RESUMEN
The Genes and Environment in Multiple Sclerosis project establishes a platform to investigate the events leading to multiple sclerosis (MS) in at-risk individuals. It has recruited 2,632 first-degree relatives from across the USA. Using an integrated genetic and environmental risk score, we identified subjects with twice the MS risk when compared to the average family member, and we report an initial incidence rate in these subjects that is 30 times greater than that of sporadic MS. We discuss the feasibility of large-scale studies of asymptomatic at-risk subjects that leverage modern tools of subject recruitment to execute collaborative projects.
Asunto(s)
Ambiente , Predisposición Genética a la Enfermedad , Esclerosis Múltiple , Adulto , Familia , Femenino , Humanos , Incidencia , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/etiología , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple , Medición de Riesgo , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
To extend our understanding of the genetic basis of human immune function and dysfunction, we performed an expression quantitative trait locus (eQTL) study of purified CD4(+) T cells and monocytes, representing adaptive and innate immunity, in a multi-ethnic cohort of 461 healthy individuals. Context-specific cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment of candidate causal regulatory variants for disease-associated loci. We note an over-representation of T cell-specific eQTLs among susceptibility alleles for autoimmune diseases and of monocyte-specific eQTLs among Alzheimer's and Parkinson's disease variants. This polarization implicates specific immune cell types in these diseases and points to the need to identify the cell-autonomous effects of disease susceptibility variants.
Asunto(s)
Enfermedades Autoinmunes/genética , Autoinmunidad/genética , Linfocitos T CD4-Positivos/inmunología , Predisposición Genética a la Enfermedad/genética , Monocitos/inmunología , Enfermedades Neurodegenerativas/genética , Inmunidad Adaptativa/genética , Alelos , Enfermedad de Alzheimer/etnología , Enfermedad de Alzheimer/genética , Enfermedades Autoinmunes/etnología , Etnicidad/genética , Predisposición Genética a la Enfermedad/etnología , Estudio de Asociación del Genoma Completo , Humanos , Inmunidad Innata/genética , Esclerosis Múltiple/etnología , Esclerosis Múltiple/genética , Enfermedades Neurodegenerativas/etnología , Enfermedad de Parkinson/etnología , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Fiebre Reumática/etnología , Fiebre Reumática/genética , TranscriptomaRESUMEN
In our functional dissection of the CD33 Alzheimer's disease susceptibility locus, we found that the rs3865444(C) risk allele was associated with greater cell surface expression of CD33 in the monocytes (t50 = 10.06, P(joint) = 1.3 × 10(-13)) of young and older individuals. It was also associated with diminished internalization of amyloid-ß 42 peptide, accumulation of neuritic amyloid pathology and fibrillar amyloid on in vivo imaging, and increased numbers of activated human microglia.
