Contribution of
            <i>APOE</i>
            promoter polymorphisms to Alzheimer’s disease risk

Lambert, Jean‐Charles; Goumidi, Louisa; Myllykangas, Liisa; Ellis, Clare; Wang, J. C.; Bullido, María J.; Harris, Jonathan; Artiga, María J.; Hernández, Damián; Kwon, Jennifer M.; Frigard, B.; Petersen, R. C.; Cumming, Alastair M.; Pasquier, Florence; Sastre, Isabel; Tienari, Pentti J.; Frank, A. Carolin; Sulkava, Raimo; Morris, John C.; Clair, David St; Mann, David; Wavrant-DeVrièze, Fabienne; Ezquerra-Trabalon, M.; Amouyel, Philippe; Hardy, John; Haltia, Matti; Valdivieso, Fernando; Goate, A; Pérez‐Tur, Jordi; Lendon, Corinne; Chartier-Harlin, Marie-Christine

doi:10.1212/wnl.59.1.59

Cited by 104 publications

(90 citation statements)

References 43 publications

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“…The analysis of the distribution of the genotypic and estimated allelic frequencies of rs405509 showed an overrepresentation of G/G genotype and the G allele in AD patients according to Myllykangas et al 36 At variance, our results are in contrast with those carried out on French population 9,22 reporting an increased frequency of the T À219 allele in AD patients. The same results were obtained in elderly AD subjects as reported in a recent meta-analysis 26 and in other studies on population-based cohort. 37,38 In line with these conflicting results, it is not clear yet how the G À219 -T polymorphism exerts its possible biological effect in AD.…”

Section: Discussionsupporting

confidence: 89%

“…This association has been reported by previous studies 9,12,20 -25 and resulted in agreement with similar data collected from several independent samples genotyped for the apoE coding region and APOE promoter polymorphisms. 26 Whereas our data support these reported positive associations between rs449647 and AD, other studies failed to show similar results. 27 -29 It is not still clear how rs449647 exerts its effect on AD risk.…”

Section: Discussionsupporting

confidence: 57%

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The complex interaction between APOE promoter and AD: an Italian case–control study

Bizzarro¹,

Seripa

Acciarri

et al. 2009

Eur J Hum Genet

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The single nucleotide polymorphisms (SNPs) rs449647, rs769446 and rs405509 in the promoter region of the APOE gene have been variously suggested to be e4-independent risk factors for Alzheimer's disease (AD). A previous Italian study found that the rs449647 was significantly associated with late-onset AD. The aim of this study was to verify whether these APOE promoter SNPs are genetic risk factors for AD and to investigate their interaction with the common APOE polymorphism. A total of 169 clinically diagnosed AD patients and 99 cognitively intact age-matched controls were included in the study. Significant associations with AD independent from sex, age and APOE/e4 status were found for rs449647 A/A and rs405509 G/G genotypes (positive), and rs449647 A/T and rs405509 T/T genotypes (negative). Haplotype frequency estimation at the APOE locus showed significant associations for the ATG4, ATT4 and ACG3 (positive) and ATT2, ATT3 and TCG3 (negative) haplotypes. Therefore this study confirms the role of the rs449647 A/A genotype as risk factor for AD in Italy and suggests that promoter genotypes and APOE haplotypes might have a complex function in AD-associated genetic risk factors.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 57%

The complex interaction between APOE promoter and AD: an Italian case–control study

Bizzarro¹,

Seripa

Acciarri

et al. 2009

Eur J Hum Genet

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show abstract

“…All AD cases were Caucasians (n = 349), ascertained from two UK centres, the central belt of Scotland and Greater Manchester. 16 Diagnoses of definite or probable AD were established according to DSM-III-R and NINDCS-ADRDA criteria. The proportion of definite AD cases was 30%.…”

Section: Populationsmentioning

confidence: 99%

Evidence for the association of the S100β gene with low cognitive performance and dementia in the elderly

et al. 2007

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Variations in the S100b gene may be instrumental in producing a continuum from mild cognitive decline to overt dementia. After screening 25 single nucleotide polymorphisms (SNPs) in S100b, we observed association of the rs2300403 intron 2 SNP with poorer cognitive function in three independent populations. Moreover, we detected a significant association of this SNP with increased risk of developing dementia or Alzheimer's disease (AD) in six independent populations, especially in women and in the oldest. Furthermore, we characterised a new primate-specific exon within intron 2 (the corresponding mRNA isoform was called S100b2). S100b2 expression was increased in AD brain compared with controls, and the rs2300403 SNP was associated with elevated levels of S100b2 mRNA in AD brains, especially in women. Therefore, this genetic variant in S100b increases the risk of low cognitive performance and dementia, possibly by favouring a splicing event increasing S100b2 isoform expression in the brain.

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“…This strategy results from two major observations: (i) the expression of numerous genes is modified during AD aetiology, [4][5][6][7][8] (ii) polymorphisms within promoters of the APOE, PS1, PS2 and APP genes have been associated with the occurrence of AD. [9][10][11][12] Consequently, we assumed that genes located in one of the loci of interest defined by previous genome scans and exhibiting a differential expression between patients and controls, could constitute potential candidate genes for AD. We applied our strategy to nine different chromosomal regions previously identified by genome scan studies 13 and selected a candidate gene expressed in cases but not in controls, the ornithine transcarbamylase (OTC) located on Xp21.1.…”

Section: Introductionmentioning

confidence: 99%

Evidence for induction of the ornithine transcarbamylase expression in Alzheimer's disease

et al. 2007

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To more rapidly identify candidate genes located within chromosomal regions of interest defined by genome scan studies in Alzheimer's disease (AD), we have developed a customized microarray containing all the ORFs (n = 2741) located within nine of these regions. Levels of gene expression were assessed in total RNA from brain tissue of 12 controls and 12 AD patients. Of all genes showing differential expression, we focused on the ornithine transcarbamylase (OTC) gene on Xp21.1., a key enzyme of the urea cycle which we found to be expressed in AD brains but not in controls, as confirmed by RT-PCR. We also detected mRNA expression of all the other urea cycle enzymes in AD brains. Immunochemistry experiments revealed that the OTC expression was strictly restricted to vascular endothelial cells in brain. Furthermore, OTC activity was 880% increased in the CSF of probable AD cases compared with controls. We analysed the association of the OTC À389 G/A and À241 A/G promoter polymorphisms with the risk of developing AD. We observed that rare haplotypes may be associated with the risk of AD through a possible modulation of the methylation of the OTC promoter. In conclusion, our results suggest the involvement of a new pathway in AD brains involving the urea cycle.

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Contribution of APOE promoter polymorphisms to Alzheimer’s disease risk

Cited by 104 publications

References 43 publications

The complex interaction between APOE promoter and AD: an Italian case–control study

The complex interaction between APOE promoter and AD: an Italian case–control study

Evidence for the association of the S100β gene with low cognitive performance and dementia in the elderly

Evidence for induction of the ornithine transcarbamylase expression in Alzheimer's disease

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