RESUMEN
Immunoglobulin E (IgE) is a central mediator of allergic (atopic) inflammation. Therapies directed against IgE can alleviate hay fever and allergic asthma. Genetic association studies have not yet identified novel therapeutic targets or pathways underlying IgE regulation. We therefore surveyed epigenetic associations between serum IgE concentrations and methylation at loci concentrated in CpG islands genome wide in 95 nuclear pedigrees, using DNA from peripheral blood leukocytes. We validated positive results in additional families and in subjects from the general population. Here we show replicated associations--with a meta-analysis false discovery rate less than 10(-4)--between IgE and low methylation at 36 loci. Genes annotated to these loci encode known eosinophil products, and also implicate phospholipid inflammatory mediators, specific transcription factors and mitochondrial proteins. We confirmed that methylation at these loci differed significantly in isolated eosinophils from subjects with and without asthma and high IgE levels. The top three loci accounted for 13% of IgE variation in the primary subject panel, explaining the tenfold higher variance found compared with that derived from large single-nucleotide polymorphism genome-wide association studies. This study identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases.
Asunto(s)
Metilación de ADN/genética , Epigénesis Genética/genética , Estudios de Asociación Genética , Genoma Humano/genética , Inmunoglobulina E/sangre , Adolescente , Adulto , Asma/sangre , Asma/genética , Niño , Islas de CpG/genética , Eosinófilos/citología , Eosinófilos/metabolismo , Femenino , Humanos , Mediadores de Inflamación , Masculino , Persona de Mediana Edad , Proteínas Mitocondriales/genética , Linaje , Polimorfismo de Nucleótido Simple/genética , Factores de Transcripción/genética , Adulto JovenRESUMEN
Interindividual variation in gene expression has been convincingly shown to be controlled, in part, by genetic differences. Determining the architecture of genetic variation, the underlying gene expression may allow deeper insight into complex phenotypes, such as differences in disease susceptibility. Mapping genetic variants accounting for expression phenotypes in human cell and tissue panels has rapidly progressed from proof-of-principle experiments to general tools in biomedical discovery. We discuss the general approach and critical considerations for carrying out expression quantitative trait mapping in human tissues.
Asunto(s)
Perfilación de la Expresión Génica , Variación Genética , Sitios de Carácter Cuantitativo , Humanos , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Previous data from our group indicate that BMD is linked to chromosome 3p14-p21. Because the filamin B (FLNB gene resides in this region, is the cause of skeletal dysplasias, and was identified among the top genes in our bioinformatics analysis, we hypothesized a role for FLNB in the regulation of bone structure in the general population. Using a tag single nucleotide polymorphism (SNP) approach, a family study of 767 female sibs in which the 3p14-p21 linkage with BMD was previously shown was examined. FLNB variants showing a BMD association were tested in two additional data sets, a study of 1085 UK female twins and a population study (CAIFOS) of 1315 Australian women. Genotype-expression studies were performed in 96 human osteoblast lines to examine the variants in vitro. rs7637505, rs9822918, rs2177153, and rs2001972 showed association with femoral neck (p = 0.0002-0.02) in the family-based study. The twin study provided further support for an association between rs7637505 and femoral neck and spine BMD (p = 0.02-0.03). The CAIFOS study further suggested an association between rs2177153 and rs9822918 and femoral neck BMD (p = 0.004-0.03). Prevalent fractures were increased in carriers of the A allele of rs2177153 (p = 0.009). In vitro studies showed association between rs11130605, itself in strong LD with rs7637505, and FLNB mRNA expression. These findings suggest common variants in FLNB have effects on bone structure in women. Although the location of variants having effects is not entirely consistent, variation at the 5' end of the gene may reflect effects on levels of FLNB transcription efficiency.