Epidemiology of Amyloidosis and Genetic Pathways to Diagnosis and Typing

We reviewed our studies on epidemiology and germline genetics of amyloidosis. In epidemiology, we considered both hereditary and non-hereditary amyloidosis. As the source of data, we used the nationwide Swedish hospital discharge register. We estimated the incidence of hereditary ATTR amyloidosis, for which Sweden is a global endemic area, at 2/million. Surprisingly, the disease was also endemic within Sweden; the incidence in the province with the highest incidence was 100 times higher than in the rest of Sweden. Risk of non-Hodgkin lymphoma increased five-fold in the affected individuals. Among non-hereditary amyloidosis, the incidence for AL amyloidosis (abbreviated as AL) was estimated at 3.2/million, with a median survival time of 3 years. Secondary systemic amyloidosis (most likely AA amyloidosis) showed an incidence of 1.15/million for combined sexes. The female rate was two times higher than the male rate, probably relating to the higher female prevalence of rheumatoid arthritis. The median survival time was 4 years. We also identified patients who likely had familial autoinflammatory disease, characterized by early onset and immigrant background from the Eastern Mediterranean area. Young Syrian descendants had the highest incidence rate, which was over 500 times higher than that in individuals with Swedish parents. Germline genetics focused on AL on which we carried out a genome-wide association study (GWAS) in three AL cohorts (N = 1129) from Germany, UK, and Italy. Single nucleotide polymorphisms (SNPs) at 10 loci showed evidence of an association at p < 10−5; some of these were previously documented to influence multiple myeloma (MM) risk, including the SNP at the IRF4 binding site. In AL, SNP rs9344 at the splice site of cyclin D1, influencing translocation (11;14), reached the highest significance, p = 7.80 × 10−11; the SNP was only marginally significant in MM. The locus close to gene SMARCD3, involved in chromatin remodeling, was also significant. These data provide evidence for common genetic susceptibility to AL and MM. We continued by analyzing genetic associations in nine clinical profiles, characterized by organ involvement or Ig profiles. The light chain only (LCO) profile associated with the SNP at the splice site of cyclin D1 with p = 1.99 × 10−12. Even for the other profiles, distinct genetic associations were found. It was concluded that the strong association of rs9344 with LCO and t(11;14) amyloidosis offer attractive mechanistic clues to AL causation. Mendelian randomization analysis identified associations of AL with increased blood monocyte counts and the tumor necrosis factor receptor superfamily member 17 (TNFRSF17 alias BCMA) protein. Two other associations with the TNFRSF members were found. We discuss the corollaries of the findings with the recent success of treating t(11;14) AL with a novel drug venetoclax, and the application of BCMA as the common target of plasma cell immunotherapies.