceptibility factors that predispose PCOS.
Asunto(s)
Síndrome del Ovario Poliquístico/genética , Polimorfismo de Nucleótido Simple , Femenino , Predisposición Genética a la Enfermedad , Humanos , Fenotipo , Síndrome del Ovario Poliquístico/diagnóstico , Síndrome del Ovario Poliquístico/fisiopatología , Medición de Riesgo , Factores de RiesgoRESUMEN
Joint destruction in rheumatoid arthritis (RA) is heritable, but knowledge on specific genetic determinants of joint damage in RA is limited. We have used the Immunochip array to examine whether genetic variants influence variation in joint damage in a cohort of Mexican Americans (MA) and European Americans (EA) with RA. We studied 720 MA and 424 EA patients with RA. Joint damage was quantified using a radiograph of both hands and wrists, scored using Sharp's technique. We conducted association analyses with the transformed Sharp score and the Immunochip single nucleotide polymorphism (SNP) data using PLINK. In MAs, 15 SNPs from chromosomes 1, 5, 9, 17 and 22 associated with joint damage yielded strong p-values (p < 1 × 10(-4) ). The strongest association with joint damage was observed with rs7216796, an intronic SNP located in the MAP3K14 gene, on chromosome 17 (ß ± SE = -0.25 ± 0.05, p = 6.23 × 10(-6) ). In EAs, 28 SNPs from chromosomes 1, 4, 6, 9, and 21 showed associations with joint damage (p-value < 1 × 10(-4) ). The best association was observed on chromosome 9 with rs59902911 (ß ± SE = 0.86 ± 0.17, p = 1.01 × 10(-6) ), a synonymous SNP within the CARD9 gene. We also observed suggestive evidence for some loci influencing joint damage in MAs and EAs. We identified two novel independent loci (MAP3K14 and CARD9) strongly associated with joint damage in MAs and EAs and a few shared loci showing suggestive evidence for association.