title: The repertoire of λ light chains causing predominant amyloid heart involvement and identification of a preferentially involved germline gene, IGLV1-44.
abstract: Monoclonal Ig light chains (LC) can be responsible for pathologic conditions in humans, as in systemic amyloid light amyloidosis. Protean clinical manifestations characterize this disorder with the most varied combination of symptoms generated by different degrees of diverse organ involvement. Kidney and heart are most frequently interested, with major heart involvement as the most relevant prognostic factor. The identification of the underlying mechanism involved in organ targeting is of major relevance for the pathobiology of this disorder. To this aim, we characterized the repertoire of variable region germline genes of λ LC preferentially targeting the heart and compared it with the repertoire of LC that do not in a case-control study. We found that the repertoires were highly restricted, showing preferential use of the same few germline genes but with a different frequency pattern. A single gene, IGVL1-44, was found associated with a 5-fold increase in the odds of dominant heart involvement (after adjusting for confounders in a multivariable logistic model). These results support an involvement of LC genetics in the determination of organ targeting. Study of the characteristics of IGVL1-44-LC with, and of the minority without, heart involvement might lead to identification of LC/tissue interactions.
authors: Amyloid Research and Treatment Center, Biotechnology Research Laboratories, Pavia, Italy. v.perfetti@smatteo.pv.it
authors: Vittorio
authors: V
authors: Perfetti
authors: Giovanni
authors: G
authors: Palladini
authors: Simona
authors: S
authors: Casarini
authors: Valentina
authors: V
authors: Navazza
authors: Paola
authors: P
authors: Rognoni
authors: Laura
authors: L
authors: Obici
authors: Rosangela
authors: R
authors: Invernizzi
authors: Stefano
authors: S
authors: Perlini
authors: Catherine
authors: C
authors: Klersy
authors: Giampaolo
authors: G
authors: Merlini
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000682:Amyloid / Q000235:genetics*; D000686:Amyloidosis / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D005803:Genes, Immunoglobulin / Q000235:genetics*; D005854:Germ Cells; D006331:Heart Diseases / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007146:Immunoglobulin lambda-Chains / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011379:Prognosis; D017386:Sequence Homology, Amino Acid; D015996:Survival Rate
chemical_list: D000682:Amyloid; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region; D007146:Immunoglobulin lambda-Chains