Multi-Omics Analysis Revealed the rSNPs Potentially Involved in T2DM Pathogenic Mechanism and Metformin Response
Abstract
:1. Introduction
2. Results
2.1. Algorithm for Searching the rSNPs Associated with Allele-Specific Events in ChIP-seq and RNA-seq Data and Construction of rSNPs Panel
2.2. Characterizing Constructed rSNP Panel with GWAS, GTEx, and ANANASTRA
2.3. Analysis of Hub Genes, Modules, and Pathways in Associative Gene Networks of rSNP-Governed Differentially Expressed Genes Related to T2DM
2.3.1. Search for Differentially Expressed Genes Related to T2DM and Harboring rSNPs within Promotors
2.3.2. Identification of Hub Genes and Analysis of Key Modules Using STRING-Based Protein Interactions, KEGG, and GO Enrichment
2.3.3. Selecting Important Regulators from PPI Network Using ROC Analysis
2.4. Search for the rSNPs Potentially Associated with Individual Response to the Antidiabetic Drug Metformin
3. Discussion
4. Materials and Methods
4.1. Subjects of Investigation
4.2. Isolation of Peripheral Blood Mononuclear Cells
4.3. mRNA Sequencing
4.4. Chromatin Immunoprecipitation
4.5. Sequencing and Aligning to Reference Genome
4.6. Search for Heterozygous Positions
4.7. Assembling Alternative Genome
4.8. Computing Allelic Asymmetry
4.9. Searching for Allele-Asymmetric SNPs in the Promoters of the Genes Displaying Allele-Specific Expression
4.10. Characterizing rSNPs with the Help of Open-Access Data
4.11. Analyzing DEGs
4.12. Search for Hub Genes
4.13. Identification of Protein Modules
4.14. Enrichment Analysis of KEGG/Reactome/GO
4.15. ROC Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Trait | Total Number of SNPs per Trait in GWAS Catalog | Number of rSNPs Directly Included in GWAS Catalog | p.adj. | Odds Ratio * |
---|---|---|---|---|
Waist-to-hip ratio adjusted for BMI | 3741 | 36 | 1.1 × 10−3 | 2.2 (1.5–3.1) |
Mean corpuscular volume | 2227 | 31 | 1.1 × 10−5 | 3.2 (2.2–4.6) |
White blood cell count | 2456 | 31 | 6.1 × 10−5 | 2.9 (2–4.2) |
Waist–hip index | 2526 | 28 | 1.1 × 10−3 | 2.5 (1.7–3.7) |
Hip circumference adjusted for BMI | 3359 | 28 | 4.1 × 10−2 | 1.9 (1.3–2.8) |
Platelet count | 2609 | 27 | 3.9 × 10−3 | 2.4 (1.6–3.5) |
Mean corpuscular hemoglobin | 2365 | 25 | 4.8 × 10−3 | 2.4 (1.6–3.6) |
Lymphocyte count | 1651 | 24 | 9.8 × 10−5 | 3.3 (2.1–5) |
Monocyte count | 1767 | 24 | 2.1 × 10−4 | 3.1 (2–4.7) |
Red blood cell count | 2487 | 24 | 1.9 × 10−2 | 2.2 (1.4–3.3) |
Neutrophil count | 1559 | 23 | 1.1 × 10−4 | 3.4 (2.1–5.1) |
Eosinophil count | 2100 | 23 | 4.8 × 10−3 | 2.5 (1.6–3.8) |
Type 2 diabetes | 2830 | 23 | 7.1 × 10−2 | 1.9 (1.2–2.8) |
Red cell distribution width | 1732 | 20 | 5.5 × 10−3 | 2.6 (1.6–4.1) |
Mean platelet volume | 1402 | 16 | 2.1 × 10−2 | 2.6 (1.5–4.3) |
A body shape index | 1514 | 16 | 3.6 × 10−2 | 2.4 (1.4–3.9) |
Monocyte percentage of white cells | 738 | 15 | 1.9 × 10−4 | 4.6 (2.6–7.7) |
Plateletcrit | 930 | 15 | 1.6 × 10−3 | 3.7 (2–6.1) |
Mean spheric corpuscular volume | 821 | 14 | 1.6 × 10−3 | 3.9 (2.1–6.6) |
Appendicular lean mass | 1569 | 14 | 8.8 × 10−2 | 2 (1.1–3.4) |
Gene | Regulation | AUC | Rs_id |
---|---|---|---|
NOTCH1 | Up | 0.7212 | rs951509664, rs3013307, and rs3013306 |
H6PD | Up | 0.8072 | rs184437520, rs3752547, rs9435144, and rs11121354 |
POLR2A | Up | 0.7314 | rs4796424, rs57985740, rs41555218, rs144575559, and rs9901161 |
NCOR2 | Up | 0.7713 | rs7960906, rs1006100, rs1199426444, rs191752208, rs1432659465, rs998518300, rs906886068, rs1458070990, rs948418315, rs79830634, rs12426514, rs1316249, rs924583078, rs868110059, and rs1407929149 |
PXN | Up | 0.7181 | rs7953949 and rs3890165 |
FASN | Up | 0.7642 | rs7209621 and rs62078751 |
SCARB1 | Up | 0.7323 | rs7305310, rs838884, and rs897715 |
GAK | Up | 0.734 | rs140032537, rs141564663, rs1403319282, rs182955420, rs3775124 and rs3733352 |
CTSD | Up | 0.7238 | rs2292963, rs144932926, rs2292962, and rs35640004 |
FZR1 | Up | 0.7145 | rs8100223 and rs8644 |
SMG1 | Up | 0.7926 | rs142606705, rs12929094, and rs560580650 |
TP53 | Up | 0.7522 | rs1800899 |
MAN1B1 | Up | 0.7762 | rs4880199 and rs10870178 |
RPL3 | Down | 0.766 | rs5757613, rs2072872, rs137626, rs2076125, rs143897309, rs969895370, rs84491, rs137627, rs470081, rs754570306, rs6509, rs137620, and rs12484030 |
RPS3 | Down | 0.7119 | rs186612441 |
HSP90AB1 | Down | 0.8227 | rs324131 |
RPL11 | Down | 0.801 | rs3753270, rs111953674, rs878908315, rs558662093, and rs1361739260 |
RPS11 | Down | 0.7358 | rs739349 |
RPL5 | Down | 0.7411 | rs34244251 |
RPS20 | Down | 0.7159 | rs17814456 |
RPL13A | Down | 0.7101 | rs11539123 |
RACK1 | Down | 0.8054 | rs2287715 and rs111326428 |
RPL14 | Down | 0.7908 | rs62263890 and rs2276869 |
RPL12 | Down | 0.8285 | rs2247310 and rs2247322 |
CCT7 | Down | 0.8027 | rs779122697 |
RUVBL1 | Down | 0.7451 | rs11719546 |
TCP1 | Down | 0.7292 | rs62621403 |
PSMA7 | Down | 0.8005 | rs73307256, rs6089665, and rs3746651 |
PSMC5 | Down | 0.7863 | rs141975038 |
ATP5F1A | Down | 0.7092 | rs3753069, rs41274316, and rs34907121 |
HNRNPK | Down | 0.742 | rs1011582290, rs796004, and rs296890 |
SKP1 | Down | 0.7163 | rs56257643 |
BCL2 | Down | 0.7176 | rs4987834 and rs1160274961 |
FYN | Down | 0.7438 | rs62413757, rs189480003, rs71564104, rs9487736, rs1295051482, rs6568706, rs17072881, and rs1057979 |
SSRP1 | Down | 0.8262 | rs61888886 and rs61888888 |
CDC42 | Down | 0.7247 | rs61778042, rs866829764, rs11801382, rs2255282, rs12038474, and rs16826302 |
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Damarov, I.S.; Korbolina, E.E.; Rykova, E.Y.; Merkulova, T.I. Multi-Omics Analysis Revealed the rSNPs Potentially Involved in T2DM Pathogenic Mechanism and Metformin Response. Int. J. Mol. Sci. 2024, 25, 9297. https://doi.org/10.3390/ijms25179297
Damarov IS, Korbolina EE, Rykova EY, Merkulova TI. Multi-Omics Analysis Revealed the rSNPs Potentially Involved in T2DM Pathogenic Mechanism and Metformin Response. International Journal of Molecular Sciences. 2024; 25(17):9297. https://doi.org/10.3390/ijms25179297
Chicago/Turabian StyleDamarov, Igor S., Elena E. Korbolina, Elena Y. Rykova, and Tatiana I. Merkulova. 2024. "Multi-Omics Analysis Revealed the rSNPs Potentially Involved in T2DM Pathogenic Mechanism and Metformin Response" International Journal of Molecular Sciences 25, no. 17: 9297. https://doi.org/10.3390/ijms25179297