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Human Molecular Genetics Advance Access published online on January 13, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi051
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Human Molecular Genetics © Oxford University Press 2005; all rights reserved

Article

Susceptibility and modifier genes in Portuguese transthyretin V30M amyloid polyneuropathy: complexity in a single gene disease

Miguel L. Soares 1, Teresa Coelho 2, Alda Sousa 3, Serge Batalov 4, Isabel Conceição 5, Maria L. Sales-Luís 5, Marylyn D. Ritchie 6, Scott M. Williams 7, Caroline M. Nievergelt 8, Nicholas J. Schork 9, Maria João Saraiva 10, and Joel N. Buxbaum 11*

1 Division of Rheumatology Research and the W.M. Keck Autoimmune Disease Center, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA; Amyloid Unit, Instituto de Biologia Molecular e Celular -IBMC, Porto, Portugal
2 Centro de Estudos de Paramiloidose, Porto; Neuropsychophysiology Unit, IBMC, Porto
3 Instituto de Ciências Biomédicas Abel Salazar, Porto; UnIGENe, IBMC, Porto
4 Computational Biology Department, The Genomics Institute of the Novartis Research Foundation, San Diego, CA
5 Department of Neurology, Hospital de Santa Maria; Centro de Estudos Egas Moniz, Faculty of Medicine, Lisbon, Portugal
6 Center for Human Genetics Research, Vanderbilt University Medical School, Nashville, TN; Department of Molecular Physiology, Vanderbilt University Medical Center, Nashville, TN
7 Center for Human Genetics Research, Vanderbilt University Medical School, Nashville, TN; Department of Molecular Physiology, Vanderbilt University Medical Center, Nashville, TN; Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN
8 Department of Psychiatry, University of California at San Diego, La Jolla CA
9 Division of Rheumatology Research and the W.M. Keck Autoimmune Disease Center, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA; Department of Psychiatry, University of California at San Diego, La Jolla CA
10 Amyloid Unit, Instituto de Biologia Molecular e Celular -IBMC, Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar, Porto
11 Division of Rheumatology Research and the W.M. Keck Autoimmune Disease Center, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, MEM-230, La Jolla, CA 92037, USA

* To whom correspondence should be addressed.
Joel N. Buxbaum, E-mail: jbux{at}scripps.edu


  Abstract

Familial amyloid polyneuropathy (FAP) 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, while 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 (MDR) indicated that the best genetic model for classical onset vs. controls involved the APCS gene, while for late-onset cases one APCS variant (APCSv1), and two RBP variants (RBPv1 and RBPv2) are involved. Thus, while the TTR V30M mutation is required for disease in Portuguese patients, different genetic factors may govern the age of onset as well as the occurrence of anticipation.


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