Causal Effects of Oxidative Stress on Diabetes Mellitus and Microvascular Complications: Insights Integrating Genome-Wide Mendelian Randomization, DNA Methylation, and Proteome
Abstract
:1. Introduction
2. Methods
2.1. Study Design
2.2. Exposure Sources
2.3. Outcome Sources
2.4. Statistical Analyses
2.4.1. Summary-Data-Based MR Analysis
2.4.2. Colocalization Analysis
2.4.3. Sensitivity Analysis
3. Results
3.1. SMR Analysis of Cis-eQTL and Diabetes Outcomes
3.2. SMR Analysis of Cis-mQTL and Diabetes Outcomes
3.3. SMR Analysis of Cis-pQTL and Diabetes Outcomes
3.4. SMR Analysis for mQTL and eQTL Data
3.5. Sensitivity Analysis
4. Discussion
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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Disease | Gene | Ensembl ID | Probe | β coefficient | OR (95%CI) | Psmr Value | PPH4 |
---|---|---|---|---|---|---|---|
T2D | ADCY5 | ENSG00000173175 | cg27182923 | 0.29 | 1.34 (1.19, 1.50) | 6.66 × 10−7 | 0.97 |
APAF1 | ENSG00000120868 | cg10957001 | −0.02 | 0.98 (0.97, 0.99) | 6.08 × 10−6 | 0.89 | |
BCL2L11 | ENSG00000153094 | cg04202892 | −0.04 | 0.96 (0.95, 0.98) | 1.06 × 10−5 | 0.93 | |
BCL2L11 | ENSG00000153094 | cg04780086 | −0.14 | 0.87 (0.81, 0.94) | 2.09 × 10−4 | 0.92 | |
BCL2L11 | ENSG00000153094 | cg18646521 | −0.08 | 0.93 (0.89, 0.96) | 4.35 × 10−5 | 0.92 | |
BCL2L11 | ENSG00000153094 | cg00997280 | 0.09 | 1.09 (1.04, 1.15) | 1.08 × 10−3 | 0.87 | |
BDNF | ENSG00000176697 | cg00298481 | 0.15 | 1.16 (1.06, 1.28) | 9.61 × 10−4 | 0.84 | |
CAMK2G | ENSG00000148660 | cg07512258 | 0.11 | 1.12 (1.06, 1.18) | 5.88 × 10−5 | 0.90 | |
CDKN1A | ENSG00000124762 | cg24425727 | 0.03 | 1.03 (1.02, 1.05) | 8.74 × 10−5 | 0.86 | |
CDKN1A | ENSG00000124762 | cg11920449 | 0.03 | 1.03 (1.02, 1.05) | 8.64 × 10−5 | 0.86 | |
CDKN1A | ENSG00000124762 | cg03714916 | 0.10 | 1.10 (1.04, 1.16) | 3.00 × 10−4 | 0.86 | |
CYB5R3 | ENSG00000100243 | cg08690876 | −0.05 | 0.95 (0.93, 0.97) | 1.16 × 10−5 | 0.86 | |
CYB5R3 | ENSG00000100243 | cg25044876 | −0.12 | 0.89 (0.83, 0.95) | 2.38 × 10−4 | 0.80 | |
CYP2E1 | ENSG00000130649 | cg01465364 | −0.15 | 0.86 (0.79, 0.93) | 2.40 × 10−4 | 0.97 | |
CYP2E1 | ENSG00000130649 | cg19571004 | −0.14 | 0.87 (0.81, 0.94) | 1.35 × 10−4 | 0.97 | |
HSF1 | ENSG00000185122 | cg18814314 | −0.04 | 0.97 (0.95, 0.98) | 2.16 × 10−6 | 0.90 | |
IGF2BP1 | ENSG00000159217 | cg09029085 | −0.05 | 0.95 (0.93, 0.97) | 7.65 × 10−8 | 0.98 | |
IGF2BP1 | ENSG00000159217 | cg14634687 | −0.05 | 0.95 (0.93, 0.97) | 1.04 × 10−7 | 0.97 | |
IGF2BP1 | ENSG00000159217 | cg19057899 | −0.05 | 0.95 (0.93, 0.97) | 1.27 × 10−7 | 0.97 | |
INSR | ENSG00000171105 | cg10381200 | 0.20 | 1.22 (1.11, 1.33) | 1.76 × 10−5 | 0.91 | |
MAP2K3 | ENSG00000034152 | cg00210768 | −0.06 | 0.94 (0.91, 0.97) | 1.55 × 10−4 | 0.85 | |
NUDT1 | ENSG00000106268 | cg12823233 | −0.03 | 0.97 (0.96, 0.98) | 3.47 × 10−6 | 0.83 | |
PPARG | ENSG00000132170 | cg04632671 | 0.26 | 1.30 (1.19, 1.42) | 8.63 × 10−9 | 0.98 | |
TP53INP1 | ENSG00000164938 | cg16049864 | 0.04 | 1.04 (1.02, 1.05) | 5.47 × 10−9 | 0.98 | |
TP53INP1 | ENSG00000164938 | cg20039814 | 0.04 | 1.04 (1.03,1.05) | 6.08 × 10−9 | 0.98 | |
TP53INP1 | ENSG00000164938 | cg13393036 | 0.04 | 1.04 (1.03, 1.06) | 6.51 × 10−9 | 0.98 | |
TP53INP1 | ENSG00000164938 | cg26343298 | −0.10 | 0.91 (0.88, 0.94) | 1.88 × 10−7 | 0.95 | |
TP53INP1 | ENSG00000164938 | cg23172400 | 0.05 | 1.05 (1.03, 1.07) | 2.13 × 10−8 | 0.95 | |
TSFM | ENSG00000123297 | cg12113251 | 0.11 | 1.11 (1.04, 1.19) | 1.73 × 10−3 | 0.84 | |
T1D | BDNF | ENSG00000176697 | cg10635145 | −0.17 | 0.84 (0.77, 0.92) | 3.16 × 10−4 | 0.81 |
DUSP1 | ENSG00000120129 | cg17560677 | 0.42 | 1.52 (1.18, 1.94) | 1.08 × 10−3 | 0.95 | |
DUSP1 | ENSG00000120129 | cg22118147 | −0.28 | 0.76 (0.64, 0.89) | 8.87 × 10−4 | 0.84 | |
SRXN1 | ENSG00000172070 | cg15557840 | −0.06 | 0.94 (0.90, 0.97) | 5.49 × 10−4 | 0.81 | |
SUOX | ENSG00000139531 | cg22580629 | −0.66 | 0.52 (0.38, 0.69) | 1.22 × 10−5 | 0.93 |
Outcome | Gene | eQTL → GWAS | Probe | mQTL → GWAS | mQTL → eQTL | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
OR (95% CI) | p Value | PPH4 | OR (95% CI) | p Value | PPH4 | Beta | se | p Value | PPH4 | |||
T2D | TP53INP1 | 1.17 (1.11, 1.23) | 1.62 × 10−8 | 0.95 | cg26343298 | 0.91 (0.88, 0.94) | 1.88 × 10−7 | 0.95 | −0.62 | 0.05 | 2.01 × 10−31 | 0.99 |
DN | 1.45 (1.22, 1.73) | 3.12 × 10−5 | 0.90 | 0.80 (0.71, 0.89) | 9.14 × 10−5 | 0.90 | ||||||
DR | SUOX | 0.77 (0.71, 0.84) | 4.57 × 10−9 | 0.99 | cg22580629 | 0.68 (0.57, 0.82) | 3.59 × 10−5 | 0.94 | 1.52 | 0.24 | 2.19 × 10−10 | 0.97 |
DR | CHEK1 | 2.21 (1.42, 3.44) | 4.81 × 10−4 | 0.81 | cg07110182 | 0.84 (0.76, 0.92) | 3.37 × 10−4 | 0.81 | −0.23 | 0.03 | 3.43 × 10−12 | 0.89 |
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Liu, K.; Chen, Z.; Liu, L.; Li, T.; Xing, C.; Han, F.; Mao, H. Causal Effects of Oxidative Stress on Diabetes Mellitus and Microvascular Complications: Insights Integrating Genome-Wide Mendelian Randomization, DNA Methylation, and Proteome. Antioxidants 2024, 13, 903. https://doi.org/10.3390/antiox13080903
Liu K, Chen Z, Liu L, Li T, Xing C, Han F, Mao H. Causal Effects of Oxidative Stress on Diabetes Mellitus and Microvascular Complications: Insights Integrating Genome-Wide Mendelian Randomization, DNA Methylation, and Proteome. Antioxidants. 2024; 13(8):903. https://doi.org/10.3390/antiox13080903
Chicago/Turabian StyleLiu, Kang, Zitong Chen, Lishan Liu, Ting Li, Changying Xing, Feng Han, and Huijuan Mao. 2024. "Causal Effects of Oxidative Stress on Diabetes Mellitus and Microvascular Complications: Insights Integrating Genome-Wide Mendelian Randomization, DNA Methylation, and Proteome" Antioxidants 13, no. 8: 903. https://doi.org/10.3390/antiox13080903