M. Ho,1 L. Wang,1 J. Ingle,1 P. Goss,2 T. Mushiroda,3 M. Kubo,3 Y. Nakamura,4 L. Shepherd,5 R. Weinshilboum,1 T. Bongartz1; 1Mayo Clinic, Rochester, MN, 2Massachusetts General Hospital, Boston, MA, 3Riken Center, Yokohama City, Japan, 4The University of Chicago Knapp Center for Biomedical Discovery, Chicago, IL, 5NCIC Clinical Trials Group, Kingston, ON, Canada

BACKGROUND: We identified four SNPs near TCL1A that were associated with aromatase inhibitor-induced arthralgia in a clinical GWAS. These SNPs were associated with changes in the estrogen-dependent expression of TCL1A and, downstream, the expression of IL17RA, IL17A, CCR6 and CCL20, and of NF-κB transcriptional activity, all of which are involved in immune response in rheumatoid arthritis (RA). We set out to determine the effect of the expression of cytokines and chemokines that have been implicated in RA after estrogen receptor (ER) blockade and the underlying mechanism of variation for gene expression in a SNP and estrogen-dependent fashion.
METHODS: ‘’Human Variation Panel’’ lymphoblastoid cell lines from 300 subjects with genome-wide mRNA expression and genome-wide SNP data were used. Gene expression was quantified by qPCR. ChIP assays were used to determine ERα binding to estrogen response elements (EREs).
RESULTS: E2 induced TCL1A expression in a SNP-dependent fashion with induction only for the variant genotype. However, this pattern could be “reversed” when the ERα antagonist ICI-182,780 was present. As a result, expression of IL17RA, IL17A, CCR6 and CCL20 was also altered. We also observed a “reversal” of estrogen-dependent ERα binding to EREs near TCL1A in response to ICI-182,780 and the antiestrogen 4-hydroxytamoxifen, as determined by ChIP assay.
CONCLUSION: The differential effects on ERα binding before and after ER blockade might be associated with underlying mechanisms for the SNP and estrogen-dependent variation of TCL1A expression and, downstream, of IL17RA, IL17A, CCR6 and CCL20. These observations potentially open the way to pharmacologic manipulation of the expression of immune mediators in a SNP-dependent fashion.