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Review
. 2014 Dec:31:51-7.
doi: 10.1016/j.coi.2014.09.007. Epub 2014 Oct 14.

Genetics of immune-mediated disorders: from genome-wide association to molecular mechanism

Vinod Kumar  1 , Cisca Wijmenga  2 , Ramnik J Xavier  3
Affiliations
Review

Genetics of immune-mediated disorders: from genome-wide association to molecular mechanism

Vinod Kumar et al. Curr Opin Immunol. 2014 Dec.

Abstract

Genetic association studies have identified not only hundreds of susceptibility loci to immune-mediated diseases but also pinpointed causal amino-acid variants of HLA genes that contribute to many autoimmune reactions. Majority of non-HLA genetic variants are located within non-coding regulatory region. Expression QTL studies have shown that these variants affect disease mainly by regulating gene expression. We discuss recent findings on shared genetic loci between infectious and immune-mediated diseases and provide potential clues to explore genetic associations in the context of these infectious agents. We propose that the interdisciplinary studies (genetics-genomics-immunology-infection-bioinformatics) are the future post-GWAS approaches to advance our understanding of the pathogenesis of immune-mediated diseases.

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Figures

Figure 1
Figure 1
Shown is a flowchart outlining the steps to identify relevant triggers of autoimmunity. Analyzing the intersection between SNPs associated with immune-mediated diseases and the genetics of infectious diseases and other endophenotypes helps us to prioritize microbial and environmental triggers. These triggers can then be used as stimuli to activate immune cells to obtain transcriptional responses by RNA sequencing. Cis- and trans-eQTL mapping can then identify both the causal genes and pathways. This information will yield insight into disease mechanisms and in turn inform the choice of relevant therapeutic targets.
Figure 2
Figure 2
SNP rs3184504 on human chromosome 12 is associated with autoimmune diseases. eQTL mapping showed that the autoimmune risk allele (A allele) up-regulates SH2B3 gene expression (cis-eQTL) and also affects 29 other genes on different chromosomes (trans-eQTL). Pathway analysis showed enrichment of genes for innate immunity among the up-regulated genes (green dotted arrows), and enrichment of genes for chemokine signalling pathway among the down-regulated genes (red dotted arrows).
See this image and copyright information in PMC

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