A. Clay-Gilmour, S. Chattopadhyay, A. T. M. Hildebrandt, H. Thomsen, N. Weinhold, P. Vodička, L. Vodičková, P. Hoffmann, M. M. Nöthen, K. H. Jöckel, B. Schmidt, Ch. Langer, R. Hajek, G. Hallmans, U. Pettersson-Kymmer, C. Ohlsson, F. Späth, R. Houlston, H. Goldschmidt, E. E. Manasanch, A. Norman, S. Kumar, S. V. Rajkumar, S. Slager, A. Försti, C. M. Vachon, K. J. Hemminki: Genome-wide meta-analysis of monoclonal gammopathy of undetermined significance (MGUS) identifies risk loci impacting IRF-6. Blood Cancer J. 2022 Apr 13. doi: 10.1038/s41408-022-00658w
Monoclonal gammopathy of undetermined significance (MGUS) is a benign plasma cell disorder, common in the Western population (3–5% ≥50 years) and characterized by an asymptomatic clonal plasma cell expansion. MGUS progresses to multiple myeloma (MM) at a rate of 1% per year but can also progress to light chain amyloidosis (AL amyloidosis), Waldenström macroglobulinemia, and lymphoma. Previous genome-wide association studies (GWAS) have successfully identified 24 common loci associated with MM risk; of these, 12 are also associated with MGUS. Identifying additional common variants contributing to MGUS may elucidate the unaccounted missing heritability for both MGUS and MM. Further, understanding genetic determinants of MGUS are important regardless of MM, given the associations of MGUS with multiple conditions, not just MM. Accordingly, in this study, we performed the largest MGUS GWAS meta-analysis to date and validated associations of known MM/MGUS risk variants. We included four independent GWAS of MGUS patients and controls (European/European–American) from the United States, Sweden, Germany, and the Czech Republic. To sum up, our MGUS meta-analysis identified a novel locus (rs195314) that may cause a motif change in the binding site of IRF-6, a member of the interferon regulatory transcription factor family. Limited data on MGUS progression suggest that this SNP is not associated with progression to MM or AL amyloidosis.