Immune Mediator Pharmacogenomics: TCL1A SNPs and Estrogen-Dependent Regulation of Inflammation

Ming-Fen Ho, Richard M. Weinshilboum

Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

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This review describes the important functional implications of TCL1A single nucleotide polymorphisms (SNPs) discovered during pharmacogenomic studies of aromatase inhibitor-induced musculoskeletal adverse events that were subsequently shown to influence the expression of cytokines, chemokines, toll-like receptors (TLR), and NF-κB in a SNP and estrogen-dependent fashion. Functional genomic studies of these SNPs led to the discovery of novel mechanisms that may contribute to disease pathophysiology and which may also increase our understanding of pharmacogenomic aspects of regulation of the expression of inflammatory mediators. Specifically, TCL1A expression was induced by estrogens in a SNP-dependent fashion, resulting in downstream effects on the expression of immune mediators that included IL17RA, IL17A, CCR6, CCL20 TLR2, TLR7, TLR9, TLR10 and NF-κB. These observations have potential implications for inflammatory diseases such as rheumatoid arthritis—a disease for which two thirds of patients are women. Strikingly, this genomic phenomenon could be “reversed” by estrogen receptor antagonist treatment—once again in a SNP-dependent, i.e., in a pharmacogenomic fashion. Specifically, differential SNP-dependent effects on estrogen receptor binding to estrogen response elements before and after estrogen receptor blockade might be associated with mechanisms underlying the SNP genotype and estrogen-dependent regulation of TCL1A and the expression of downstream immune mediators. Furthermore, this SNP and estrogen-dependent phenotypic response could be “reversed” by SERM treatment. These observations could potentially open the way to understand, predict and even pharmacologically manipulate the expression of selected immune mediators in a SNP-dependent fashion. Journal of Nature and Science (JNSCI), 3(8):e416, 2017

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