In amyloid light chain (AL) amyloidosis, amyloid fibrils derived from immunoglobulin light chain are deposited in many organs, interfering with their function. The etiology of AL amyloidosis is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited by Mendelian randomization (MR) methodology to search for factors influencing AL amyloidosis risk. We performed a 2-sample MR analyzing 72 phenotypes, proxied by 3461 genetic variants, and summary genetic data from a GWAS of 1129 AL amyloidosis cases and 7589 controls. Associations with a Bonferroni-defined significance level were observed for genetically predicted increased monocyte counts (P = 3.8 × 10-4) and the tumor necrosis factor receptor superfamily member 17 (TNFRSF17) gene (P = 3.4 × 10-5). Two other associations with the TNFRSF (members 6 and 19L) reached a nominal significance level. The association between genetically predicted decreased fibrinogen levels may be related to roles of fibrinogen other than blood clotting. be related to its nonhemostatic role. It is plausible that a causal relationship with monocyte concentration could be explained by selection of a light chain-producing clone during progression of monoclonal gammopathy of unknown significance toward AL amyloidosis. Because TNFRSF proteins have key functions in lymphocyte biology, it is entirely plausible that they offer a potential link to AL amyloidosis pathophysiology. Our study provides insight into AL amyloidosis etiology, suggesting high circulating levels of monocytes and TNFRSF proteins as risk factors.

Amyloidosis Research and Treatment Center Foundation Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and Department of Molecular Medicine University of Pavia Pavia Italy

Biomedical Center Faculty of Medicine and Biomedical Center in Pilsen Charles University Prague Pilsen Czech Republic; and

Department of Biology University of Pisa Pisa Italy

Department of Biomedicine University of Basel Basel Switzerland

Department of Clinical Genetics Lund University Lund Sweden

Department of Internal Medicine 5 University of Heidelberg Heidelberg Germany

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Genetics and Epidemiology The Institute of Cancer Research London United Kingdom

Division of Pediatric Neuro oncology German Cancer Research Center German Cancer Consortium Heidelberg Germany

Hopp Children's Cancer Center Heidelberg Germany

Institute for Medical Informatics Biometry and Epidemiology University Hospital Essen University of Duisburg Essen Essen Germany

Institute of Human Genetics University of Bonn School of Medicine and University Hospital Bonn Bonn Germany

National Amyloidosis Centre University College London Medical School Royal Free Hospital Campus London United Kingdom

National Centre of Tumor Diseases Heidelberg Germany

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