Cardiac Amyloid: It's All in the Genes

The most common form of systemic amyloidosis is light chain disease (AL amyloid) that is a consequence of secretion of pathologic monoclonal immunoglobulin light chains (LC) by a clonal population of plasma cells. Tissue deposition of these misfolded proteins results in progressive organ damage and, in some cases, sudden death as a result of cardiac involvement. Diagnosis can be challenging, requiring histology confirmation and specialized testing to determine disease subtype. Kidney and heart are the most frequently involved organs, with the extent of cardiac disease being the most important prognostic factor. The current goal of treatment is eradication or reduction of the monoclonal plasma cell mass, thereby eliminating or reducing the production of pathologic light chains. Such treatment leads to a decrease in amyloid deposits with corresponding improvement in organ function and added survival time. However, to hasten organ recovery and to enhance survival further, there is a need to increase the rate at which AL amyloid deposits are cleared, especially in cases in which cardiac involvement is extensive. To this end, recent studies have focused on the genetics of AL amyloid with a goal of understanding the properties of the pathological proteins that account for their diverse clinical manifestations.

In a case-control study, Perfetti and colleagues from the University of Pavia characterized the repertoire of the variable region of germline genes of λ LC that preferentially target the heart and compared it with that of LC lacking cardiac tropism (the control group). They found that the repertoires were highly restricted, showing preferential use of the same few germline genes, with a different frequency of Vλ family usage. A five-fold increase in the odds of being associated with heart-dominant disease was observed for a single gene, IGVL1-44, while cardiac involvement was absent when the monoclonal LC was a product of IGVL6-57. LC expression in the control population was dominated by the VλIII family (involved in 46% of cases), with the VλII and VλVI families each accounting for approximately 20 percent of LC expression and the VλI family involved in 11 percent of cases. In contrast, the heart-dominant group was characterized by even distribution of LC expression by VλI, VλII, and VλIII families (equally contributing ~30% of sequences) and under-representation of the VλVI family (this latter family is known to be preferentially expressed in cases with kidney involvement). Based on these comparisons, the frequency of involvement by the VλI family was almost three times greater in the heart-dominant group (odds ratio 3.48, 95% CI 1.08-13.17), suggesting biased expression at the level of germline genes.