Polymorphisms in the presenilin 1 and presenilin 2 genes and risk for sporadic Alzheimer’s disease

Combarros, Onofre; Alvarez-Arcaya, A.; Oterino, Agustı́n; Berciano, José; Delgado-Rodrı́guez, Miguel; Peña, Nicolás; Fernández-Viadero, Carlos; Pérez-López, José Luis; Setién, Sonia; Carvajal, Alejandra

doi:10.1016/s0022-510x(99)00254-3

Cited by 12 publications

(11 citation statements)

References 19 publications

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“…The most likely reason for this discrepancy is an expansion of the sample set and the use of a more accurate and reliable genotyping technique. The current findings are in agreement with the two other published investigations of this same polymorphism [Singleton et al, 1997;Combarros et al, 1999], where there was no increased risk of AD associated with this polymorphism.…”

Section: Discussionsupporting

confidence: 94%

“…An initial study by our study group [Brookes et al, 1997] presented a positive association with homozygosity of a CC genotype of a polymorphism in the 3 0 untranslated region of PSEN2. Two follow-up studies did not confirm this association [Singleton et al, 1997;Combarros et al, 1999]. A third study reported a positive association in a separate PSEN2 silent substitution in exon 2 [Korovaitseva et al, 1997].…”

Section: Introductionmentioning

confidence: 94%

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Evaluation of multiple presenilin 2 SNPs for association with early‐onset sporadic Alzheimer disease

Howell

Brookes

2002

Am. J. Med. Genet.

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The presenilin genes encode proteins that modify, mediate, or perform similar functions to gamma-secretase, the enzyme responsible for converting amyloid beta precursor protein (APP) into beta-amyloid. Mutations in the presenilin genes cause an increased production of Abeta42, the aberrant form of beta-amyloid found in the neural plaques of Alzheimer disease patients. Previously reported association studies of presenilin 2 (PSEN2) polymorphisms with early-onset Alzheimer disease (EOAD) have produced contradictory results. In an effort to resolve these differences, we tested eight single nucleotide polymorphisms in and around the 3' region of the PSEN2 gene for association with EOAD. An initial set of Scottish EOAD cases (n = 121) and controls (n = 152) was screened using the genotyping method dynamic allele-specific hybridization (DASH). No significant differences were seen between allele or genotype frequencies of cases and controls. However, when conditioned on the risk allele (epsilon 4) APOE, three polymorphisms showed allelic association with a P value below 0.05. These same polymorphisms were in near 100% linkage disequilibrium with each other (P < 5 x 10(-5)), and in each, one of the homozygous genotypes was absent in controls but present in the cases. Replication in an independent set of Scottish EOAD cases (n = 84) and controls (n = 173) did not confirm this finding. From this study we find no evidence to suggest that variations in the PSEN2 gene pose as major risk factors for sporadic EOAD.

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Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 94%

Evaluation of multiple presenilin 2 SNPs for association with early‐onset sporadic Alzheimer disease

Howell

Brookes

2002

Am. J. Med. Genet.

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“…Unlike the finding of an association between homozygosity for the C allele in the 3)-untranslated region of the PS2 gene and an increased risk for AD [46], other studies [41,43] found no increased risk for AD directly dependent on this polymorphism, although homozygosity for the C allele of the PS2 gene may increase the risk conferred by the presence of an APOE Â4 allele [43].…”

Section: Ps1 and Ps2mentioning

confidence: 79%

“…Moreover, all these studies disclosed the lack of a synergistic effect of the PS1 and APOE Â4 loci on the risk of AD. Other studies [41,42] reported no increased risk for AD as a direct consequence of PS1 intron 8 polymorphism, and an analysis suggested a trend towards an increase in the APOE Â4 risk by the PS1/11 genotype [43]. A meta-analysis from 16 studies including 2,663 AD patients and 2,598 controls showed that the association between the PS1/11 genotype and AD was significant (OR = 1.16) [44].…”

Section: Ps1 and Ps2mentioning

confidence: 98%

Candidate Gene Association Studies in Sporadic Alzheimer’s Disease

Combarros

Alvarez-Arcaya²,

Sánchez-Guerra³

et al. 2002

Dement Geriatr Cogn Disord

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The genetics of Alzheimer’s disease (AD) is complex. Three genes (amyloid precursor protein, presenilin 1 and presenilin 2) have been described in the relatively rare, early-onset, autosomal dominant familial form of AD. In the common, non-familial (sporadic) late-onset AD, the major known genetic risk factor is the Ε4 allele of the apolipoprotein E (APOE) gene. However, at least half of the people who develop AD do not carry this allele, and not all people who do carry this allele develop AD even if they live to an old age. Therefore, approximately 30 other candidate genes involving a protein in a critical pathway in the pathogenesis of disease (principally interaction with amyloid-β, oxidative stress and inflammation/apoptosis) have been considered as risk factors for sporadic AD. Then these genes have been sequenced in search of genetic variability or polymorphisms, and each putative polymorphism has been reported to alter the risk of AD either directly or by an interaction with the APOE Ε4 allele. However, positive-association studies with these candidate genes have not been consistently confirmed.

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“…Estes genes parecem estar relacionados, basicamente, à formação de agregados, estresse oxidativo e resposta inflamatória. Por exemplo, podemos citar, para a formação de agregados, a proteína precursora de beta amilóide (APP) (Goate et al, 1991), preselinina (PS1 e PS2) (Combarros et al, 1999), apolipoproteína E (APOE) (Poirier et al, 1993), cistatina C (Palsdottir et al, 1989), ubiquitina 1 (Xue & Jia, 2006), alfa2-macroglobulina (Blacker et al, 1998); para estresse oxidativo, a óxido nítrico sintase (NOS2, NOS3) (Singleton et al, 2001); e para resposta inflamatória, IL-1 alfa (Nicoll et al, 2000), IL-1 beta, IL-6 (Ravaglia et al, 2006) e TNF alfa (Alvarez et al, 2002).…”

Section: Considerações E Conclusões Finaisunclassified

Sistemas neuromodulatórios: implicações fisiopatológicas

Carrettiero¹

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Polymorphisms in the presenilin 1 and presenilin 2 genes and risk for sporadic Alzheimer’s disease

Cited by 12 publications

References 19 publications

Evaluation of multiple presenilin 2 SNPs for association with early‐onset sporadic Alzheimer disease

Evaluation of multiple presenilin 2 SNPs for association with early‐onset sporadic Alzheimer disease

Candidate Gene Association Studies in Sporadic Alzheimer’s Disease

Sistemas neuromodulatórios: implicações fisiopatológicas

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