title: Susceptibility and modifier genes in Portuguese transthyretin V30M amyloid polyneuropathy: complexity in a single-gene disease.
abstract: Familial amyloid polyneuropathy type I is an autosomal dominant disorder caused by mutations in the transthyretin (TTR) gene; however, carriers of the same mutation exhibit variability in penetrance and clinical expression. We analyzed alleles of candidate genes encoding non-fibrillar components of TTR amyloid deposits and a molecule metabolically interacting with TTR [retinol-binding protein (RBP)], for possible associations with age of disease onset and/or susceptibility in a Portuguese population sample with the TTR V30M mutation and unrelated controls. We show that the V30M carriers represent a distinct subset of the Portuguese population. Estimates of genetic distance indicated that the controls and the classical-onset group were furthest apart, whereas the late-onset group appeared to differ from both. Importantly, the data also indicate that genetic interactions among the multiple loci evaluated, rather than single-locus effects, are more likely to determine differences in the age of disease onset. Multifactor dimensionality reduction indicated that the best genetic model for classical onset group versus controls involved the APCS gene, whereas for late-onset cases, one APCS variant (APCSv1) and two RBP variants (RBPv1 and RBPv2) are involved. Thus, although the TTR V30M mutation is required for the disease in Portuguese patients, different genetic factors may govern the age of onset, as well as the occurrence of anticipation.
authors.affiliation: Department of Molecular and Experimental Medicine, Division of Rheumatology Research and the WM Keck Autoimmune Disease Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Miguel L
authors.initials: ML
authors.lastname: Soares
authors.forename: Teresa
authors.initials: T
authors.lastname: Coelho
authors.forename: Alda
authors.initials: A
authors.lastname: Sousa
authors.forename: Serge
authors.initials: S
authors.lastname: Batalov
authors.forename: Isabel
authors.initials: I
authors.lastname: Conceição
authors.forename: Maria L
authors.initials: ML
authors.lastname: Sales-Luís
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.forename: Scott M
authors.initials: SM
authors.lastname: Williams
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Nievergelt
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Saraiva
authors.forename: Joel N
authors.initials: JN
authors.lastname: Buxbaum
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D017772:Amyloid Neuropathies / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D011174:Portugal; D011228:Prealbumin / Q000235:genetics*; D012177:Retinol-Binding Proteins / Q000235:genetics*; D054839:Retinol-Binding Proteins, Plasma; D000683:Serum Amyloid P-Component / Q000235:genetics*
chemical_list: D011228:Prealbumin; C101326:RBP4 protein, human; D012177:Retinol-Binding Proteins; D054839:Retinol-Binding Proteins, Plasma; D000683:Serum Amyloid P-Component