RESUMEN
Chronic obstructive pulmonary disease (COPD) is a major health burden in adults and cigarette smoking is considered the most important environmental risk factor of COPD. Chromosome 15q25.1 locus is associated with both COPD and smoking. Our study aims at understanding the mechanism underlying the association of chromosome 15q25.1 with COPD through epigenetic and transcriptional variation in a population-based setting. To assess if COPD-associated variants in 15q25.1 are methylation quantitative trait loci, epigenome-wide association analysis of four genetic variants, previously associated with COPD (P < 5 × 10-8) in the 15q25.1 locus (rs12914385:C>T-CHRNA3, rs8034191:T>C-HYKK, rs13180:C>T-IREB2 and rs8042238:C>T-IREB2), was performed in the Rotterdam study (n = 1489). All four variants were significantly associated (P < 1.4 × 10-6) with blood DNA methylation of IREB2, CHRNA3 and PSMA4, of which two, including IREB2 and PSMA4, were also differentially methylated in COPD cases and controls (P < 0.04). Further additive and multiplicative effects of smoking were evaluated and no significant effect was observed. To evaluate if these four genetic variants are expression quantitative trait loci, transcriptome-wide association analysis was performed in 1087 lung samples. All four variants were also significantly associated with differential expression of the IREB2 3'UTR in lung tissues (P < 5.4 × 10-95). We conclude that regulatory mechanisms affecting the expression of IREB2 gene, such as DNA methylation, may explain the association between genetic variants in chromosome 15q25.1 and COPD, largely independent of smoking.
Asunto(s)
Metilación de ADN/genética , Proteína 2 Reguladora de Hierro/genética , Complejo de la Endopetidasa Proteasomal/genética , Enfermedad Pulmonar Obstructiva Crónica/genética , Receptores Nicotínicos/genética , Anciano , Cromosomas Humanos Par 15/genética , Fumar Cigarrillos/efectos adversos , Fumar Cigarrillos/genética , Femenino , Regulación de la Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Sitios de Carácter Cuantitativo/genética , Factores de RiesgoRESUMEN
OBJECTIVE: Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism. METHODS: We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage. RESULTS: We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10-10) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10-9) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three additional studies, which resulted in a highly significant association between the MGP variant and hand OA (rs4764133, Betameta=0.83, Pmeta=1.8*10-15). This variant is high linkage disequilibrium with a coding variant in MGP, a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was significantly lowercompared with the MGP RNA expression of the reference allele (40.7%, p<5*10-16). CONCLUSIONS: Our results indicate that the association between the MGP variant and increased risk for hand OA is caused by a lower expression of MGP, which may increase the burden of hand OA by decreased inhibition of cartilage calcification.
Asunto(s)
Proteínas de Unión al Calcio/genética , Cartílago Articular/patología , Proteínas de la Matriz Extracelular/genética , Predisposición Genética a la Enfermedad/genética , Articulaciones de la Mano/patología , Osteoartritis/genética , Adulto , Anciano , Alelos , Calcinosis/genética , Proteínas Portadoras/genética , Proteínas del Citoesqueleto , Femenino , Expresión Génica/genética , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Persona de Mediana Edad , Factores de Riesgo , Análisis de Secuencia de ARN , Proteína Gla de la MatrizRESUMEN
Osteoarthritis (OA), the most prevalent form of arthritis in the elderly, is characterized by the degradation of articular cartilage and has a strong genetic component. Our aim was to identify genetic variants involved in risk of knee OA in women. A pooled genome-wide association scan with the Illumina550 Duo array was performed in 255 controls and 387 cases. Twenty-eight variants with p < 1 x 10(-5) were estimated to have probabilities of being false positives Asunto(s)
Ciclooxigenasa 2/genética
, Variación Genética
, Osteoartritis de la Rodilla/enzimología
, Osteoartritis de la Rodilla/genética
, Anciano
, Anciano de 80 o más Años
, Alelos
, Secuencia de Bases
, Estudios de Casos y Controles
, Condrocitos/enzimología
, Estudios de Cohortes
, Cartilla de ADN/genética
, Femenino
, Predisposición Genética a la Enfermedad
, Genómica
, Fosfolipasas A2 Grupo IV/genética
, Humanos
, Desequilibrio de Ligamiento
, Persona de Mediana Edad
, Análisis de Secuencia por Matrices de Oligonucleótidos
, Polimorfismo de Nucleótido Simple
, ARN Mensajero/genética
, Factores de Riesgo
