Genetic Association and Altered Gene Expression of Mir-155 in Multiple Sclerosis Patients
Abstract
:1. Introduction
2. Results and Discussion
2.1. miRNA Selection
- human miRNA genes mapping within loci previously associated with MS or EAE (experimental autoimmune encephalitis, the experimentally-induced form of MS in animal models) were extracted using the UCSC genome browser (reference sequence NCBI Build 36.1/hg18), crossing data extracted with the sno/miRNA track with those extracted either with the GAD View or with the RGD-Rat-QTL/ MGI-Mouse-QTL tracks;
- miRNAs known to be preferentially expressed in tissues/cells involved in MS were retrieved from the literature, as well as through publicly available miRNA expression repositories (i.e., the smiRNAdb database and the miRNA Map website [44]).
2.2. Mir-155: An MS Signature?
2.3. Association Analysis with the Mir-155 Locus
3. Experimental Section
3.1. Subjects
3.2. RNA Samples
3.3. MiRNA Expression Profiling By Microbead-Based Technology
3.4. Real-Time qRT-PCR Analyses
3.5. DNA Samples and Genotyping
3.6. Association Analysis
3.7. Web Resources
- OMIM, Online Mendelian Inheritance in Man, http://www.ncbi.nlm.nih.gov/omim/
- The dChip software, http://www.dchip.org/
- The PLINK software, http://pngu.mgh.harvard.edu/~purcell/plink/
- The Haploview software, http://www.broad.mit.edu/mpg/haploview/
- The University of California Santa Cruz Genome Browser (UCSC), http://genome.ucsc.edu/
- The smiRNAdb repository, http://www.mirz.unibas.ch/cloningprofiles/
- The miRNA MAP website, http://mirnamap.mbc.nctu.edu.tw/
- The GeneCards website, http://www.genecards.org/
- The dbGaP database, http://www.ncbi.nlm.nih.gov/gap
4. Limitations and Conclusions
Acknowledgments
References
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miRNA | Genomic location 1 | Expression 2 | Known targets 2, 3 | Function2 | Association 1 | ||
---|---|---|---|---|---|---|---|
MS | EAE | ||||||
1 | let-7f | chr9q22 chrXp11 | CD8+ T cells (ubiquitous) | TLR4 | innate immune response | no | yes |
2 | mir-15a | chr13q14 | thymus, spleen | DMP1/DMTF1 | unknown | no | |
3 | mir-15b | 3q26 | CD8+ T cells, lymphocyte development | no validated targets | mutations in mir16–15 cause autoimmune and B lymphoproliferative disease in mice | ||
4 | mir-16 | chr3q26 chr13q14 | BCL2, TPPP3 | ||||
5 | mir-17-3p | chr13q31 | lymphocytes, lymphoid tissues | PTEN, Bim, AML1 | mir-17–92 cluster higher expression in lymphocytes causes autoimmune disease in mice | ||
6 | mir-17-5p | chr13q32 | myeloid cells | no validated targets | mir-17–92 cluster higher expression in lymphocytes causes autoimmune disease in mice; monocyte proliferation and differentiation | ||
7 | mir-18a | chr13q31 | placenta, spleen, kidney, thymus | no validated targets | mir-17–92 cluster higher expression in lymphocytes causes autoimmune disease in mice | ||
8 | mir-19a | chr13q31 chrXq26 | lymphocytes, lymphoid tissues | PTEN, Bim | |||
9 | mir-19b-1 | chr13q31 | thymus, ovary, prostate, spleen | no validated targets | |||
10 | mir-20a | lymphocyte development; bladder, lung, thymus | AML1 | ||||
11 | mir-21 | chr17q23 | CD8+ T cells, lymphocyte development | PTEN, Pdcd4, TPM1, IL12a | macrophage activation | no 4 | |
12 | mir-23b | chr9q22 | hematopoietic cells | Notch1 | neural development | no | yes |
13 | mir-27b | lung, UBC-EPC, MVEC, CTCL | CYP1B1, Notch1 | neural development | |||
14 | mir-92a | chr13q31 Xq26 | lymphocytes, lymphoid tissues | PTEN, Bim | mir-17–92 cluster higher expression in lymphocytes causes autoimmune disease in mice | no | |
15 | mir-105 | Xq28 | nervous and reproductive system | no validated targets | unknown | yes | |
16 | mir-142-3p | chr17q22 | CD8+ T cells, lymphocyte development | no validated targets | unknown | no 4 | |
17 | mir-142-5p | ||||||
18 | mir-146a | chr5q33 | B cells, monocytes | IRF7, TRAF6, IRAK1, IRAK2 | innate immune response, induced by EBV, TLR signaling | no | yes |
19 | mir-150 | chr19q13 | CD8+ T cells, spleen, thymus, lymphocyte development | Myb, AID, BACH1, CEBPB, CSFR | B-cell development, T-cell activation, innate and adaptive immune response | no | |
20 | mir-155 | chr21q21 | B, T, and dendritic cells, monocytes, spleen, thymus, lung | MAF, AGTR1, FADD, IKK, JARID2, PU.1, Ripk1, SOCS1, TAB2, CD47 | macrophages germinal center response, IgG class switch, peripheral T-cell development | ||
21 | mir-181a | chr1q32.1 chr9q33.3 | lymphocyte maturation (highest in CD4+CD8+ T cells) | SHP2, PTPN22, AID, DUSP5-6, CD69, BCL2, TCR alpha | lymphocyte maturation, both positive and negative selection | yes | yes |
22 | mir-181b | brain, thymus, lymphocytes | Tcl1, AID | B-cell class switch |
SNP | Minor allele | Minor allele frequency in MS cases (%) | Minor allele frequency in controls (%) | P value | OR | 95% CI |
---|---|---|---|---|---|---|
rs1893650 | T | 29.4 | 28.1 | 0.53 | 1.07 | 0.86–1.32 |
rs2829803 | G | 26.9 | 24.0 | 0.15 | 1.17 | 0.94–1.44 |
rs2282471 | T | 16.6 | 14.6 | 0.28 | 1.16 | 0.89–1.51 |
rs2829806 | T | 28.1 | 24.4 | 0.076 | 1.22 | 0.98–1.52 |
SNP | Minor allele | Major allele | Genotype frequencies in MS cases (%) | Genotype frequencies in controls (%) | P value |
---|---|---|---|---|---|
rs1893650 | T | C | 7.5/44.0/48.5 | 8.9/38.4/52.7 | 0.24 |
rs2829803 | G | A | 7.2/39.5/53.3 | 6.5/35.1/58.4 | 0.30 |
rs2282471 | T | C | 2.0/29.2/68.8 | 3.1/23.1/73.8 | 0.099 |
rs2829806 | T | G | 6.1/44.2/49.7 | 5.1/38.5/56.4 | 0.16 |
SNPs | Haplotype | Haplotype frequency in MS cases (%) | Haplotype frequency in controls (%) | P value |
---|---|---|---|---|
rs1893650 rs2829803 rs2282471 | TGT | 13.4 | 11.7 | 0.28 |
TAT | 2.4 | 2.3 | 0.99 | |
TGC | 10.9 | 11.4 | 0.70 | |
CGC | 1.1 | 1.3 | 0.70 | |
TAC | 3.3 | 2.8 | 0.55 | |
CAC | 68.9 | 70.4 | 0.51 | |
rs2829803 rs2282471 rs2829806 | GTT | 13.5 | 10.3 | 0.035 |
ATT | 2.3 | 2.4 | 0.88 | |
GCT | 10.6 | 9.7 | 0.52 | |
ACT | 2.3 | 2.0 | 0.61 | |
GTG | 0.3 | 1.6 | 0.016 | |
GCG | 1.4 | 2.9 | 0.039 | |
ACG | 69.5 | 71.2 | 0.46 |
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Paraboschi, E.M.; Soldà, G.; Gemmati, D.; Orioli, E.; Zeri, G.; Benedetti, M.D.; Salviati, A.; Barizzone, N.; Leone, M.; Duga, S.; et al. Genetic Association and Altered Gene Expression of Mir-155 in Multiple Sclerosis Patients. Int. J. Mol. Sci. 2011, 12, 8695-8712. https://doi.org/10.3390/ijms12128695
Paraboschi EM, Soldà G, Gemmati D, Orioli E, Zeri G, Benedetti MD, Salviati A, Barizzone N, Leone M, Duga S, et al. Genetic Association and Altered Gene Expression of Mir-155 in Multiple Sclerosis Patients. International Journal of Molecular Sciences. 2011; 12(12):8695-8712. https://doi.org/10.3390/ijms12128695
Chicago/Turabian StyleParaboschi, Elvezia Maria, Giulia Soldà, Donato Gemmati, Elisa Orioli, Giulia Zeri, Maria Donata Benedetti, Alessandro Salviati, Nadia Barizzone, Maurizio Leone, Stefano Duga, and et al. 2011. "Genetic Association and Altered Gene Expression of Mir-155 in Multiple Sclerosis Patients" International Journal of Molecular Sciences 12, no. 12: 8695-8712. https://doi.org/10.3390/ijms12128695