RESUMO
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.
Assuntos
Meio Ambiente , Predisposição Genética para Doença , Esclerose Múltipla , Adulto , Família , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/etiologia , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
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.
Assuntos
Doenças Autoimunes/genética , Autoimunidade/genética , Linfócitos T CD4-Positivos/imunologia , Predisposição Genética para Doença/genética , Monócitos/imunologia , Doenças Neurodegenerativas/genética , Imunidade Adaptativa/genética , Alelos , Doença de Alzheimer/etnologia , Doença de Alzheimer/genética , Doenças Autoimunes/etnologia , Etnicidade/genética , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Humanos , Imunidade Inata/genética , Esclerose Múltipla/etnologia , Esclerose Múltipla/genética , Doenças Neurodegenerativas/etnologia , Doença de Parkinson/etnologia , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Febre Reumática/etnologia , Febre Reumática/genética , TranscriptomaRESUMO
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.