Two sites in the MAPT region confer genetic risk for Guam ALS/PDC and dementia
Identifieur interne : 000E88 ( Main/Exploration ); précédent : 000E87; suivant : 000E89Two sites in the MAPT region confer genetic risk for Guam ALS/PDC and dementia
Auteurs : Purnima Desai Sundar ; Chang-En Yu ; Weiva Sieh ; Ellen Steinbart ; Ralph M. Garruto ; Kiyomitsu Oyanagi ; Ulla-Katrina Craig ; Thomas D. Bird ; Ellen M. Wijsman ; Douglas R. Galasko [États-Unis] ; Gerard D. Schellenberg [États-Unis]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2007-02-01.
Abstract
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 (CI)1.108.25] for GD, 4-fold (95 CI1.4011.64) for PDC-G and 6-fold (95 CI1.4432.14) 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 CI1.002.62) for GD, 2-fold (95 CI1.283.66) for PDC-G, and 1.5-fold (95 CI0.743.00) 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 neuro-degenerative disorders by regulating MAPT expression.
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DOI: 10.1093/hmg/ddl463
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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 (CI)1.108.25] for GD, 4-fold (95 CI1.4011.64) for PDC-G and 6-fold (95 CI1.4432.14) 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 CI1.002.62) for GD, 2-fold (95 CI1.283.66) for PDC-G, and 1.5-fold (95 CI0.743.00) 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 neuro-degenerative disorders by regulating MAPT expression.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><noCountry><name sortKey="Bird, Thomas D" sort="Bird, Thomas D" uniqKey="Bird T" first="Thomas D." last="Bird">Thomas D. Bird</name><name sortKey="Craig, Ulla Katrina" sort="Craig, Ulla Katrina" uniqKey="Craig U" first="Ulla-Katrina" last="Craig">Ulla-Katrina Craig</name><name sortKey="Garruto, Ralph M" sort="Garruto, Ralph M" uniqKey="Garruto R" first="Ralph M." last="Garruto">Ralph M. Garruto</name><name sortKey="Oyanagi, Kiyomitsu" sort="Oyanagi, Kiyomitsu" uniqKey="Oyanagi K" first="Kiyomitsu" last="Oyanagi">Kiyomitsu Oyanagi</name><name sortKey="Sieh, Weiva" sort="Sieh, Weiva" uniqKey="Sieh W" first="Weiva" last="Sieh">Weiva Sieh</name><name sortKey="Steinbart, Ellen" sort="Steinbart, Ellen" uniqKey="Steinbart E" first="Ellen" last="Steinbart">Ellen Steinbart</name><name sortKey="Sundar, Purnima Desai" sort="Sundar, Purnima Desai" uniqKey="Sundar P" first="Purnima Desai" last="Sundar">Purnima Desai Sundar</name><name sortKey="Wijsman, Ellen M" sort="Wijsman, Ellen M" uniqKey="Wijsman E" first="Ellen M." last="Wijsman">Ellen M. Wijsman</name><name sortKey="Yu, Chang En" sort="Yu, Chang En" uniqKey="Yu C" first="Chang-En" last="Yu">Chang-En Yu</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Galasko, Douglas R" sort="Galasko, Douglas R" uniqKey="Galasko D" first="Douglas R." last="Galasko">Douglas R. Galasko</name></noRegion><name sortKey="Schellenberg, Gerard D" sort="Schellenberg, Gerard D" uniqKey="Schellenberg G" first="Gerard D." last="Schellenberg">Gerard D. Schellenberg</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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