Research Topic

The Contribution of Genomic Variations in Innate Immunity to Complex Disease

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Background and rationale: As cancer biologists we have found that variants of the Toll-like receptor pathway associate with breast and prostate cancer risk among individuals of African descent [1-3], including an Ala428Thr variant of the central regulatory kinase interluekin-1 receptor associated kinase 4 ...

Background and rationale: As cancer biologists we have found that variants of the Toll-like receptor pathway associate with breast and prostate cancer risk among individuals of African descent [1-3], including an Ala428Thr variant of the central regulatory kinase interluekin-1 receptor associated kinase 4 (IRAK4) [3]. Further studies are needed to address the molecular, functional and clinical implications of introducing a threonine on or near the surface of IRAK4 close to its carboxyl terminus. We hypothesize that the Ala428Thr IRAK4 variant associated with these two cancers (and possibly other complex diseases affected by inflammation) is an adaptation that provides protection from one or more tropical/subtropical environmental insults or pathogens. Two examples illustrate an overarching hypothesis that the same genetic adaptations in innate immunity that enable indigenous peoples of the tropics to survive also drive inflammatory pathologies that promote a wide range of complex diseases (such as cancer, cardiovascular disease, mental illness, autoimmunity and susceptibility to infection). First is the classic example of the Glu7Val variant of β-globin (HBB) that provides protection against malaria but produces multiple pathologies associated with sickled red blood cells. Second is the more recent discovery of two Apolipoprotein L1 (APOL1) variants that confer protection against the acute fast onset Trypanosoma brucei rhodesiense but associate with two forms of kidney disease [4-5].
Compelling questions: 1) Does the Ala428Thr IRAK4 variant confer innate immune protection? If so, what is/are the targeted pathogen(s) and how is protection conferred? If not, does the variant alter overall pathogen sensitivity/tolerance? 2) What roles in innate immunity are played by isoforms and variants, family members, and proteins that share structural similarities with the functional domains of APOL1 and IRAK4? 3) Does a panel of innate immune serum proteins that includes APOL1 exist that collectively displays the breadth and specificity of immune recognition seen among the integral membrane Toll-like receptors? Do variants in this panel contribute to modern complex disease pathology? 4) What endogenous or pathologic pathways, players and their variants (discoverable via gene-gene and protein-protein interaction studies) combine with variants of APOL1, IRAK4 et al. to impact immune protection and complex disease?
REFERENCES
1. Kidd L, Rogers E, Yeyeodu S, Jones D, Kimbro K (2013) Contribution of toll-like receptor signaling pathways to breast tumorigenesis and treatment. Breast Cancer: Targets and Therapy 2013, 5:43-51 5: 43-51. Total views: 3,687
2. Rogers EN, Jones DZ, Kidd NC, Yeyeodu S, Brock G, et al. (2013) Toll-like receptor-associated sequence variants and prostate cancer risk among men of African descent. Genes Immun 14: 347-355.
3. Yeyeodu ST, Kidd LR, Oprea-Ilies GM, Burns BG, Vancleave TT, et al. (2013) IRAK4 and TLR3 Sequence Variants may Alter Breast Cancer Risk among African-American Women. Front Immunol 4: 338. Total views: 2,776
4. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, et al. (2010) Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329: 841-845. Cited by 563
5. Limou S, Dummer PD, Nelson GW, Kopp JB, Winkler CA (2015) APOL1 toxin, innate immunity, and kidney injury. Kidney Int. doi:10.1038/ki.2015.109


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