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.

Variants in RBP4 and AR genes modulate age at onset in familial amyloid polyneuropathy (FAP ATTRV30M)

“…We also included five SNPs previously studied in order to replicate the results found by Soares et al 9 The SNP frequencies in the European population were obtained by resorting to the HapMap Project and dbSNP. All variants were submitted to the Leiden Open Variation Database shared installation (URL: http://databases.lovd.nl/ shared/screenings?search_owned_by_=="Carolina%20Lemos"), with the following submission IDs: APCS: http://www.lovd.nl/APCS; AR: http://www.…”

“…7 Some modifier genes such as amyloid P component, serum (APCS), complement C1QA and C1QC and plasma retinol-binding protein 4 (RBP4) have been unraveled so far but they only explain a small part of the AO variability in FAP ATTRV30M. 8,9 In a previous study, Soares et al 9 compared Portuguese patients in a classic casecontrol approach; these authors found that the variants studied in the APCS gene had a combined modifier effect when analyzing early-onset group versus controls, whereas the combination of one variant from APCS (rs6689429) and two variants from RBP4 (rs7091052 and rs28383574) seemed to be involved with late-onset group. 9 No comparisons were made between early-and late-onset cases.…”

The genetics of the amyloidoses: interactions with immunity and inflammation

“…Those studies did not show significant effects of any of the five genes analyzed, but demonstrated that many more interactions among alleles at these loci occurred in patients with late onset of the disease than among individuals with early onset. 109 These results suggested that early onset was the default state of the mutation and interactions with the products of some of these alleles delayed the appearance of symptoms, contributing perhaps 25% to the late onset phenotype. The sample size was not sufficiently large to establish whether single gene effects were also present.…”

Confirmation of the biological significance of transthyretin as a biomarker for cutaneous T-cell lymphoma by its protein interaction partners

“…We have demonstrated an interaction between TTR and RBP-4. Moreover, Soares et al (25) reported RBP-4 to play a role in Portuguese TTR v30M amyloid polyneuropathy.…”