Two sites in the MAPT region confer genetic risk for Guam ALS/PDC and dementia
| Autor: | U. K. Craig, Ellen J. Steinbart, Purnima Desai Sundar, Thomas D. Bird, Chang En Yu, Ralph M. Garruto, Ellen M. Wijsman, Weiva Sieh, Gerard D. Schellenberg, Douglas Galasko, Kiyomitsu Oyanagi |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Tau protein Single-nucleotide polymorphism tau Proteins Biology Polymorphism Single Nucleotide Progressive supranuclear palsy Degenerative disease Gene Frequency Parkinsonian Disorders Risk Factors Genetics medicine Dementia SNP Humans Genetic Predisposition to Disease Allele Amyotrophic lateral sclerosis Molecular Biology Genetics (clinical) Aged Aged 80 and over Amyotrophic Lateral Sclerosis Chromosome Mapping General Medicine Middle Aged medicine.disease Haplotypes Case-Control Studies biology.protein Guam Female Chromosomes Human Pair 17 |
| Zdroj: | Human molecular genetics. 16(3) |
| ISSN: | 0964-6906 |
| Popis: | Unusual forms of amyotrophic lateral sclerosis (ALS-G), Parkinsonism dementia complex (PDC-G) and Guam dementia (GD) are found in Chamorros, the indigenous people of Guam. Neurofibrillary tangles composed of hyperphosphorylated tau are a neuropathologic feature of these closely related disorders. To determine if variation in the gene that encodes microtubule-associated protein tau gene (MAPT) contributes to risk for these disorders, we genotyped nine single nucleotide polymorphism (SNP) sites and one insertion/deletion in the 5' end of MAPT in 54 ALS-G, 135 PDC-G, 153 GD and 258 control subjects, all of whom are Chamorros. Variation at three SNPs (sites 2, 6 and 9) influenced risk for ALS-G, PDC-G and GD. SNP2 acts through a dominant mechanism and is independent of the risk conferred by SNPs 6 and 9, the latter two acting by a recessive mechanism. Persons with the high-risk SNP6 and SNP9 AC/AC diplotype had an increased risk of 3-fold [95% confidence interval (Cl) = 1.10-8.25] for GD, 4-fold (95% Cl = 1.40-11.64) for PDC-G and 6-fold (95% Cl = 1.44-32.14) for ALS-G, compared to persons with other diplotypes after adjusting for SNP2. Carriers of the SNP2 G allele had an increased risk of 1.6-fold (95% Cl = 1.00-2.62) for GD, 2-fold (95% Cl = 1.28-3.66) for PDC-G, and 1.5-fold (95% Cl = 0.74-3.00) for ALS-G, compared to non-carriers after adjusting for SNPs 6 and 9. Others have shown that SNP6 is also associated with risk for progressive supranuclear palsy. These two independent cis-acting sites presumably influence risk for Guam neurodegenerative disorders by regulating MAPT expression. |
| Databáze: | OpenAIRE |
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