Comprehensive Statistical and Bioinformatics Analysis in the Deciphering of Putative Mechanisms by Which Lipid-Associated GWAS Loci Contribute to Coronary Artery Disease
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Participants
2.2. Clinical Examination of Patients
2.3. Biochemical Investigations
2.4. SNP Genotyping
2.5. Statistical Analysis
2.6. Bioinformatics Analysis
3. Results
3.1. Association of Gene Polymorphisms with the Risk of Coronary Artery Disease, Plasma Lipids, and Carotid Intima-Media Thickness
3.2. Smoking as a Triggering Factor Modifying the Genetic Effects on Plasma Lipids, CIMT, and CAD Risk
3.3. Replication for Associations between SNPs and Cardiovacsular Phenotypes in Independent Populations
3.4. Analysis of Pairwise SNP-SNP Interactions Contributing to the Studied Cardiovascular Phenotypes
3.5. Modeling for Gene–Gene and Gene–Environment Interactions Determining the Cardiovascular Phenotypes
3.6. Functional Annotation of the Studied Gene Polymorphisms
3.7. Enrichment Analysis of Regulatory Gene Networks in Which the Studied Gene Polymorphism Might Be Involved
4. Discussion
4.1. Summary of the Study Findings and Their Comparison with Literature
4.2. The Contribution of Gene–Gene Interactions to the Studied Cardiovascular Phenotypes
4.3. Functional Effects of the Studied SNPs and Their Link to the Pathogenesis of Coronary Artery Disease
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Baseline Characteristics | CAD Patients, n = 991 | Healthy Controls, n = 709 | p-Value | |
---|---|---|---|---|
Age, mean ± standard deviation | 59.9 ± 8.8 | 60.4 ± 8.1 | 0.23 | |
Sex | Males, n (%) | 633 (63.9) | 452 (63.8) | 0.96 |
Females, n (%) | 358 (36.1) | 257 (36.2) | ||
Body mass index (kg/m2), mean ± standard deviation | 29.98 ± 6.55 | 27.04 ± 4.48 | <0.001 | |
Hypertension 1, n (%) | 935 (94.3) | 0 (0.0) | - | |
Diabetes 2, n (%) | 214 (21.6) | 0 (0.0) | - | |
Smokers 3 (ever/never), n (%) | 434 (43.9) | 355 (51.5) | 0.002 | |
TC (mmol/L), Me (Q1; Q3) | 5.76 (4.83; 6.24) | NA | - | |
LDL-C (mmol/L), Me (Q1; Q3) | 2.20 (1.50; 3.77) | NA | - | |
HDL-C (mmol/L), Me (Q1; Q3) | 1.30 (1.05; 1.62) | NA | - | |
TG (mmol/L), Me (Q1; Q3) | 2.40 (1.59; 3.70) | NA | - | |
CIMT (mm), Me (Q1; Q3) | 0.61 (0.53; 0.80) | NA | - |
Gene | Polymorphism (SNP ID) | SNP Location | Association of SNP with Plasma Lipids | References |
---|---|---|---|---|
ABCA1 | C > T (rs1883025) | Intron | Decrease in TC and HDL-C | [8,25] |
APOC1 | A > G (rs4420638) | Intergenic | Increase in LDL-C | [11] |
CETP | C > A (rs3764261) | Promoter | Increase in TC and HDL-C, decrease in LDL-C and TG | [8] |
COBLL1 | T > C (rs12328675) | 3′UTR | Increase in HDL-C | [8] |
F2 | T > C (rs3136441) | Intron | Increase in HDL-C | [8] |
GALNT2 | A > G (rs4846914) | Intron | Increase in HDL-C, increase in TG | [8,25] |
LILRA3 | G > C (rs386000) | Intron | Increase in HDL-C | [8] |
LPA | C > T (rs55730499) | Intron | Increase in Lp(a), Increaed risk of CAD | [9,26] |
NPC1L1 | C > G (rs217406) | intron | Increase in TC | [8] |
PLTP | T > C (rs6065906) | Promoter | Decrease in HDL-Cl, increase in TG | [8] |
PSKH1 | G > A (rs16942887) | Intron | Increase in HDL-C | [8,12] |
ST3GAL4 | A > T (rs11220463) | Intron | Decrease in TC and LDL-C | [8] |
STARD3 | G > C (rs881844) | Intron | Decrease in HDL-C | [12] |
ZNF648 | A > G (rs1689800) | Intron | Decrease in HDL-C | [8,12] |
SCARB1 | T > C (rs838880) | 3′UTR | Increase in HDL-C | [8] |
PPP1R3B | G > A (rs9987289) | exon, non-coding region | Decrease in TC and HDL-C, increase in LDL-C | [8,27] |
Gene (SNP ID) | Minor Allele | Minor Allele Frequencies (MAF) in Populations | p | |
---|---|---|---|---|
Central Russia (Sample Size) | European Population | |||
ABCA1 (rs1883025) | T | 0.222 (1697) | 0.240 | 0.40 |
APOC1 (rs4420638) | G | 0.153 (1669) | 0.198 | 0.02 |
CETP (rs3764261) | A | 0.251 (1681) | 0.292 | 0.07 |
COBLL1 (rs12328675) | C | 0.165 (1340) | 0.157 | 0.68 |
F2 (rs3136441) | C | 0.205 (1675) | 0.121 | <0.0001 |
GALNT2 (rs4846914) | A | 0.617 (1686) | 0.601 | 0.52 |
LILRA3 (rs386000) | C | 0.185 (1699) | 0.191 | 0.76 |
LPA (rs55730499) | T | 0.077 (1673) | 0.076 | 0.94 |
NPC1L1 (rs217406) | G | 0.211 (1700) | 0.173 | 0.06 |
PLTP (rs6065906) | C | 0.168 (1697) | 0.204 | 0.06 |
PSKH1 (rs16942887) | A | 0.122 (1678) | 0.134 | 0.48 |
ST3GAL4 (rs11220463) | T | 0.166 (1699) | 0.131 | 0.06 |
STARD3 (rs881844) | G | 0.663 (1693) | 0.668 | 0.83 |
ZNF648 (rs1689800) | G | 0.353 (1696) | 0.347 | 0.80 |
SCARB1 (rs838880) | T | 0.684 (1698) | 0.687 | 0.90 |
PPP1R3B (rs9987289) | A | 0.076 (1699) | 0.075 | 0.94 |
Gene (SNP ID) | Genotypes | Healthy Controls N (%) | CAD Patients N (%) | OR (95% CI) 1 | p2 |
---|---|---|---|---|---|
ABCA1 (rs1883025) | C/C | 234 (59.2) | 466 (62.4) | 1.00 | 0.19 |
C/T-T/T | 161 (40.8) | 281 (37.6) | 0.84 (0.65–1.09) | ||
APOC1 (rs4420638) | A/A-G/G | 295 (78.7) | 535 (71.4) | 1.00 | 0.009 |
A/G | 80 (21.3) | 214 (28.6) | 1.49 (1.10–2.03) | ||
CETP (rs3764261) | C/C-A/A | 238 (60.2) | 402 (55.1) | 1.00 | 0.17 |
C/A | 157 (39.8) | 328 (44.9) | 1.20 (0.92–1.56) | ||
COBLL1 (rs12328675) | T/T-T/C | 333 (93.8) | 447 (90.5) | 1.00 | 0.08 |
C/C | 22 (6.2) | 47 (9.5) | 1.61 (0.93–2.81) | ||
F2 (rs3136441) | T/T | 213 (54.3) | 512 (69) | 1.00 | <0.0001 |
T/C-C/C | 179 (45.7) | 230 (31) | 0.49 (0.37–0.64) | ||
GALNT2 (rs4846914) | A/A-A/G | 340 (87.6) | 628 (84.3) | 1.00 | 0.17 |
G/G | 48 (12.4) | 117 (15.7) | 1.30 (0.89–1.89) | ||
LILRA3 (rs386000) | G/G-G/C | 382 (96.7) | 728 (97.3) | 1.00 | 0.51 |
C/C | 13 (3.3) | 20 (2.7) | 0.78 (0.37–1.63) | ||
LPA (rs55730499) | C/C | 354 (89.6) | 596 (81.8) | 1.00 | 0.0007 |
C/T-T/T | 41 (10.4) | 133 (18.2) | 1.92 (1.30–2.83) | ||
NPC1L1 (rs217406) | C/C-G/G | 270 (68.3) | 474 (63.3) | 1.00 | 0.056 |
C/G | 125 (31.6) | 275 (36.7) | 1.30 (0.99–1.70) | ||
PLTP (rs6065906) | T/T | 251 (63.5) | 536 (71.8) | 1.00 | 0.002 |
T/C-C/C | 144 (36.5) | 210 (28.1) | 0.66 (0.50–0.86) | ||
PSKH1 (rs16942887) | G/G-G/A | 378 (98.4) | 733 (98.8) | 1.00 | 0.47 |
A/A | 6 (1.6) | 9 (1.2) | 0.66 (0.22–1.98) | ||
ST3GAL4 (rs11220463) | A/A-A/T | 383 (97) | 735 (98.3) | 1.00 | 0.10 |
T/T | 12 (3) | 13 (1.7) | 0.50 (0.22–1.14) | ||
STARD3 (rs881844) | G/G | 155 (39.2) | 333 (44.6) | 1.00 | 0.059 |
G/C-C/C | 240 (60.8) | 413 (55.4) | 0.78 (0.60–1.01) | ||
ZNF648 (rs1689800) | A/A-A/G | 349 (88.3) | 669 (89.6) | 1.00 | 0.23 |
G/G | 46 (11.7) | 78 (10.4) | 0.78 (0.52–1.17) | ||
SCARB1 (rs838880) | T/T | 191 (48.4) | 327 (43.7) | 1.00 | 0.074 |
T/C-C/C | 204 (51.6) | 421 (56.3) | 1.26 (0.98–1.63) | ||
PPP1R3B (rs9987289) | G/G | 348 (88.3) | 632 (84.4) | 1.00 | 0.062 |
G/A-A/A | 46 (11.7) | 117 (15.6) | 1.43 (0.98–2.08) |
Gene (SNP ID) | Genotypes | Genotype Frequencies | TC | LDL-C | HDL-C | TG | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
N | % | Me | Q1/Q3 1 | p2 | Me | Q1/Q3 1 | p2 | Me | Q1/Q3 1 | p2 | Me | Q1/Q3 1 | p2 | ||
ABCA1 (rs1883025) | CC | 386 | 60.9 | 5.72 | 4.82/6.27 | 0.67 | 2.13 | 1.50/3.54 | 0.19 | 1.32 | 1.04/1.63 | 0.09 | 2.46 | 1.67/3.72 | 0.26 |
CT | 212 | 33.4 | 5.78 | 4.76/6.20 | 2.50 | 1.73/3.96 | 1.24 | 1.07/1.53 | 1.94 | 1.50/3.68 | |||||
TT | 36 | 5.7 | 5.80 | 4.99/6.20 | 2.07 | 1.29/3.89 | 1.37 | 1.07/1.62 | 2.39 | 1.41/3.60 | |||||
APOC1 (rs4420638) | AA | 446 | 70.2 | 5.80 | 4.90/6.20 | 0.17 | 2.20 | 1.48/3.80 | 0.67 | 1.30 | 1.04/1.62 | 0.30 | 2.45 | 1.63/3.68 | 0.052 |
AG | 177 | 27.9 | 5.52 | 4.70/6.20 | 2.24 | 1.60/3.55 | 1.30 | 1.07/1.63 | 2.20 | 1.51/3.73 | |||||
GG | 12 | 1.9 | 5.97 | 5.21/6.50 | 2.09 | 1.89/3.40 | 1.46 | 1.12/1.58 | 3.44 | 1.80/4.01 | |||||
CETP (rs3764261) | CC | 333 | 54.0 | 5.67 | 4.70/6.30 | 0.25 | 2.46 | 1.72/3.80 | 0.042 D | 1.24 | 1.02/1.58 | 0.005 OD | 2.37 | 1.59/3.70 | 0.17 |
CA | 275 | 44.6 | 5.73 | 4.90/6.20 | 2.10 | 1.48/3.73 | 1.32 | 1.10/1.67 | 2.40 | 1.59/3.71 | |||||
AA | 9 | 1.5 | 5.90 | 4.88/6.30 | 4.07 | 3.79/4.74 | 1.03 | 0.87/1.24 | 1.81 | 1.53/1.96 | |||||
COBLL1 (rs12328675) | TT | 296 | 75.5 | 5.59 | 4.60/6.18 | 0.028 OD | 3.51 | 2.31/4.20 | 0.16 | 1.10 | 0.99/1.34 | 0.17 | 1.80 | 1.472.69 | 0.06 |
TC | 60 | 15.3 | 5.80 | 4.89/6.29 | 3.76 | 2.50/4.20 | 1.18 | 1.01/1.40 | 1.72 | 1.28/2.14 | |||||
CC | 36 | 9.2 | 5.25 | 4.43/6.00 | 2.94 | 2.06/3.95 | 1.30 | 1.02/1.48 | 1.47 | 0.90/2.68 | |||||
F2 (rs3136441) | TT | 436 | 69.1 | 5.69 | 4.80/6.20 | 0.18 | 2.13 | 1.46/3.53 | 0.09 | 1.32 | 1.08/1.66 | 0.12 | 2.55 | 1.59/3.71 | 0.80 |
TC | 179 | 28.4 | 5.80 | 4.81/6.30 | 2.46 | 1.80/3.94 | 1.29 | 1.01/1.58 | 2.05 | 1.63/3.71 | |||||
CC | 16 | 2.5 | 5.89 | 5.20/6.20 | 3.27 | 1.90/4.08 | 1.05 | 0.92/1.14 | 1.93 | 1.50/3.50 | |||||
GALNT2 (rs4846914) | AA | 239 | 37.9 | 5.70 | 4.77/6.20 | 0.02 OD | 2.18 | 1.48/3.52 | 0.31 | 1.30 | 1.04/1.62 | 0.07 | 2.49 | 1.62/3.71 | 0.12 |
AG | 289 | 45.8 | 5.80 | 4.87/6.30 | 2.30 | 1.50/3.90 | 1.30 | 1.07/1.63 | 2.20 | 1.57/3.71 | |||||
GG | 103 | 16.3 | 5.70 | 4.73/6.20 | 2.18 | 1.77/3.56 | 1.24 | 1.04/1.53 | 2.40 | 1.60/3.54 | |||||
LILRA3 (rs386000) | GG | 417 | 65.8 | 5.79 | 4.82/6.27 | 0.18 | 2.18 | 1.48/3.68 | 0.68 | 1.30 | 1.06/1.63 | 0.33 | 2.43 | 1.59/3.73 | 0.14 |
GC | 198 | 31.2 | 5.70 | 4.87/6.20 | 2.24 | 1.70/3.85 | 1.26 | 1.04/1.60 | 2.38 | 1.62/3.68 | |||||
CC | 19 | 3.0 | 5.46 | 4.14/5.80 | 2.59 | 1.77/3.90 | 1.31 | 1.06/1.50 | 1.86 | 1.39/2.47 | |||||
LPA (rs55730499) | CC | 515 | 82.5 | 5.80 | 4.86/6.29 | 0.037 OD | 2.18 | 1.50/3.63 | 0.0007 R | 1.30 | 1.07/1.62 | 0.42 | 2.43 | 1.62/3.73 | 0.06 |
CT | 108 | 17.3 | 5.43 | 4.59/6.17 | 3.30 | 1.80/4.00 | 1.20 | 1.00/1.44 | 1.88 | 1.34/3.04 | |||||
TT | 1 | 0.2 | 6.00 | 5.80/7.69 | 4.27 | 4.03/5.80 | 0.95 | 0.93/1.19 | 1.63 | 1.59/6.59 | |||||
NPC1L1 (rs217406) | CC | 375 | 59.1 | 5.80 | 4.81/6.27 | 0.47 | 2.30 | 1.54/3.88 | 0.63 | 1.30 | 1.05/1.62 | 0.09 | 2.40 | 1.61/3.70 | 0.022 R |
CG | 233 | 36.7 | 5.71 | 4.84/6.22 | 2.09 | 1.48/3.40 | 1.29 | 1.07/1.62 | 2.40 | 1.60/3.75 | |||||
GG | 27 | 4.3 | 5.40 | 4.89/6.00 | 2.20 | 1.75/4.02 | 1.28 | 0.91/1.59 | 1.92 | 1.51/3.12 | |||||
PLTP (rs6065906) | TT | 449 | 71.0 | 5.70 | 4.81/6.24 | 0.50 | 2.20 | 1.51/3.72 | 0.17 | 1.30 | 1.07/1.62 | 0.052 | 2.24 | 1.57/3.53 | 0.035 D |
TC | 172 | 27.2 | 5.80 | 4.88/6.21 | 2.18 | 1.46/3.82 | 1.24 | 1.02/1.62 | 2.72 | 1.66/3.80 | |||||
CC | 11 | 1.7 | 5.90 | 4.98/6.20 | 2.82 | 2.06/4.06 | 1.10 | 0.96/1.40 | 1.92 | 1.57/3.75 | |||||
PSKH1 (rs16942887) | GG | 495 | 78.7 | 5.70 | 4.80/6.20 | 0.13 | 2.20 | 1.48/3.69 | 0.06 | 1.28 | 1.03/1.60 | 0.18 | 2.38 | 1.57/3.70 | 0.23 |
GA | 127 | 20.2 | 5.80 | 4.89/6.30 | 2.26 | 1.61/3.88 | 1.31 | 1.10/1.63 | 2.40 | 1.63/3.53 | |||||
AA | 7 | 1.1 | 6.27 | 5.40/6.50 | 3.90 | 2.20/4.33 | 1.32 | 0.92/1.53 | 2.00 | 1.62/3.80 | |||||
ST3GAL4 (rs11220463) | AA | 431 | 68.0 | 5.80 | 4.88/6.30 | 0.25 | 2.25 | 1.50/3.90 | 0.62 | 1.29 | 1.05/1.62 | 0.20 | 2.37 | 1.62/3.71 | 0.52 |
AT | 192 | 30.3 | 5.56 | 4.75/6.20 | 2.10 | 1.49/3.15 | 1.32 | 1.07/1.62 | 2.45 | 1.48/3.54 | |||||
TT | 11 | 1.7 | 5.60 | 4.88/6.02 | 2.49 | 1.48/4.54 | 0.94 | 0.83/1.63 | 3.12 | 2.31/4.22 | |||||
STARD3 (rs881844) | GG | 283 | 44.8 | 5.78 | 4.79/6.27 | 0.59 | 2.18 | 1.51/3.73 | 0.82 | 1.30 | 1.04/1.66 | 0.27 | 2.40 | 1.62/3.73 | 0.57 |
GC | 285 | 45.1 | 5.70 | 4.87/6.23 | 2.18 | 1.48/3.66 | 1.30 | 1.09/1.60 | 2.55 | 1.59/3.70 | |||||
CC | 64 | 10.1 | 5.81 | 4.84/6.20 | 2.80 | 1.61/4.08 | 1.25 | 1.05/1.62 | 1.90 | 1.50/3.25 | |||||
ZNF648 (rs1689800) | AA | 254 | 254 | 5.69 | 4.80/6.30 | 0.53 | 2.20 | 1.50/3.80 | 0.026 R | 1.31 | 1.03/1.58 | 0.18 | 2.44 | 1.62/3.74 | 0.62 |
AG | 318 | 318 | 5.80 | 4.86/6.20 | 2.10 | 1.45/3.40 | 1.30 | 1.07/1.66 | 2.41 | 1.59/3.70 | |||||
GG | 61 | 61 | 5.70 | 4.71/6.18 | 3.00 | 2.00/3.93 | 1.20 | 1.05/1.41 | 2.00 | 1.59/3.70 | |||||
SCARB1 (rs838880) | TT | 275 | 43.4 | 5.80 | 4.80/6.20 | 0.035 R | 2.31 | 1.69/3.93 | 0.043 OD | 1.27 | 1.04/1.62 | 0.65 | 2.20 | 1.59/3.50 | 0.30 |
TC | 301 | 47.5 | 5.70 | 4.80/6.29 | 2.06 | 1.45/3.67 | 1.30 | 1.07/1.62 | 2.59 | 1.62/3.75 | |||||
CC | 58 | 9.1 | 5.81 | 5.00/6.32 | 2.70 | 2.10/3.88 | 1.30 | 1.10/1.58 | 2.24 | 1.50/3.70 | |||||
PPP1R3B (rs9987289) | GG | 538 | 84.7 | 5.70 | 4.81/6.20 | 0.10 | 2.18 | 1.49/3.74 | - | 1.30 | 1.06/1.61 | - | 2.45 | 1.60/3.71 | 0.51 |
GA | 96 | 15.1 | 5.90 | 5.00/6.30 | 2.40 | 1.69/3.84 | 1.30 | 1.03/1.70 | 2.03 | 1.59/3.68 | |||||
AA | 1 | 0.2 | 4.06 | 3.97/4.14 | - | - | - | - | - | - |
Gene (SNP ID) | Genotypes | Genotype Frequencies | CIMT, mm | ||||
---|---|---|---|---|---|---|---|
N | % | Me | Q1/Q3 1 | p2 | padj3 | ||
ABCA1 (rs1883025) | CC | 386 | 60.9 | 0.62 | 0.53/0.80 | 0.48 | 0.30 |
CT | 212 | 33.4 | 0.60 | 0.52/0.79 | |||
TT | 36 | 5.7 | 0.68 | 0.58/0.80 | |||
APOC1 (rs4420638) | AA | 446 | 70.2 | 0.63 | 0.53/0.80 | 0.68 | 0.65 |
AG | 177 | 27.9 | 0.60 | 0.52/0.80 | |||
GG | 12 | 1.9 | 0.61 | 0.55/0.63 | |||
CETP (rs3764261) | CC | 333 | 54.0 | 0.60 | 0.52/0.80 | 0.62 | 0.40 |
CA | 275 | 44.6 | 0.63 | 0.55/0.80 | |||
AA | 9 | 1.5 | 0.57 | 0.57/0.57 | |||
COBLL1 (rs12328675) | TT | 296 | 75.5 | 0.70 | 0.55/0.85 | 0.05 | 0.009 R |
TC | 60 | 15.3 | 0.65 | 0.50/0.78 | |||
CC | 36 | 9.2 | 0.56 | 0.48/0.69 | |||
F2 (rs3136441) | TT | 436 | 69.1 | 0.63 | 0.55/0.80 | 0.21 | 0.13 |
TC | 179 | 28.4 | 0.60 | 0.50/0.75 | |||
CC | 16 | 2.5 | 0.60 | 0.50/0.69 | |||
GALNT2 (rs4846914) | AA | 239 | 37.9 | 0.60 | 0.54/0.75 | 0.39 | 0.18 |
AG | 289 | 45.8 | 0.64 | 0.55/0.80 | |||
GG | 103 | 16.3 | 0.61 | 0.50/0.85 | |||
LILRA3 (rs386000) | GG | 417 | 65.8 | 0.60 | 0.53/0.80 | 0.49 | 0.13 |
GC | 198 | 31.2 | 0.63 | 0.53/0.80 | |||
CC | 19 | 3.0 | 0.55 | 0.44/0.73 | |||
LPA (rs55730499) | CC | 515 | 82.5 | 0.62 | 0.53/0.80 | 0.31 | 0.31 |
CT | 108 | 17.3 | 0.60 | 0.55/0.78 | |||
TT | 1 | 0.2 | 0.40 | 0.40/0.40 | |||
NPC1L1 (rs217406) | CC | 375 | 59.1 | 0.61 | 0.53/0.80 | 0.19 | 0.10 |
CG | 233 | 36.7 | 0.62 | 0.54/0.80 | |||
GG | 27 | 4.3 | 0.55 | 0.45/0.72 | |||
PLTP (rs6065906) | TT | 449 | 71.0 | 0.61 | 0.53/0.80 | 0.34 | 0.48 |
TC | 172 | 27.2 | 0.60 | 0.50/0.75 | |||
CC | 11 | 1.7 | 0.79 | 0.63/0.85 | |||
PSKH1 (rs16942887) | GG | 495 | 78.7 | 0.62 | 0.53/0.80 | 0.93 | 0.88 |
GA | 127 | 20.2 | 0.61 | 0.54/0.80 | |||
AA | 7 | 1.1 | 0.60 | 0.55/0.78 | |||
ST3GAL4 (rs11220463) | AA | 431 | 68.0 | 0.64 | 0.55/0.80 | 0.046 | 0.01 OD |
AT | 192 | 30.3 | 0.60 | 0.50/0.73 | |||
TT | 11 | 1.7 | 0.55 | 0.55/0.80 | |||
STARD3 (rs881844) | GG | 283 | 44.8 | 0.63 | 0.55/0.78 | 0.48 | 0.20 |
GC | 285 | 45.1 | 0.60 | 0.52/0.80 | |||
CC | 64 | 10.1 | 0.57 | 0.50/0.78 | |||
ZNF648 (rs1689800) | AA | 254 | 254 | 0.62 | 0.55/0.80 | 0.20 | 0.02 D |
AG | 318 | 318 | 0.60 | 0.52/0.78 | |||
GG | 61 | 61 | 0.65 | 0.52/0.85 | |||
SCARB1 (rs838880) | TT | 275 | 43.4 | 0.62 | 0.53/0.78 | 0.98 | 0.51 |
TC | 301 | 47.5 | 0.61 | 0.51/0.80 | |||
CC | 58 | 9.1 | 0.60 | 0.53/0.78 | |||
PPP1R3B (rs9987289) | GG | 538 | 84.7 | 0.62 | 0.55/0.80 | - | - |
GA | 96 | 15.1 | 0.60 | 0.48/0.75 | |||
AA | 1 | 0.2 | - | - |
Gene (SNP ID) | Smoking Habit | Cardiovascular Phenotypes | |||||
---|---|---|---|---|---|---|---|
TC | LDL-C | HDL-C | TG | CIMT | CAD | ||
ABCA1 (rs1883025) | Smokers | - | 0.003 D | - | - | - | - |
Non-smokers | - | - | - | - | - | - | |
APOC1 (rs4420638) | Smokers | - | - | - | - | - | - |
Non-smokers | - | - | - | - | - | 0.009 AD | |
CETP (rs3764261) | Smokers | - | - | - | - | - | - |
Non-smokers | - | - | 0.006 OD | - | - | - | |
COBLL1 (rs12328675) | Smokers | 0.03 OD | - | - | - | - | - |
Non-smokers | - | - | - | - | - | 0.02 R | |
F2 (rs3136441) | Smokers | 0.02 AD | - | - | - | - | 0.004 D |
Non-smokers | - | - | - | - | - | 0.02 R | |
GALNT2 (rs4846914) | Smokers | - | - | - | - | 0.05 OD | - |
Non-smokers | - | - | - | 0.008 R | - | - | |
LILRA3 (rs386000) | Smokers | - | - | - | - | - | - |
Non-smokers | - | - | - | 0.03 R | - | - | |
LPA (rs55730499) | Smokers | - | 0.0001 R | - | - | - | - |
Non-smokers | - | - | - | - | - | 0.01 OD | |
NPC1L1 (rs217406) | Smokers | - | - | - | - | - | 0.01 OD |
Non-smokers | - | - | - | - | 0.02 R | - | |
PSKH1 (rs16942887) | Smokers | 0.049 D | - | - | - | - | - |
Non-smokers | - | - | - | - | - | - | |
STARD3 (rs881844) | Smokers | - | - | - | - | - | - |
Non-smokers | - | - | - | - | 0.03 R | - | |
ZNF648 (rs1689800) | Smokers | - | 0.02 R | - | - | - | - |
Non-smokers | - | - | - | - | - | - |
Gene, Effective Allele | Phenotype | p-Value * | Beta/Odds Ratio | Sample Size |
---|---|---|---|---|
ABCA1 rs1883025-T | Coronary artery disease | 0.0000218 | ▼0.9790 | 1,524,980 |
Total cholesterol | 3.40 × 10−91 | ▼−0.0583 | 431,334 | |
LDL cholesterol | 4.80 × 10−43 | ▼−0.0296 | 682,058 | |
HDL cholesterol | 2.19 × 10−139 | ▼−0.0679 | 385,758 | |
Triglycerides | 1.92 × 10−18 | ▼−0.0190 | 711,468 | |
APOC1 rs4420638-G | Coronary artery disease | 5.80 × 10−32 | ▲1.0814 | 1,477,190 |
Total cholesterol | 1.15 × 10−203 | ▲0.1357 | 314,177 | |
LDL cholesterol | 1.77 × 10−37 | ▲0.1941 | 113,518 | |
HDL cholesterol | 1.21 × 10−54 | ▼−0.0624 | 252,659 | |
Triglycerides | 1.06 × 10−259 | ▲0.0605 | 598,528 | |
CETP rs3764261-A | Coronary artery disease | 3.57 × 10−10 | ▼0.9671 | 1,591,550 |
Total cholesterol | 1.15 × 10−61 | ▲0.0469 | 410,790 | |
LDL cholesterol | 1.49 × 10−192 | ▼−0.0356 | 662,996 | |
HDL cholesterol | 7.08 × 10−36 | ▲0.2124 | 14,126 | |
Triglycerides | 5.97 × 10−68 | ▼−0.0362 | 692,195 | |
COBLL1 (GRB14) rs12328675-C | Coronary artery disease | 0.004766 | ▼0.9835 | 1,481,940 |
Total cholesterol | 0.1169 | ▼−0.0097 | 303,083 | |
LDL cholesterol | 0.00017 | ▼−0.0142 | 609,213 | |
HDL cholesterol | 3.99 × 10−13 | ▲0.0381 | 315,152 | |
Triglycerides | 4.45 × 10−31 | ▼−0.0406 | 605,928 | |
F2 rs3136441-C | Coronary artery disease | 0.6976 | ▲1.0021 | 1,513,820 |
Total cholesterol | 0.0002989 | ▲0.0096 | 418,936 | |
LDL cholesterol | 0.2641 | ▼−0.0031 | 668,268 | |
HDL cholesterol | 4.24 × 10−23 | ▲0.0289 | 371,896 | |
Triglycerides | 5.12 × 10−23 | ▼−0.0234 | 699,079 | |
GALNT2 rs4846914-G | Coronary artery disease | 1.14 × 10−8 | ▼0.9757 | 1,593,010 |
Total cholesterol | 0.04971 | ▲0.0054 | 433,614 | |
LDL cholesterol | 0.000917 | ▼−0.0071 | 684,307 | |
HDL cholesterol | 7.61 × 10−47 | ▲0.0401 | 388,040 | |
Triglycerides | 4.74 × 10−227 | ▼−0.0404 | 713,750 | |
LILRA3 rs386000-C | Coronary artery disease | 0.5958 | ▲1.0029 | 1,448,870 |
Total cholesterol | 0.0000164 | ▲0.0143 | 379,606 | |
LDL cholesterol | 0.08641 | ▲0.0047 | 624,565 | |
HDL cholesterol | 6.26 × 10−23 | ▲0.0314 | 324,003 | |
Triglycerides | 0.02057 | ▼−0.0056 | 663,279 | |
LPA rs55730499-T | Coronary artery disease | 1.45 × 10−174 | ▲1.3562 | 1,010,500 |
Total cholesterol | 7.87 × 10−11 | ▲0.0776 | 45,549 | |
LDL cholesterol | 4.16 × 10−298 | ▲0.1235 | 356,869 | |
HDL cholesterol | 0.8817 | ▲0.0067 | 45,509 | |
Triglycerides | 6.52 × 10−14 | ▼−0.0357 | 360,181 | |
NPC1L1 rs217406-G | Coronary artery disease | 0.0008186 | ▲1.0234 | 1,543,540 |
Total cholesterol | 4.77 × 10−13 | ▲0.0321 | 243,481 | |
LDL cholesterol | 3.23 × 10−36 | ▲0.0364 | 542,160 | |
HDL cholesterol | 0.03886 | ▼−0.0128 | 245,165 | |
Triglycerides | 0.01255 | ▲0.0073 | 548,639 | |
PLTP (PCIF1) rs6065906-C | Coronary artery disease | 0.009999 | ▼0.9865 | 1,593,110 |
Total cholesterol | 0.627 | ▼−0.0021 | 380,779 | |
LDL cholesterol | 6.84 × 10−8 | ▲0.0156 | 625,258 | |
HDL cholesterol | 3.62 × 10−36 | ▼−0.0484 | 326,104 | |
Triglycerides | 1.59 × 10−201 | ▲0.0515 | 663,221 | |
PSKH1 rs16942887-A | Coronary artery disease | 0.03214 | ▲1.0153 | 1,524,990 |
Total cholesterol | 2.80 × 10−6 | ▲0.0220 | 385,717 | |
LDL cholesterol | 0.7133 | ▲0.0015 | 637,521 | |
HDL cholesterol | 5.23 × 10−41 | ▲0.0641 | 338,751 | |
Triglycerides | 0.0000296 | ▼−0.0132 | 668,145 | |
ST3GAL4 rs11220463-T | Coronary artery disease | 0.0000982 | ▲1.0234 | 1,591,520 |
Total cholesterol | 3.52 × 10−14 | ▲0.0220 | 382,747 | |
LDL cholesterol | 4.62 × 10−47 | ▲0.0378 | 625,938 | |
HDL cholesterol | 0.06697 | ▼−0.0055 | 326,790 | |
Triglycerides | 0.03181 | ▲0.0065 | 665,187 | |
STARD3 rs881844-G | Coronary artery disease | 0.0001801 | ▼0.9825 | 1,592,970 |
Total cholesterol | 5.93 × 10−6 | ▲0.0122 | 374,624 | |
LDL cholesterol | 0.05305 | ▲0.0043 | 617,962 | |
HDL cholesterol | 4.85 × 10−20 | ▲0.0262 | 318,709 | |
Triglycerides | 0.1204 | ▼−0.0036 | 657,086 | |
ZNF648 rs1689800-G | Coronary artery disease | 0.2033 | ▲1.0063 | 1,524,990 |
Total cholesterol | 0.8575 | ▲0.0006 | 433,743 | |
LDL cholesterol | 2.72 × 10−9 | ▲0.0120 | 684,428 | |
HDL cholesterol | 3.72 × 10−23 | ▼−0.0237 | 388,167 | |
Triglycerides | 0.00359 | ▲0.0064 | 713,877 | |
SCARB1 rs838880-T | Coronary artery disease | 0.0000238 | ▲1.0190 | 1,524,990 |
Total cholesterol | 0.0000147 | ▼−0.0139 | 292,669 | |
LDL cholesterol | 0.6628 | ▲0.0009 | 597,781 | |
HDL cholesterol | 1.12 × 10−31 | ▼−0.0316 | 303,498 | |
Triglycerides | 0.03555 | ▲0.0053 | 595,585 | |
PPP1R3B (RP11-10A14.4) rs9987289-G | Coronary artery disease | 0.284 | ▲1.0118 | 1,516,240 |
Total cholesterol | 3.89 × 10−25 | ▲0.0675 | 373,464 | |
LDL cholesterol | 1.35 × 10−47 | ▲0.0520 | 618,405 | |
HDL cholesterol | 1.72 × 10−32 | ▲0.0640 | 314,374 | |
Triglycerides | 0.01654 | ▼−0.0066 | 656,355 |
G × G/G × E Interaction Models | NH | β-H | WH | NL | β-L | WL | Pperm | |
---|---|---|---|---|---|---|---|---|
Two-order models | ||||||||
1 | LILRA3 rs386000 × GALNT2 rs4846914 | 3 | 0.352 | 17.72 | 0 | - | - | 0.001 |
2 | LPA rs55730499 × GALNT2 rs4846914 | 1 | 0.883 | 12.48 | 2 | −0.164 | 5.09 | 0.004 |
3 | SCARB1 rs838880 × COBLL1 rs12328675 | 0 | - | - | 2 | −0.372 | 9.46 | 0.04 |
4 | SCARB1 rs838880 × LPA rs55730499 | 1 | 0.377 | 8.78 | 1 | −2.089 | 4.42 | 0.044 |
Three-order models | ||||||||
1 | SCARB1 rs838880 × LPA rs55730499 × APOC1 rs4420638 | 3 | 0.436 | 23.04 | 5 | −0.248 | 9.45 | <0.002 |
2 | LPA rs55730499 × LILRA3 rs386000 × GALNT2 rs4846914 | 4 | 0.549 | 22.04 | 3 | −0.287 | 9.45 | <0.002 |
3 | LILRA3 rs386000 × GALNT2 rs4846914 × SMOKING | 4 | 0.426 | 21.87 | 1 | −0.443 | 3.13 | <0.002 |
4 | LPA rs55730499 × GALNT2 rs4846914× ABCA1 rs1883025 | 4 | 0.947 | 20.61 | 3 | −0.199 | 6.14 | <0.002 |
Four-order models | ||||||||
1 | LILRA3 rs386000 × GALNT2 rs4846914 × COBLL1 rs12328675 × SMOKING | 6 | 0.688 | 32.02 | 2 | −0.859 | 12.06 | <0.002 |
2 | STARD3 rs881844 × ST3GAL4 rs11220463× LPA rs55730499 × APOC1 rs4420638 | 5 | 0.544 | 25.21 | 2 | −0.206 | 4.43 | <0.002 |
3 | SCARB1 rs838880 × LPA rs55730499 × APOC1 rs4420638 × SMOKING | 4 | 0.562 | 23.56 | 4 | −0.870 | 12.15 | <0.002 |
4 | SCARB1 rs838880 × LILRA3 rs386000 × GALNT2 rs4846914 × COBLL1 rs12328675 | 6 | 0.856 | 35.96 | 3 | −0.759 | 13.91 | 0.002 |
G × G/G × E Interaction Models | NH | β-H | WH | NL | β-L | WL | Pperm | |
---|---|---|---|---|---|---|---|---|
Two-order models | ||||||||
1 | PSKH1 rs16942887 × SMOKING | 2 | 0.596 | 47.25 | 2 | −0.561 | 40.94 | <0.001 |
2 | ABCA1 rs1883025 × SMOKING | 3 | 0.569 | 43.18 | 3 | −0.569 | 43.18 | <0.001 |
3 | ST3GAL4 rs11220463 × SMOKING | 2 | 0.563 | 42.46 | 3 | −0.566 | 42.68 | <0.001 |
4 | SCARB1 rs838880 × SMOKING | 2 | 0.547 | 40.48 | 3 | −0.566 | 42.68 | <0.001 |
Three-order models | ||||||||
1 | PSKH1 rs16942887 × F2 rs3136441 × SMOKING | 3 | 0.626 | 53.01 | 3 | −0.498 | 28.45 | <0.002 |
2 | ABCA1 rs1883025 × PLTP rs6065906 × SMOKING | 3 | 0.609 | 51.58 | 3 | −0.619 | 39.64 | <0.002 |
3 | PSKH1 rs16942887 × LILRA3 rs386000 × SMOKING | 4 | 0.615 | 51.45 | 3 | −0.521 | 33.49 | <0.002 |
4 | SCARB1 rs838880 × ABCA1 rs1883025 × SMOKING | 4 | 0.532 | 37.84 | 7 | −0.663 | 50.48 | <0.002 |
Four-order models | ||||||||
1 | SCARB1 rs838880 × PSKH1 rs16942887 × NPC1L1 rs217406 × SMOKING | 7 | 0.662 | 57.46 | 7 | −0.685 | 47.82 | <0.002 |
2 | STARD3 rs881844 × NPC1L1 rs217406 × LILRA3 rs386000 × SMOKING | 6 | 0.681 | 56.28 | 4 | −0.547 | 19.32 | <0.002 |
3 | SCARB1 rs838880 × ST3GAL4 rs11220463 × GALNT2 rs4846914 × SMOKING | 3 | 0.473 | 17.22 | 10 | −0.696 | 55.97 | <0.002 |
4 | PSKH1 rs16942887 × PLTP rs6065906 × F2 rs3136441 × SMOKING | 5 | 0.648 | 55.90 | 7 | −0.579 | 36.11 | <0.002 |
G × G/G × E Interaction Models | NH | β-H | WH | NL | β-L | WL | Pperm | |
---|---|---|---|---|---|---|---|---|
Two-order models | ||||||||
1 | LPA rs55730499 × COBLL1 rs12328675 | 2 | 0.220 | 41.65 | 2 | −0.209 | 43.84 | <0.001 |
2 | STARD3 rs881844 × F2 rs3136441 | 1 | 0.119 | 20.13 | 4 | −0.161 | 40.10 | <0.001 |
3 | LILRA3 rs386000 × F2 rs3136441 | 2 | 0.142 | 33.29 | 3 | −0.128 | 25.97 | <0.001 |
4 | LPA rs55730499 × F2 rs3136441 | 3 | 0.133 | 28.12 | 2 | −0.150 | 33.18 | <0.001 |
Three-order models | ||||||||
1 | PLTP rs6065906 × LPA rs55730499 × COBLL1 rs12328675 | 3 | 0.280 | 52.83 | 3 | −0.099 | 13.26 | <0.002 |
2 | LPA rs55730499 × COBLL1 rs12328675 × SMOKING | 3 | 0.265 | 51.27 | 2 | −0.104 | 13.95 | <0.002 |
3 | LPA rs55730499 × LILRA3 rs386000 × COBLL1 rs12328675 | 4 | 0.253 | 50.63 | 3 | −0.132 | 23.58 | <0.002 |
4 | SCARB1 rs838880 × LPA rs55730499 × COBLL1 rs12328675 | 4 | 0.277 | 48.58 | 2 | −0.127 | 19.67 | <0.002 |
Four-order models | ||||||||
1 | SCARB1 rs838880 × STARD3 rs881844 × LPA rs55730499 × COBLL1 rs12328675 | 9 | 0.345 | 68.48 | 4 | −0.157 | 29.20 | <0.002 |
2 | SCARB1 rs838880 × LPA rs55730499 × COBLL1 rs12328675 × SMOKING | 6 | 0.331 | 67.94 | 2 | −0.147 | 16.68 | <0.002 |
3 | STARD3 rs881844 × PLTP rs6065906 × NPC1L1 rs217406 NPC1L1 × F2 rs3136441 | 3 | 0.139 | 16.98 | 12 | −0.221 | 64.49 | <0.002 |
4 | LPA rs55730499 × F2 rs3136441 COBLL1 rs12328675 × SMOKING | 6 | 0.312 | 63.97 | 5 | −0.189 | 38.10 | <0.002 |
SNP ID | Gene | FuncPred 1 | Number eQTL (GTEx 2) | Binding Sites for TF 3 | Regulatory Potential (rSNPbase 4) | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Regulatory Potential | Conservatism | cis | trans | Loss | Gain | rSNP | rSNP in LD | Post-Transcriptional Regulation | Circular RNA Binding Regions (circRNA) | ||
rs1883025 | ABCA1 | 0.149 | 0.001 | −/− | - | 24 | 9 | + | 18 | + | 5 |
rs4420638 | APOC1 | - | 0 | −/− | - | 2 | 25 | - | 7 | - | 4 |
rs3764261 | CETP | 0 | 0.001 | −/+ | 1 | 11 | 13 | + | 1 | - | - |
rs12328675 | COBLL1 | 0 | 0 | −/+ | 1 | 8 | 10 | + | 3 | - | 1 |
rs3136441 | F2 | - | 0.017 | −/+ | 33 | 13 | 8 | + | 49 | + | 1 |
rs4846914 | GALNT2 | 0.199 | 0 | −/− | - | 5 | 7 | + | 21 | + | 3 |
rs386000 | LILRA3 | 0 | 0.001 | 26/+ | - | - | - | - | 19 | - | 10 |
rs55730499 | LPA | - | - | −/− | 1 | 11 | 5 | - | 2 | - | 3 |
rs217406 | NPC1L1 | 0.339 | 0 | 1/+ | 17 | 9 | 7 | + | 18 | + | 4 |
rs6065906 | PLTP | - | 0 | 13/+ | 7 | 41 | 3 | + | 20 | - | - |
rs16942887 | PSKH1 | - | 0.006 | −/+ | 45 | 12 | 4 | + | 81 | + | - |
rs11220463 | ST3GAL4 | 0 | 0.001 | 8/+ | - | 19 | 9 | + | 24 | + | - |
rs881844 | STARD3 | 0.273 | 0.002 | 1/+ | 38 | 26 | 11 | + | 73 | + | 1 |
rs1689800 | ZNF648 | 0 | 0 | −/− | - | 8 | 21 | - | 5 | - | - |
rs838880 | SCARB1 | - | 0 | −/− | - | 3 | 22 | + | 1 | - | - |
rs9987289 | PPP1R3B | 0.045 | 0.001 | −/− | - | 9 | 26 | + | 51 | - | - |
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Lazarenko, V.; Churilin, M.; Azarova, I.; Klyosova, E.; Bykanova, M.; Ob'edkova, N.; Churnosov, M.; Bushueva, O.; Mal, G.; Povetkin, S.; et al. Comprehensive Statistical and Bioinformatics Analysis in the Deciphering of Putative Mechanisms by Which Lipid-Associated GWAS Loci Contribute to Coronary Artery Disease. Biomedicines 2022, 10, 259. https://doi.org/10.3390/biomedicines10020259
Lazarenko V, Churilin M, Azarova I, Klyosova E, Bykanova M, Ob'edkova N, Churnosov M, Bushueva O, Mal G, Povetkin S, et al. Comprehensive Statistical and Bioinformatics Analysis in the Deciphering of Putative Mechanisms by Which Lipid-Associated GWAS Loci Contribute to Coronary Artery Disease. Biomedicines. 2022; 10(2):259. https://doi.org/10.3390/biomedicines10020259
Chicago/Turabian StyleLazarenko, Victor, Mikhail Churilin, Iuliia Azarova, Elena Klyosova, Marina Bykanova, Natalia Ob'edkova, Mikhail Churnosov, Olga Bushueva, Galina Mal, Sergey Povetkin, and et al. 2022. "Comprehensive Statistical and Bioinformatics Analysis in the Deciphering of Putative Mechanisms by Which Lipid-Associated GWAS Loci Contribute to Coronary Artery Disease" Biomedicines 10, no. 2: 259. https://doi.org/10.3390/biomedicines10020259
APA StyleLazarenko, V., Churilin, M., Azarova, I., Klyosova, E., Bykanova, M., Ob'edkova, N., Churnosov, M., Bushueva, O., Mal, G., Povetkin, S., Kononov, S., Luneva, Y., Zhabin, S., Polonikova, A., Gavrilenko, A., Saraev, I., Solodilova, M., & Polonikov, A. (2022). Comprehensive Statistical and Bioinformatics Analysis in the Deciphering of Putative Mechanisms by Which Lipid-Associated GWAS Loci Contribute to Coronary Artery Disease. Biomedicines, 10(2), 259. https://doi.org/10.3390/biomedicines10020259