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Graham R Wallace, Alice M Roberts, Rhodri L Smith, Robert J Moots, IM; A Darwinian view of Behcet’s Disease. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1717.
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Purpose - Behçet’s Disease (BD) is a multi-system inflammatory disorder of unknown aetiology, characterised by oral and genital ulceration, with other complications including eye, skin, joint and CNS lesions that may cause blindness or stroke. The MHC gene, HLA-B*51, is the strongest genetic association across the geographic spread of disease. Many genetic studies including GWAS have identified gene loci and we propose that BD is based on several mutants with small effect, which together lead to disease and which have accumulated over time. Interestingly, these mutations vary in different parts of the world. Recent studies have catalogued archaic human genomes, and show admixture with early humans, which can impact on human disease. We sought to address the role of such introgression with known genetic associations in Behcet’s Disease.<br />
Methods - analysis of genome-wide association, imputation and candidate gene studies, was used to determine links between early hominid DNA, geographical differences in gene association and pathway analysis to determine how these mutations are linked.<br />
Results - HLA molecules associated with BD have be shown to be derived from archaic genomes. Maintenance of these alleles into modern day strongly supports a protective effect. Analysis of five biological processes as examples to show that mutations mutations specific to different geographical areas affect have a similar functional outcome.<br />
Conclusion - admixture or archaic and early human genomes has led to particular genes that are now associated with disease being introgressed into modern humans as protection against infection. However, further mutations in different genes, that affect the same cellular process have led to the association with disease. This knowledge might allow us to target pathways rather than individual gene products, ultimately leading to better diagnosis and control of disease.<br />
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