Thursday, 20 February 2014

Genetic Risk controlled by factors affecting immune cells

Elangovan RI, Disanto G, Berlanga-Taylor AJ, Ramagopalan SV, Handunnetthi L. Regulatory genomic regions active in immune cell types explain a large proportion of the genetic risk of multiple sclerosis. J Hum Genet. 2014 Feb 13. doi: 10.1038/jhg.2014.3.

There is little understanding of how genetic variants discovered in recent genome-wide association studies are involved in the pathogenesis of multiple sclerosis (MS). We aimed to investigate which chromatin states and cell types explain genetic risk in MS. We used genotype data from 1854 MS patients and 5164 controls produced by the International Multiple Sclerosis Genetics Consortium and Wellcome Trust Case Control Consortium. We estimated the proportion of phenotypic variance between cases and controls explained by cell-specific chromatin state and DNase I hypersensitivity sites (DHSs) using the Genome-wide Complex Trait Analysis software. A large proportion of variance was explained by single-nucleotide polymorphisms (SNPs) in strong enhancer (SE) elements of immortalized B lymphocytes (5.39%). Three independent SNPs located within SE showed suggestive evidence of association with MS: rs12928822 (odds ratio (OR)=0.81, 95% confidence interval (CI)=0.73-0.89, P=2.48E-05), rs727263 (OR=0.75, 95% CI=0.66-0.85, P=3.26E-06) and rs4674923 (OR=0.85, 95% CI=0.79-0.92, P=1.63E-05). Genetic variants located within DHSs of CD19+ B cells explained the greatest proportion of variance. Genetic variants influencing the risk of MS are located within regulatory elements active in immune cells. This study also identifies a number of immune cell types likely to be involved in the causal cascade and that carry important implications for future studies of therapeutic design.

In genetics DNase I hypersensitive sites (DHSs) are regions of chromatin which are sensitive to cleavage by the DNase I enzyme. In these specific regions of the genome, chromatin has lost its condensed structure, exposing the DNA, and making it accessible. This raises the availability of DNA to degradation by enzymes, like DNase I. These accessible chromatin zones are functionally related to transcriptional activity, since this remodeled state is necessary for the binding of proteins such as transcription factors.

This study shows that MS-associated genetic variants within regulatory regions specifically active in immune cells (and therefore likely to exert a functional effect on the expression of close genes and ultimately cell activity) account for a large proportion of the variation between people with MS compared to people without MS.

In contrast, within non-immune cells variation between MSers and non-MSers was largely accounted for by genetic variants within functionally inactive regions, in which the genetic variants are unlikely to have a functional effect.

Regulatory regions specifically active in immune cells are therefore important in explaining the contribution of genetics to MS risk. They support the involvement of numerous immune cell types in MS, but particularly a role for the B cell immune cell type.

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