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Alzheimer's disease and HLA-A2: linking neurodegenerative to immune processes through an in silico approach.

Cifuentes RA, Murillo-Rojas J - Biomed Res Int (2014)

Bottom Line: It has been suggested a modifier effect on the risk that depends on genetic loadings.Next, by means of an in silico approach, we used experimental knowledge of protein-protein interactions to evaluate the top ranked genes shared by both concepts, previously found through text mining.The meta-analysis did not show a significant pooled OR (1.11, 95% CI: 0.98 to 1.24 in Caucasians), in spite of the fact that four of the included studies had a significant OR > 1 and none of them a significant OR < 1.

View Article: PubMed Central - PubMed

Affiliation: Area of Basic Sciences, Faculty of Medicine, Universidad Militar Nueva Granada, Bogotá, Colombia.

ABSTRACT
There is a controversial relationship between HLA-A2 and Alzheimer's disease (AD). It has been suggested a modifier effect on the risk that depends on genetic loadings. Thus, the aims of this study were to evaluate this relationship and to reveal genes associated with both concepts the HLA-A gene and AD. Consequently, we did first a classical systematic review and a meta-analysis of case-control studies. Next, by means of an in silico approach, we used experimental knowledge of protein-protein interactions to evaluate the top ranked genes shared by both concepts, previously found through text mining. The meta-analysis did not show a significant pooled OR (1.11, 95% CI: 0.98 to 1.24 in Caucasians), in spite of the fact that four of the included studies had a significant OR > 1 and none of them a significant OR < 1. In contrast, the in silico approach retrieved nonrandomly shared genes by both concepts (P = 0.02), which additionally encode truly interacting proteins. The network of proteins encoded by APP, ICAM-1, ITGB2, ITGAL, SELP, SELL, IL2, IL1B, CD4, and CD8A linked immune to neurodegenerative processes and highlighted the potential roles in AD pathogenesis of endothelial regulation, infectious diseases, specific antigen presentation, and HLA-A2 in maintaining synapses.

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Related in: MedlinePlus

Interaction network of the proteins encoded by genes that contribute at least 0.1% to the cohesion score between HLA-A and AD. The nodes correspond to proteins encoded by the seed genes, to significant intermediary ones (indicated by one asterisk) and to a nonsignificant intermediary one (indicated by two asterisks).
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fig2: Interaction network of the proteins encoded by genes that contribute at least 0.1% to the cohesion score between HLA-A and AD. The nodes correspond to proteins encoded by the seed genes, to significant intermediary ones (indicated by one asterisk) and to a nonsignificant intermediary one (indicated by two asterisks).

Mentions: Regarding the interaction analysis, proteins encoded from 10 of the 21 genes used as input were kept in the network, (Figure 2). Some genes shared by HLA-A and AD such as APLP2, HLA-DRB1, and HFE did not appear in the network despite their studied association with AD and/or HLA-A2 [8, 38, 39] and even the linkage disequilibrium with the HLA-A gene [40]. This could have been because of the strict threshold, a maximum pathway length of two, established to avoid weak interactions. Furthermore, the network had 13 intermediary nodes, 12 significant with a z-score above the cutoff of 2.5 (Table 3), thus indicating that the seed genes encode proteins that had strong and specific interactions.


Alzheimer's disease and HLA-A2: linking neurodegenerative to immune processes through an in silico approach.

Cifuentes RA, Murillo-Rojas J - Biomed Res Int (2014)

Interaction network of the proteins encoded by genes that contribute at least 0.1% to the cohesion score between HLA-A and AD. The nodes correspond to proteins encoded by the seed genes, to significant intermediary ones (indicated by one asterisk) and to a nonsignificant intermediary one (indicated by two asterisks).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150521&req=5

fig2: Interaction network of the proteins encoded by genes that contribute at least 0.1% to the cohesion score between HLA-A and AD. The nodes correspond to proteins encoded by the seed genes, to significant intermediary ones (indicated by one asterisk) and to a nonsignificant intermediary one (indicated by two asterisks).
Mentions: Regarding the interaction analysis, proteins encoded from 10 of the 21 genes used as input were kept in the network, (Figure 2). Some genes shared by HLA-A and AD such as APLP2, HLA-DRB1, and HFE did not appear in the network despite their studied association with AD and/or HLA-A2 [8, 38, 39] and even the linkage disequilibrium with the HLA-A gene [40]. This could have been because of the strict threshold, a maximum pathway length of two, established to avoid weak interactions. Furthermore, the network had 13 intermediary nodes, 12 significant with a z-score above the cutoff of 2.5 (Table 3), thus indicating that the seed genes encode proteins that had strong and specific interactions.

Bottom Line: It has been suggested a modifier effect on the risk that depends on genetic loadings.Next, by means of an in silico approach, we used experimental knowledge of protein-protein interactions to evaluate the top ranked genes shared by both concepts, previously found through text mining.The meta-analysis did not show a significant pooled OR (1.11, 95% CI: 0.98 to 1.24 in Caucasians), in spite of the fact that four of the included studies had a significant OR > 1 and none of them a significant OR < 1.

View Article: PubMed Central - PubMed

Affiliation: Area of Basic Sciences, Faculty of Medicine, Universidad Militar Nueva Granada, Bogotá, Colombia.

ABSTRACT
There is a controversial relationship between HLA-A2 and Alzheimer's disease (AD). It has been suggested a modifier effect on the risk that depends on genetic loadings. Thus, the aims of this study were to evaluate this relationship and to reveal genes associated with both concepts the HLA-A gene and AD. Consequently, we did first a classical systematic review and a meta-analysis of case-control studies. Next, by means of an in silico approach, we used experimental knowledge of protein-protein interactions to evaluate the top ranked genes shared by both concepts, previously found through text mining. The meta-analysis did not show a significant pooled OR (1.11, 95% CI: 0.98 to 1.24 in Caucasians), in spite of the fact that four of the included studies had a significant OR > 1 and none of them a significant OR < 1. In contrast, the in silico approach retrieved nonrandomly shared genes by both concepts (P = 0.02), which additionally encode truly interacting proteins. The network of proteins encoded by APP, ICAM-1, ITGB2, ITGAL, SELP, SELL, IL2, IL1B, CD4, and CD8A linked immune to neurodegenerative processes and highlighted the potential roles in AD pathogenesis of endothelial regulation, infectious diseases, specific antigen presentation, and HLA-A2 in maintaining synapses.

Show MeSH
Related in: MedlinePlus