Search for AL amyloidosis risk factors using Mendelian randomization

Abstract

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.

Subtyping based on immune cell fractions reveal heterogeneity of cardiac fibrosis in end-stage heart failure

“…Literature review also indicated that functions of 17G-subtype1 and 13G-subtype2 were related to features of their corresponding subtypes. Most genes from 17G-subtype1 directly participated in [for example, TNFRSF17, MEP1B, TNFRSF9, CST6, CANT1, IGF2BP1, IL13, LRP8 ( 62 – 71 )] or at least were relevant to [for example, PLXNC1, DUOX2, SLITRK3, ST6GAL2, F11 ( 72 – 77 )] inflammation and adaptive immune responses ( Supplementary Table 6 ), which were major physiological features of the pro-inflammatory subtype. Meanwhile, genes from 13G-subtype2 were related to down-regulation of inflammatory responses [for example, LIMD1, VSIG4, ADAMTS5, VTCN1 ( 78 – 81 )], blood vessel development [for example, VEGFD, RLN2, KLK12, and ANGPTL3 ( 82 – 86 )], and maladaptive responses to reduced cardiac functions [for example, VEGFD, ANGPTL3, LIMD1, VSIG4, IDI2 ( 79 , 83 – 88 ) ( Supplementary Table 6 ), which were physiological features related to M2 macrophage ( 13 ).…”

U-Shaped Association Between Monocyte-Lymphocyte Ratio and Risk of Cardiac Conduction Block

“…36 Additionally, a recent Mendelian randomization analysis provided evidence of a causal relationship between elevated MC and decreased LC and the deposition of abnormal cardiac proteins, which are known to be significantly associated with the occurrence of conduction blocks. 37,38 Overall, the precise mechanisms underlying the association between high MLR and increased risk of CCB are still not fully understood.…”

Exploring the role of circulating proteins in multiple myeloma risk: a Mendelian randomization study

“…Both SNPs used to instrument MM risk were also associated with amyloidosis (rs555992394) and had evidence for having an effect on blood cell counts including lymphocyte count and red cell distribution width (rs8141529) in the pheWAS analysis. These effects may be part of the shared causal pathway rather than pleiotropic given that amyloidosis and MM both share the precursor condition, MGUS [55], and that MM is known to have an effect on blood cell counts through myelosuppression [56].…”