Apolipoprotein-CIII O-Glycosylation, a Link between GALNT2 and Plasma Lipids
Abstract
:1. Introduction
2. Results
2.1. Cohort Characteristics
2.2. Apo-CIII O-Glycosylation, Type 2 Diabetes and Lipid Parameters
2.3. GWASs of Apo-CIII O-Glycosylation Proteoforms
3. Discussion
4. Material and Methods
4.1. DiaGene Study
4.2. The Hoorn Diabetes Care System Cohort
4.3. Apo-CIII Glycosylation Measurements
4.4. GWAS of Apo-CIII Glycosylation
4.5. Statistical Methods
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Declaration of Generative AI and AI-assisted technologies in the writing process
References
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DiaGene | Hoorn DCS | |
---|---|---|
Number of participants | 2318 | 5409 |
Female sex, n (%) | 1175 (50.7) | 2414 (44.6) |
Age, year, mean (±SD) | 65.3 (9.5) | 61.1 (11,0) |
BMI, kg/m2, median (IQR) | 28.0 (25.2–31.6) | 29.4 (26.6–33.1) |
Type 2 diabetes, n (%) | 1572 (67.8) | 5409 (100) |
HDL-cholesterol, mmol/L, median (IQR) | 1.2 (1.0–1.5) | 1.2 (1–1.4) |
Non-HDL cholesterol, mmol/L, mean (±SD) | 3.4 (1.0) | 3.8 (1.5) |
LDL-cholesterol, mmol/L, mean (±SD) | 2.8 (1.0) | 2.9 (1.5) |
Triglycerides, mmol/L, median (IQR) | 1.4 (1.0–1.9) | 1.7 (1.2–2.3) |
Total cholesterol, mmol/L, mean (±SD) | 4.7 (1.1) | 5.0 (1.6) |
Use of any lipid-lowering therapy, n (%) | 1113 (50.3) | 2276 (42.1) |
Use of statins, n (%) | 1090 (47.0) | 2182 (40.3) |
Use of fibrates, n (%) | 33 (1.4) | 68 (1.3) |
Use of bile acid sequestrants, n (%) | 1 (0.04) | 6 (0.1) |
Use of nicotinic acid and derivates, n (%) | 5 (0.2) | 7 (0.1) |
Use of other lipid modifying agents, n (%) | 56 (2.4) | 56 (1.0) |
HDL-c | |||
---|---|---|---|
Proteoform | Beta | 95% CI | p-Value |
Apo-CIII0a | 0.007 | 0.005 to 0.009 | 5.81 × 10−9 |
Apo-CIII0c | −0.002 | −0.005 to 0.001 | 0.232 |
Apo-CIII1 | −0.011 | −0.015 to −0.007 | 3.24 × 10−8 |
Apo-CIII2 | 0.013 | 0.008 to 0.018 | 3.20 × 10−7 |
Apo-CIII1/apo-CIII2 ratio | −0.321 | −0.422 to −0.221 | 4.00 × 10−10 |
Non-HDL-c | |||
Proteoform | Beta | 95% CI | p-Value |
Apo-CIII0a | 0.004 | 0.003 to 0.004 | 1.48 × 10−18 |
Apo-CIII0c | 0.002 | 0.001 to 0.003 | 3.09 × 10−4 |
Apo-CIII1 | 0.006 | 0.004 to 0.007 | 9.04 × 10−16 |
Apo-CIII2 | −0.007 | −0.009 to −0.006 | 3.60 × 10−17 |
Apo-CIII1/apo-CIII2 ratio | 0.133 | 0.099 to 0.167 | 2.82 × 10−14 |
LDL-c | |||
Proteoform | Beta | 95% CI | p-Value |
Apo-CIII0a | 0.004 | 0.003 to 0.005 | 3.86 × 10−20 |
Apo-CIII0c | 0.001 | 0.000 to 0.002 | 0.041 |
Apo-CIII1 | 0.004 | 0.003 to 0.005 | 4.33 × 10−8 |
Apo-CIII2 | −0.005 | −0.007 to −0.003 | 5.74 × 10−8 |
Apo-CIII1/apo-CIII2 ratio | 0.080 | 0.045 to 0.116 | 9.65 × 10−6 |
Total cholesterol | |||
Proteoform | Beta | 95% CI | p-Value |
Apo-CIII0a | 0.004 | 0.003 to 0.005 | 4.37 × 10−24 |
Apo-CIII0c | 0.002 | 0.001 to 0.003 | 0.003 |
Apo-CIII1 | 0.004 | 0.002 to 0.005 | 8.99 × 10−9 |
Apo-CIII2 | −0.005 | −0.007 to −0.004 | 4.17 × 10−10 |
Apo-CIII1/apo-CIII2 ratio | 0.084 | 0.052 to 0.116 | 2.99 × 10−7 |
Triglycerides | |||
Proteoform | Beta | 95% CI | p-Value |
Apo-CIII0a | 0.001 | 0.000 to 0.001 | 0.045 |
Apo-CIII0c | 0.003 | 0.002 to 0.004 | 2.08 × 10−8 |
Apo-CIII1 | 0.008 | 0.007 to 0.009 | 9.66 × 10−49 |
Apo-CIII2 | −0.011 | −0.012 to −0.009 | 1.03 × 10−49 |
Apo-CIII1/apo-CIII2 ratio | 0.225 | 0.193 to 0.257 | 2.26 × 10−51 |
Type 2 diabetes | |||
Proteoform | Beta | 95% CI | p-Value |
Apo-CIII0a | −29.59 | −34.43 to −24.74 | 5.42 × 10−33 |
Apo-CIII0c | −0.963 | −4.338 to 2.412 | 0.576 |
Apo-CIII1 | 1.275 | −1.399 to 3.950 | 0.350 |
Apo-CIII2 | −0.296 | −2.377 to 1.786 | 0.781 |
Apo-CIII1/apo-CIII2 ratio | 0.110 | 0.002 to 0.217 | 0.046 |
Proteoform | rsID | Chr | Pos | EA | RA | EAF | Beta | SE | p-Value | Locus |
---|---|---|---|---|---|---|---|---|---|---|
Apo-CIII0a | rs35498929 | 1 | 230286016 | T | C | 0.1249 | −0.1223 | 0.02472 | 7.44 × 10−7 | GALNT2 (intronic) |
rs4846913 | 1 | 230294715 | A | C | 0.5964 | −0.2027 | 0.01624 | 9.77 × 10−36 | GALNT2 (intronic) | |
rs3213497 | 1 | 230416320 | T | C | 0.1282 | −0.1271 | 0.02407 | 1.30 × 10−7 | GALNT2:RP5-956O18.3 (ncRNA exonic) | |
Apo-CIII0c | rs9378785 | 6 | 3316862 | C | T | 0.0508 | −0.0918 | 0.01705 | 7.34 × 10−8 | SLC22A23 (intronic) |
Apo-CIII1 | rs10842926 | 12 | 27689893 | C | G | 0.0826 | −0.0145 | 0.002928 | 7.07 × 10−7 | PPFIBP1 (intronic) |
Apo-CIII2 | rs67086575 | 2 | 27686480 | G | A | 0.1502 | −0.0469 | 0.009473 | 7.32 × 10−7 | IFT172 (intronic) |
rs2493926 | 6 | 148614267 | C | T | 0.1112 | 0.0520 | 0.01058 | 9.12 × 10−7 | SASH1 (intronic) | |
rs2481968 | 13 | 28567172 | C | A | 0.4874 | 0.0334 | 0.006647 | 4.90 × 10−7 | RN7SL272P (intergenic) | |
rs7175584 | 15 | 97500494 | T | C | 0.5638 | −0.0339 | 0.00671 | 4.48 × 10−7 | RN7SKP181 (intergenic) | |
rs10412211 | 19 | 13591542 | T | G | 0.4579 | −0.0336 | 0.006713 | 5.62 × 10−7 | CACNA1A (intronic) | |
Apo-CIII1/apo-CIII2 ratio | rs67086575 | 2 | 27686480 | G | A | 0.1502 | 0.0561 | 0.01133 | 7.37 × 10−7 | IFT172 (intronic) |
rs9462715 | 6 | 12368221 | C | A | 0.0571 | −0.0826 | 0.01676 | 8.35 × 10−7 | RN7SKP293 (intergenic) | |
rs2493926 | 6 | 148614267 | C | T | 0.1112 | −0.0627 | 0.01266 | 7.46 × 10−7 | SASH1 (intronic) | |
rs7175584 | 15 | 97500494 | T | C | 0.5638 | 0.0419 | 0.008028 | 1.80 × 10−7 | RN7SKP181 (intergenic) | |
rs10412211 | 19 | 13591542 | T | G | 0.4579 | 0.0396 | 0.008031 | 8.24 × 10−7 | CACNA1A (intronic) |
HDL-c | DiaGene | Hoorn DCS | Meta-Analysis | |||||
---|---|---|---|---|---|---|---|---|
rsID | EA | Beta | 95% C.I. | p-Value | Beta | 95% C.I. | p-Value | p-Value |
rs4846913 | A | 0.006 | −0.017 to 0.030 | 0.606 | 0.011 | −0.001 to 0.023 | 0.076 | 0.065 |
rs9378785 | C | −0.058 | −0.113 to −0.003 | 0.040 | 0.005 | −0.025 to 0.033 | 0.751 | 0.472 |
Non-HDL-c | DiaGene | Hoorn DCS | Meta-analysis | |||||
rsID | EA | Beta | 95% C.I. | p-Value | Beta | 95% C.I. | p-Value | p-Value |
rs67086575 | G | 0.120 | 0.025 to 0.215 | 0.013 | 0.001 | −0.056 to 0.059 | 0.961 | 0.207 |
rs2493926 | C | −0.157 | −0.266 to −0.048 | 0.005 | 0.030 | −0.041 to 0.101 | 0.412 | 0.522 |
LDL-c | DiaGene | Hoorn DCS | Meta-analysis | |||||
rsID | EA | Beta | 95% C.I. | p-Value | Beta | 95% C.I. | p-Value | p-Value |
rs67086575 | G | 0.109 | 0.018 to 0.201 | 0.019 | −0.045 | −0.097 to 0.006 | 0.086 | 0.707 |
rs2493926 | C | −0.183 | −0.288 to −0.078 | 0.001 | 0.035 | −0.029 to 0.099 | 0.289 | 0.464 |
rs10842926 | C | 0.038 | −0.084 to 0.160 | 0.547 | 0.089 | 0.016 to 0.162 | 0.016 | 0.016 |
Total cholesterol | DiaGene | Hoorn DCS | Meta-analysis | |||||
rsID | EA | Beta | 95% C.I. | p-Value | Beta | 95% C.I. | p-Value | p-Value |
rs67086575 | G | 0.115 | 0.014 to 0.216 | 0.025 | 0.007 | −0.051 to 0.065 | 0.817 | 0.190 |
rs2493926 | C | −0.171 | −0.286 to −0.055 | 0.004 | 0.017 | −0.055 to 0.088 | 0.650 | 0.311 |
Triglycerides | DiaGene | Hoorn DCS | Meta-analysis | |||||
rsID | EA | Beta | 95% C.I. | p-Value | Beta | 95% C.I. | p-Value | p-Value |
rs4846913 | A | −0.063 | −0.135 to 0.008 | 0.032 | −0.052 | −0.097 to −0.006 | 0.034 | 0.006 |
rs67086575 | G | 0.084 | −0.014 to 0.183 | 0.017 | 0.084 | 0.023 to 0.145 | 2.20 × 10−4 | 1.07 × 10−5 |
rs10842926 | C | −0.081 | −0.212 to 0.051 | 0.061 | −0.061 | −0.147 to 0.025 | 0.185 | 0.039 |
rs2481968 | C | −0.076 | −0.146 to −0.007 | 0.025 | 0.017 | −0.028 to 0.062 | 0.759 | 0.391 |
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Naber, A.; Demus, D.; Slieker, R.; Nicolardi, S.; Beulens, J.W.J.; Elders, P.J.M.; Lieverse, A.G.; Sijbrands, E.J.G.; ’t Hart, L.M.; Wuhrer, M.; et al. Apolipoprotein-CIII O-Glycosylation, a Link between GALNT2 and Plasma Lipids. Int. J. Mol. Sci. 2023, 24, 14844. https://doi.org/10.3390/ijms241914844
Naber A, Demus D, Slieker R, Nicolardi S, Beulens JWJ, Elders PJM, Lieverse AG, Sijbrands EJG, ’t Hart LM, Wuhrer M, et al. Apolipoprotein-CIII O-Glycosylation, a Link between GALNT2 and Plasma Lipids. International Journal of Molecular Sciences. 2023; 24(19):14844. https://doi.org/10.3390/ijms241914844
Chicago/Turabian StyleNaber, Annemieke, Daniel Demus, Roderick Slieker, Simone Nicolardi, Joline W. J. Beulens, Petra J. M. Elders, Aloysius G. Lieverse, Eric J. G. Sijbrands, Leen M. ’t Hart, Manfred Wuhrer, and et al. 2023. "Apolipoprotein-CIII O-Glycosylation, a Link between GALNT2 and Plasma Lipids" International Journal of Molecular Sciences 24, no. 19: 14844. https://doi.org/10.3390/ijms241914844