Common and Rare PCSK9 Variants Associated with Low-Density Lipoprotein Cholesterol Levels and the Risk of Diabetes Mellitus: A Mendelian Randomization Study
Abstract
:1. Introduction
2. Results
2.1. Regional Plot Association Analysis for the PCSK9 Region
2.2. Association between Rare PCSK9 Nonsynonymous Exonic Mutations and LDL-C Levels
2.3. Stepwise Linear Regression Analysis
2.4. Association between LDL-C Levels and DM Status
2.5. GWAS Analysis for LDL-C Levels
2.6. Association between LDL-C-Level-Associated PCSK9 Genotypes and Clinical and Laboratory Parameters
2.7. MR Analysis along with 2SLS IV Regression for Determining the Association of Genetic Determinants of LDL-C Levels with DM Status
2.8. Scatter Plots and Test for Heterogeneity
2.9. Sensitivity Analysis for Causal Inference from Standard Mendelian Randomization with Multiple Genetic Variants Determining LDL-C Levels
3. Discussion
3.1. Ethnic Heterogeneity of PCSK9 Gain-of-Function and Loss-of-Function Mutations
3.2. Role of Noncoding PCSK9 Variants
3.3. Mendelian Randomization for LDL-C and DM
3.4. Limitations
4. Methods and Materials
4.1. TWB Participants
4.2. Genomic DNA Extraction and Genotyping
4.3. Clinical Phenotypes and Laboratory Examinations
4.4. Regional Plot Analysis and GWAS
4.5. Statistical Analysis
4.6. MR Analysis
4.7. Scatterplots and Testing for Heterogeneity
4.8. Sensitivity Analysis
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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PCSK9 Variants | Chr | Position | Ref/Alt | Func.refGene | Gene.refGene | HWE | MAF | MM | Mm | mm | p Value | Beta | SE | p * Value |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
rs10788994 | 1 | 55,500,976 | C/T | intergenic | BSND;PCSK9 | 0.7616 | 0.3475 | 121.80 ± 31.26 (31,728) | 120.41 ± 30.84 (33,743) | 119.23 ± 30.86 (9015) | 6.44 × 10−13 | −0.0047 | 0.0006 | 1.99 × 10−14 |
rs151193009 | 1 | 55,509,585 | C/T | exon2:c.C277T:p.R93C | PCSK9 | 0.4419 | 0.0027 | 120.98 ± 30.98 (73,449) | 106.76 ± 28.53 (405) | -- | 1.76 × 10−18 | −0.0579 | 0.0057 | 1.19 × 10−24 |
rs557211 | 1 | 55,514,215 | T/G | Intron Variant | PCSK9 | 0.8433 | 0.1916 | 121.42 ± 31.179 (49,044) | 119.81 ± 30.701 (23,300) | 119.30 ± 30.654 (2740) | 1.69 × 10−11 | −0.0052 | 0.0007 | 3.75 × 10−12 |
rs768846693 | 1 | 55,518,412 | C/A | exon5:c.C747A:p.S249R | PCSK9 | 0.9078 | 0.0004 | 120.88 ± 31.02 (75,324) | 91.73 ± 28.18 (63) | -- | 1.18 × 10−9 | −0.1301 | 0.0143 | 1.12 × 10−19 |
rs757143429 | 1 | 55,523,828 | C/T | exon8:c.C1300T:p.R434W | PCSK9 | 0.7454 | 0.0011 | 120.89 ± 31.02 (75,239) | 107.81 ± 30.25 (175) | -- | 1.47 × 10−7 | −0.0509 | 0.0086 | 3.46 × 10−9 |
rs565436 | 1 | 55,524,601 | G/A | Intron Variant | PCSK9 | 0.3577 | 0.1033 | 121.22 ± 31.11 (60,123) | 119.41 ±30.65 (13,901) | 118.19 ± 31.05 (780) | 8.08 × 10−10 | −0.0067 | 0.0010 | 3.81 × 10−12 |
rs505151 | 1 | 55529187 | G/A | exon12:c.G2009A:p.G670E | PCSK9 | 0.9202 | 0.0534 | 119.0 ± 31.00 (67,530) | 120.00 ± 31.21 (7603) | 121.00 ± 32.37 (215) | 6.00 × 10−6 | 0.0065 | 0.0013 | 5.89 × 10−7 |
Serum Total Cholesterol Level | Serum LDL-C Level | |||||
---|---|---|---|---|---|---|
Beta | r2 | p Value | Beta | r2 | p Value | |
Age (years) | 0.0014 | 0.0362 | <10−307 | 0.0015 | 0.0186 | <10−307 |
Sex (male vs. female) | 0.0154 | 0.0049 | 1.15 × 10−131 | -- | -- | -- |
Body mass index (kg/m2) | 0.0017 | 0.0066 | 1.09 × 10−108 | 0.0051 | 0.0268 | <10−307 |
Current smoking status (%) | 0.0060 | 0.0004 | 8.49 × 10−9 | -- | -- | -- |
rs10788994 (TT vs.TC vs. CC) | −0.0022 | 0.0007 | 9.21 × 10−6 | −0.0039 | 0.0009 | 6.80 × 10−8 |
rs151193009 (CC vs. CT) | −0.0388 | 0.0013 | 1.47 × 10−24 | −0.0615 | 0.0014 | 3.03 × 10−27 |
rs557211 (TT vs.TG vs. GG) | −0.0018 | 0.0001 | 0.0024 | −0.0024 | 0.0001 | 0.0052 |
rs768846693 (CC vs. CA) | −0.0662 | 0.0006 | 8.4 × 10−12 | −0.1261 | 0.0011 | 3.87 × 10−18 |
rs757143429 (CC vs. CT) | −0.0310 | 0.0004 | 7.69 × 10−8 | −0.0511 | 0.0005 | 3.43 × 10−9 |
rs565436 (AA vs. AG vs. GG) | −0.0038 | 0.0005 | 7.55 × 10−9 | −0.0060 | 0.0005 | 1.19 × 10−9 |
rs505151 (AA vs. AG vs. GG) | 0.0036 | 0.0002 | 0.0001 | 0.0065 | 0.0003 | 1.23 × 10−6 |
TA | TB | GA | TA-TB | GA-TA | GA-TB | IVA-TB | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Beta | SE | p a | Beta | SE | p a | Beta | SE | p a | Beta | SE | p a (p b) | |||
LDL-C | DM | WGRS_PCSK9_7SNVs | −1.9993 | 0.1185 | 6.76 × 10−64 | 0.5599 | 0.0301 | 4.66 × 10−77 | −2.3685 | 0.8918 | 0.0079 | −4.2294 | 1.5926 | 0.0079 (0.0098 c) |
WGRS_LDL-C_41SNVs | −1.9993 | 0.1185 | 6.76 × 10−64 | 0.9823 | 0.0202 | <10−307 | −1.9743 | 0.6972 | 0.0046 | −1.9710 | 0.6961 | 0.0046 (5.02 × 10−7 c) |
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Hsu, L.-A.; Teng, M.-S.; Wu, S.; Chou, H.-H.; Ko, Y.-L. Common and Rare PCSK9 Variants Associated with Low-Density Lipoprotein Cholesterol Levels and the Risk of Diabetes Mellitus: A Mendelian Randomization Study. Int. J. Mol. Sci. 2022, 23, 10418. https://doi.org/10.3390/ijms231810418
Hsu L-A, Teng M-S, Wu S, Chou H-H, Ko Y-L. Common and Rare PCSK9 Variants Associated with Low-Density Lipoprotein Cholesterol Levels and the Risk of Diabetes Mellitus: A Mendelian Randomization Study. International Journal of Molecular Sciences. 2022; 23(18):10418. https://doi.org/10.3390/ijms231810418
Chicago/Turabian StyleHsu, Lung-An, Ming-Sheng Teng, Semon Wu, Hsin-Hua Chou, and Yu-Lin Ko. 2022. "Common and Rare PCSK9 Variants Associated with Low-Density Lipoprotein Cholesterol Levels and the Risk of Diabetes Mellitus: A Mendelian Randomization Study" International Journal of Molecular Sciences 23, no. 18: 10418. https://doi.org/10.3390/ijms231810418