RESUMEN
BACKGROUND: Rare sequence variants in at least five genes are known to cause monogenic obesity. In this study we aimed to investigate the prevalence of, and characterize, rare coding and splice site variants in LEP, LEPR, MC4R, PCSK1 and POMC in patients with morbid obesity and normal weight controls. METHOD: Targeted next-generation sequencing of all exons in LEP, LEPR, MC4R, PCSK1 and POMC was performed in 485 patients with morbid obesity and 327 normal weight population-based controls from Norway. RESULTS: In total 151 variants were detected. Twenty-eight (18.5%) of these were rare, coding or splice variants and five (3.3%) were novel. All individuals, except one control, were heterozygous for the 28 variants, and the distribution of the rare variants showed a significantly higher carrier frequency among cases than controls (9.9% vs. 4.9%, p=0.011). Four variants in MC4R were classified as pathogenic or likely pathogenic. CONCLUSION: Four cases (0.8%) of monogenic obesity were detected, all due to MC4R variants previously linked to monogenic obesity. Significant differences in carrier frequencies among patients with morbid obesity and normal weight controls suggest an association between heterozygous rare coding variants in these five genes and morbid obesity. However, additional studies in larger cohorts and functional testing of the novel variants identified are required to confirm the findings.
Asunto(s)
Variación Genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Obesidad Mórbida/genética , Análisis de Secuencia de ADN/métodos , Adolescente , Adulto , Distribución por Edad , Estudios de Casos y Controles , Niño , Femenino , Predisposición Genética a la Enfermedad , Humanos , Leptina/genética , Masculino , Persona de Mediana Edad , Tasa de Mutación , Noruega , Proopiomelanocortina/genética , Proproteína Convertasa 1/genética , Receptor de Melanocortina Tipo 4/genética , Receptores de Leptina/genética , Adulto JovenRESUMEN
Copy number variations (CNVs) are important in relation to diversity and evolution but can sometimes cause disease. The most common genetic cause of the inherited peripheral neuropathy Charcot-Marie-Tooth disease is the PMP22 duplication; otherwise, CNVs have been considered rare. We investigated CNVs in a population-based sample of Charcot-Marie-Tooth (CMT) families. The 81 CMT families had previously been screened for the PMP22 duplication and point mutations in 51 peripheral neuropathy genes, and a genetic cause was identified in 37 CMT families (46%). Index patients from the 44 CMT families with an unknown genetic diagnosis were analysed by whole-genome array comparative genomic hybridization to investigate the entire genome for larger CNVs and multiplex ligation-dependent probe amplification to detect smaller intragenomic CNVs in MFN2 and MPZ. One patient had the pathogenic PMP22 duplication not detected by previous methods. Three patients had potentially pathogenic CNVs in the CNTNAP2, LAMA2, or SEMA5A, that is, genes related to neuromuscular or neurodevelopmental disease. Genotype and phenotype correlation indicated likely pathogenicity for the LAMA2 CNV, whereas the CNTNAP2 and SEMA5A CNVs remained potentially pathogenic. Except the PMP22 duplication, disease causing CNVs are rare but may cause CMT in about 1% (95% CI 0-7%) of the Norwegian CMT families.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Variaciones en el Número de Copia de ADN/genética , Adulto , Niño , Femenino , Estudios de Asociación Genética/métodos , Genotipo , Humanos , Laminina/genética , Masculino , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Enfermedades del Sistema Nervioso Periférico/genética , Fenotipo , Mutación Puntual/genética , SemaforinasRESUMEN
OBJECTIVE: The MHC exerts the greatest contribution to RA susceptibility, where certain HLA-DRB1 alleles confer the greatest risk. Interestingly, there is evidence for more risk factors in the MHC with regions surrounding the HLA class I loci, but whether these antigen-presenting loci could be causal risk variants has not been directly investigated. In this study we investigate the HLA association by direct genotyping of the HLA loci. METHODS: Nine hundred and fifty RA patients and 933 healthy controls were genotyped for HLA-A, -B and -C. Eleven single-nucleotide polymorphisms (SNPs) and one insertion/deletion in the MHC were also included. Conditional logistic regression analyses were performed separately in ACPA-positive and -negative RA to identify the strongest susceptibility locus and additional risk loci. RESULTS: In ACPA-positive RA, the most significantly associated locus was HLA-DRB1 (P = 1.58 × 10(-54)), with SE alleles being predisposing. After controlling for HLA-DRB1, the HLA-C locus was found to confer susceptibility (P = 2.32 × 10(-9)), particularly, the HLA-C*03 allele. Also, in ACPA-negative RA, HLA-DRB1 was the most significant locus (P = 7.22 × 10(-9)), but with other risk alleles (particularly DRB1*03). A possible independent involvement of HLA-C was also observed for ACPA-negative RA (P = 0.02). CONCLUSION: HLA-DRB1 was the major MHC risk locus in both ACPA-positive and ACPA-negative RA, but with allelic risk heterogeneity. Joint analyses of the HLA class I loci together with previously proposed SNP associations pointed at HLA-C as a second susceptibility locus in ACPA-positive RA.
Asunto(s)
Artritis Reumatoide/genética , Autoanticuerpos/sangre , Antígenos HLA-C/genética , Cadenas HLA-DRB1/genética , Péptidos Cíclicos/inmunología , Alelos , Artritis Reumatoide/inmunología , Biomarcadores/sangre , Estudios de Casos y Controles , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Prueba de Histocompatibilidad/métodos , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVES: Polymorphisms in genes related to the IFN pathway were investigated for susceptibility to rheumatic diseases and correlation with gene expression in thymus. METHODS: Forty-five polymorphisms were genotyped in Norwegian patients with RA (n = 518), JIA (n = 440), SLE (n = 154) and healthy controls (n = 756). Forty-two thymic samples were used for gene expression analysis. Six hundred and fifty SLE patients and 737 healthy controls from Spain were available for replication. RESULTS: We found a novel association between interferon regulatory factor 5 (IRF5), rs2004640 and JIA, in particular with the polyarthritis RF-negative patients [odds ratio (OR) = 1.60; 95% confidence interval (CI) 1.17, 2.20; P = 0.003]. Also, we confirmed the associations between rs2004640 and SLE (OR = 1.95; 95% CI 1.50, 2.53; P = 3.75 × 10(-7)), which was further strengthened in a meta-analysis (OR = 1.44; 95% CI 1.36, 1.52; P = 2.11 × 10(-37)). Suggestive evidence of association between rs2004640 and RA was found in the Norwegian discovery cohort (OR = 1.19; 95% CI 1.02, 1.40; P = 0.029) and strengthened in a meta-analysis (OR = 1.11; 95% CI 1.05, 1.18; P = 0.00028). Expression levels of exon 1B IRF5 transcripts were dependent on the presence of the rs2004640 T risk allele in thymic tissue, while exon 1A transcript levels correlated with IRF5 promoter CGGGG-indel variants. CONCLUSION: The IFN pathway gene, IRF5, is a common susceptibility factor for several rheumatic and autoimmune diseases, and risk variants are correlated with expression of alternative IRF5 transcripts in thymus implying a regulatory role.
Asunto(s)
Factores Reguladores del Interferón/genética , Polimorfismo de Nucleótido Simple , Enfermedades Reumáticas/genética , Timo/metabolismo , Adolescente , Artritis Juvenil/genética , Artritis Juvenil/metabolismo , Artritis Reumatoide/genética , Artritis Reumatoide/metabolismo , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lactante , Recién Nacido , Factores Reguladores del Interferón/metabolismo , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/metabolismo , Masculino , Isoformas de Proteínas/metabolismo , Enfermedades Reumáticas/metabolismo , Transducción de Señal/genéticaRESUMEN
OBJECTIVE: The protective effect of HLA-DRB1 alleles on the development of rheumatoid arthritis (RA) is poorly understood. The aim of this study was to perform a meta-analysis of 4 European populations to investigate which HLA-DRB1 alleles are associated with protection in anti-citrullinated protein antibody (ACPA)-positive RA and ACPA-negative RA. METHODS: Data for >2,800 patients and >3,000 control subjects for whom information on HLA-DRB1 typing and ACPA status was available were collected from 4 European countries: Norway, Sweden, The Netherlands, and Spain. The odds ratios (ORs) and 95% confidence intervals (95% CIs) associated with the different HLA-DRB1 alleles were analyzed in a combined meta-analysis focused on protective alleles and classifications. The analysis of ACPA-positive RA was stratified for the shared epitope (SE) alleles, to correct for skewing due to this association. RESULTS: In ACPA-positive RA, the only alleles that conveyed protection after stratification for SE were HLA-DRB1*13 alleles (OR 0.54 [95% CI 0.38-0.77]). The protective effect of the allele classifications based on the DERAA and D70 sequences was no longer present after exclusion of DRB1*13 (for D70, OR 0.97 [95% CI 0.75-1.25]), indicating that DRB1*13, rather than the DERAA or D70 sequence as such, is associated with protection. Among the DRB1*13 alleles, only DRB1*1301 was associated with protection (OR 0.24 [95% CI 0.09-0.59]). Protection appeared to follow a north-to-south gradient, with the strongest association in northern European countries. In ACPA-negative RA, there were no robust associations with HLA-DRB1 alleles. CONCLUSION: Our data do not support any of the classifications of protective alleles and indicate that protection against ACPA-positive RA is predominantly associated with HLA-DRB1*1301.
Asunto(s)
Artritis Reumatoide , Autoanticuerpos/inmunología , Antígenos HLA-DR/genética , Antígenos HLA-DR/inmunología , Péptidos Cíclicos/inmunología , Artritis Reumatoide/etnología , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Europa (Continente)/epidemiología , Genotipo , Cadenas HLA-DRB1 , HumanosRESUMEN
OBJECTIVE: Elevated levels of IL-17A have been detected in the inflamed synovium of RA patients, and murine arthritis models deficient in IL17A have shown reduced inflammation. Our aim was to investigate IL17A as a candidate gene for RA, and to assess correlations between risk variants and disease phenotypes. METHODS: Five single nucleotide polymorphisms (SNPs) were selected to tag the genetic variability of the IL17A region and were genotyped by TaqMan technology on 950 RA cases and 933 random controls from Norway. Associations to progression of radiographic damage and presence of autoantibodies were examined in a 10-yr follow-up cohort of early RA. In addition, 580 RA patients and 504 controls from New Zealand were used as a replication data set. RESULTS: A weak association between RA and the promoter SNP rs2275913 [odds ratio (OR) = 1.17; 95% CI 1.02, 1.34; P = 0.02] was found in the Norwegian population. The association was also evident at the genotype level where it indicated a recessive model. The allelic association was not replicated in the RA cohort from New Zealand (OR = 0.96; 95% CI 0.81, 1.16; P = 0.69). However, combined analysis suggested a weak recessive association (OR = 1.19; 95% CI 1.02, 1.37; P = 0.02). No significant associations were observed with radiographic progression, anti-cyclic citrullinated peptide or IgM-RF. CONCLUSIONS: Modest evidence of an association with IL17A in Norwegian RA patients was observed. Although, our findings were not replicated in an independent RA material from New Zealand, a significant common risk estimate indicated that IL17A warrants further investigation in RA.
Asunto(s)
Artritis Reumatoide/genética , Interleucina-17/genética , Polimorfismo de Nucleótido Simple , Población Blanca/genética , Adulto , Anciano , Alelos , Artritis Reumatoide/inmunología , Autoanticuerpos/sangre , Distribución de Chi-Cuadrado , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Genes Recesivos , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Nueva Zelanda , Noruega , Oportunidad Relativa , RiesgoRESUMEN
BACKGROUND: The chemokine receptor CCR5 has been detected at elevated levels on synovial T cells, and a 32 bp deletion in the CCR5 gene leads to a non-functional receptor. A negative association between the CCR5Delta32 and rheumatoid arthritis (RA) has been reported, although with conflicting results. In juvenile idiopathic arthritis (JIA), an association with CCR5 was recently reported. The purpose of this study was to investigate if the CCR5Delta32 polymorphism is associated with RA or JIA in Norwegian cohorts. METHODS: 853 RA patients, 524 JIA patients and 658 controls were genotyped for the CCR5Delta32 polymorphism. RESULTS: The CCR5Delta32 allele frequency was 11.5% in the controls vs. 10.4% in RA patients (OR = 0.90; P = 0.36) and 9.7% in JIA patients (OR = 0.85; P = 0.20). No decreased homozygosity was observed for CCR5Delta32, as previously suggested. CONCLUSION: Our data do not support an association between the CCR5Delta32 allele and Norwegian RA or JIA patients. Combining our results with those from a recently published meta-analysis still provide evidence for a role for CCR5Delta32 in RA, albeit substantially weaker than the effect first reported.