Dataset Information

Genetic Variants Associated With Neurodegenerative Diseases Regulate Gene Expression in Immune Cell CD14+ Monocytes.

ABSTRACT: Until now, large-scale genome-wide association studies have identified 94 genes associated with Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Expression quantitative trait locus (eQTL) analysis showed that six genetic variants around six of these 94 genes could drive both disease susceptibility and altered expression of six nearby genes including CD33 (rs3865444), PILRB (rs1476679), NUP160 (rs10838725), LRRK2 (rs76904798), RGS1 (rs1323292), and METTL21B (rs701006). However, two of these six genetic variants rs1476679 and rs76904798 variants could regulate the expression of PILRB and LRRK2 only in the human monocyte-derived microglia-like (MDMi) cells, but not in human peripheral blood monocytes. Here, we aim to verify these findings using another two eQTL datasets in human peripheral blood immune cell CD14+ monocytes. The results that showed that rs1476679 and rs76904798 variants or their proxy variants could significantly regulate the expression of PILRB and LRRK2 in immune cell CD14+ monocytes and human peripheral blood. We believe that these findings provide important supplementary information about the regulatory mechanisms by which both variants influence PILRB and LRRK2 gene expression and neurodegenerative disease risk.

SUBMITTER: Sun JY

PROVIDER: S-EPMC6305550 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Genetic Variants Associated With Neurodegenerative Diseases Regulate Gene Expression in Immune Cell CD14+ Monocytes.

Sun Jing-Yi JY Hou Ya-Jun YJ Zhang Yan Y Wang Longcai L Liu Lidong L Sun Bao-Liang BL Yuan Hui H

Frontiers in genetics 20181218

Until now, large-scale genome-wide association studies have identified 94 genes associated with Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Expression quantitative trait locus (eQTL) analysis showed that six genetic variants around six of these 94 genes could drive both disease susceptibility and altered expression of six nearby genes including CD33 (rs3865444), PILRB (rs1476679), NUP160 (rs10838725), LRRK2 (rs76904798), RGS1 (rs1323292), and METTL21B (rs701006). However, t ...[more]

PMID: 30619483

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Project description:Depression often accompanies the perimenopausal transition and it often precedes overt symptomology in common neurodegenerative diseases (NDDs, such as Alzheimer's, Parkinson's, Huntington, amyotrophic lateral sclerosis). Serotonin dysfunction is frequently found in the different etiologies of depression. We have shown that ovariectomized (Ovx) monkeys treated with estradiol (E) for 28 days supplemented with placebo or progesterone (P) on days 14-28 had reduced DNA fragmentation in serotonin neurons of the dorsal raphe nucleus, and long-term Ovx monkeys had fewer serotonin neurons than intact controls. We questioned the effect of E alone or E+P (estradiol supplemented with progesterone) on gene expression related to DNA repair, protein folding (chaperones), the ubiquitin-proteosome, axon transport and NDD-specific genes in serotonin neurons. Ovx macaques were treated with placebo, E or E+P (n=3 per group) for 1 month. Serotonin neurons were laser captured and subjected to microarray analysis and quantitative real-time PCR (qRT-PCR). Increases were confirmed with qRT-PCR in five genes that code for proteins involved in repair of strand breaks and nucleotide excision. NBN1, PCNA (proliferating nuclear antigen), GADD45A (DNA damage-inducible), RAD23A (DNA damage recognition) and GTF2H5 (gene transcription factor 2H5) significantly increased with E or E+P treatment (all analysis of variance (ANOVA), P<0.01). Chaperone genes HSP70 (heat-shock protein 70), HSP60 and HSP27 significantly increased with E or E+P treatment (all ANOVA, P<0.05). HSP90 showed a similar trend. Ubiquinase coding genes UBEA5, UBE2D3 and UBE3A (Parkin) increased with E or E+P (all ANOVA, P<0.003). Transport-related genes coding kinesin, dynein and dynactin increased with E or E+P treatment (all ANOVA, P<0.03). SCNA (α-synuclein) and ADAM10 (α-secretase) increased (both ANOVA, P<0.02) but PSEN1 (presenilin1) decreased (ANOVA, P<0.02) with treatment. APP decreased 10-fold with E or E+P administration. Newman-Keuls post hoc comparisons indicated variation in the response to E alone versus E+P across the different genes. In summary, E or E+P increased gene expression for DNA repair mechanisms in serotonin neurons, thereby rendering them less vulnerable to stress-induced DNA fragmentation. In addition, E or E+P regulated four genes encoding proteins that are often misfolded or malfunctioning in neuronal populations subserving overt NDD symptomology. The expression and regulation of these genes in serotonergic neurons invites speculation that they may mediate an underlying disease process in NDDs, which in turn may be ameliorated or delayed with timely hormone therapy in women.

Project description:BackgroundCD14 is an important player in host innate immunity in that it confers lipopolysaccharide sensitivity to cell types like neutrophils, monocytes and macrophages. The study was aimed at characterizing the CD14 gene of cattle for sequence variations and to determine the effect of variations on the expression of the protein on the surfaces of monocytes and neutrophils in healthy dairy cows.ResultsFive SNPs were identified: two within the coding regions (g.A1908G and g.A2318G, numbering is according to GenBank No. EU148609), one in the 5' (g.C1291T) and two in the 3' (g.A2601G and g.G2621T) untranslated regions. SNP 1908 changes amino acid 175 of the protein (p.Asn175Asp, numbering is according to GenBank No. ABV68569), while SNP 2318 involves a synonymous codon change. Coding region SNPs characterized three gene alleles A (GenBank No. EU148609), A1 (GenBank No. EU148610) and B (GenBank No. EU148611) and two deduced protein variants A (ABV68569 and ABV68570) and B (ABV68571). Protein variant A is more common in the breeds analyzed. All SNPs gave rise to 3 haplotypes for the breeds. SNP genotype 1908AG was significantly (P<0.01) associated with a higher percentage of neutrophils expressing more CD14 molecules on their surfaces. The promoter region contains several transcription factor binding sites, including multiple AP-1 and SP1 sites and there is a high conservation of amino acid residues between the proteins of closely related species.ConclusionThe study has provided information on sequence variations within the CD14 gene and proteins of cattle. The SNP responsible for an amino acid exchange may play an important role in the expression of CD14 on the surfaces of neutrophils. Further observations involving a larger sample size are required to validate our findings. Our SNP and association analyses have provided baseline information that may be used at defining the role of CD14 in mediating bacterial infections. The computational analysis on the promoter and comparative analysis with other species has revealed regions of regulatory element motifs that may indicate important regulatory effects on the gene.

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Genetic Variants Associated With Neurodegenerative Diseases Regulate Gene Expression in Immune Cell CD14+ Monocytes.

Publications

Genetic Variants Associated With Neurodegenerative Diseases Regulate Gene Expression in Immune Cell CD14+ Monocytes.

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