Human Molecular Genetics Advance Access originally published online on January 13, 2005
Human Molecular Genetics 2005 14(4):543-553; doi:10.1093/hmg/ddi051
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Human Molecular Genetics, Vol. 14, No. 4 © Oxford University Press 2005; all rights reserved
Susceptibility and modifier genes in Portuguese transthyretin V30M amyloid polyneuropathy: complexity in a single-gene disease
1Department of Molecular and Experimental Medicine, Division of Rheumatology Research and the W.M. Keck Autoimmune Disease Center, The Scripps Research Institute, La Jolla, CA, USA, 2Amyloid Unit, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal, 3Neuropsychophysiology Unit and 4UnIGENe, IBMC, 5Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal, 6Centro de Estudos de Paramiloidose, Porto, Portugal, 7Computational Biology Department, The Genomics Institute of the Novartis Research Foundation, San Diego, CA, USA, 8Department of Neurology, Faculty of Medicine, Centro de Estudos Egas Moniz, Hospital de Santa Maria, Lisbon, Portugal, 9Center for Human Genetics Research, 10Department of Molecular Physiology and Biophysics, 11Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA and 12Department of Psychiatry, University of California at San Diego, La Jolla, CA, USA
Received October 12, 2004; Accepted December 23, 2004
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.
* To whom correspondence should be addressed at: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, MEM-230, La Jolla, CA 92037, USA. Tel: +1 8587848895; Fax: +1 8587848891; Email: jbux{at}scripps.edu
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