Biomedical Science Letters (대한의생명과학회지)

The Korean Society for Biomedical Laboratory Sciences (대한의생명과학회)
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Associations Between APOE Gene Variants and Metabolite Levels in Hypercholesterolemia: A Metabolite GWAS Study in a Korean Cohort

  • Sangjung Park (Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University)
  • Received : 2024.08.05
  • Accepted : 2024.08.22
  • Published : 2024.09.30
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Abstract

Hypercholesterolemia, a form of hyperlipidemia, is a significant risk factor for cardiovascular diseases, often linked to genetic variations in the APOE gene, particularly the ε4 allele, which influences LDL cholesterol levels. This study aimed to examine the association between APOE gene variants and plasma sphingomyelin levels in Korean individuals with hypercholesterolemia, using a metabolite genome-wide association study (mGWAS) approach. Data from 7,031 participants in the Korean Genome and Epidemiology Study (KoGES) were analyzed. Genetic associations with cholesterol and sphingomyelin levels were evaluated through Exome chip analysis and metabolite profiling. Significant associations were identified between specific APOE variants (e.g., rs769449, rs4420638) and serum cholesterol levels. Additionally, certain SNPs were linked to variations in plasma sphingomyelin levels, suggesting a genetic influence on both lipid and sphingomyelin metabolism. The findings underscore the relevance of mGWAS in unraveling the genetic and metabolic pathways involved in hypercholesterolemia, offering potential biomarkers for disease risk and therapeutic targets.

Keywords

Acknowledgement

This study was conducted with bioresources from National Biobank of Korea, the Korea Disease Control and Prevention Agency, Republic of Korea (NBK-2022-45). This research was supported by the Academic Research Fund of Hoseo University in 20210805

References

  1. Borodzicz-Jazdzyk S, Jazdzyk P, Lysik W, et al. Sphingolipid metabolism and signaling in cardiovascular diseases. J Front Cardiovasc Med. 2022. 9: 915961.
  2. Corder EH, Saunders AM, Strittmatter, WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993. 261: 921-923. https://doi.org/10.1126/science.8346443
  3. Demirkan A, van Duijn CM, Ugocsai P, et al. Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations. PLOS Genet. 2012. 8: e1002490.
  4. Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009. 29: 431-438. https://doi.org/10.1161/ATVBAHA.108.179564
  5. Heeren J, Beisiegel U, Grewal T. Apolipoprotein E recycling: implications for dyslipidemia and atherosclerosis. Arterioscler Thromb Vasc Biol. 2006. 26: 442-448. https://doi.org/10.1161/01.ATV.0000201282.64751.47
  6. Huang Y, Mahley RW. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases. Neurobiol Dis. 2014. 72: 3-12. https://doi.org/10.1016/j.nbd.2014.08.025
  7. Illig T, Gieger C, Zhai G, et al. A genome-wide perspective of genetic variation in human metabolism. Nat Genet. 2010. 42: 137-141. https://doi.org/10.1038/ng.507
  8. Jeon TE, Jin HS. PDGFC, MARK3 and BCL2 polymorphisms are associated with left ventricular hypertrophy in Korean population. Biomed Sci Letters. 2019. 25: 237-246. https://doi.org/10.15616/BSL.2019.25.3.237
  9. Karjalainen MK, Karthikeyan S, Oliver-Williams C, et al. Genome-wide characterization of circulating metabolic biomarkers. Nature. 2024. 628: 130-138. https://doi.org/10.1038/s41586-024-07148-y
  10. Kettunen J, Tukiainen T, Sarin AP, et al. Genome-wide association study identifies multiple loci influencing human serum metabolite levels. Nat Genet. 2012. 44: 269-276. https://doi.org/10.1038/ng.1073
  11. Kong Y, Kim M, Jin HS, et al. Association with Genetic Polymorphism of rs117033348 and Allergic Disease in Korean Population. Biomed Sci Letters. 2021. 27: 177-181. https://doi.org/10.15616/BSL.2021.27.3.177
  12. Koopal C, Geerlings MI, Muller M, et al. The relation between apolipoprotein E (APOE) genotype and peripheral artery disease in patients at high risk for cardiovascular disease. Atherosclerosis. 2016. 246: 187-192. https://doi.org/10.1016/j.atherosclerosis.2016.01.009
  13. Krauss RM. Lipids and lipoproteins in patients with type 2 diabetes. Diabetes Care. 2004. 27: 1496-1504. https://doi.org/10.2337/diacare.27.6.1496
  14. Long T, Hicks M, Yu HC, et al. Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites. Nat Genet. 2017. 49: 568-578. https://doi.org/10.1038/ng.3809
  15. Mahley RW, Huang Y. Apolipoprotein E: from atherosclerosis to Alzheimer's disease and beyond. Curr Opin Lipidol. 1999. 10: 207-217. https://doi.org/10.1097/00041433-199906000-00003
  16. Mahley RW. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. J Mol Med (Berl). 2016. 94: 739-746. https://doi.org/10.1007/s00109-016-1427-y
  17. Meikle PJ, Wong G, Tan R, Barlow CK, et al. Lipidomics: potential role in risk prediction and therapeutic monitoring for cardiovascular disease. Pharmacol Ther. 2014. 138: 34-53.
  18. Rhee EP, Ho JE, Chen MH, et al. A genome-wide association study of the human metabolome in a community-based cohort. Cell Metab. 2013. 18: 130-143. https://doi.org/10.1016/j.cmet.2013.06.013
  19. Sandesara PB, Virani SS, Fazio S, et al. The Forgotten Lipids: Triglycerides, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease Risk. Endocr Rev. 2019. 40: 537-557. https://doi.org/10.1210/er.2018-00184
  20. Schork NJ, Murray SS, Frazer KA, et al. Common vs. rare allele hypotheses for complex diseases. Curr Opin Genet Dev. 2009. 23: 212-219. https://doi.org/10.1016/j.gde.2009.04.010
  21. Shin SY, Fauman EB, Petersen AK, et al. An atlas of genetic influences on human blood metabolites. Nat Genet. 2014. 46: 543-550. https://doi.org/10.1038/ng.2982
  22. Song K, Jeon S, Lee HS, et al. Trends of Dyslipidemia in Korean Youth According to Sex and Body Mass Index: Based on the Korea National Health and Nutrition Examination Survey (2007-2018). J Pediatr. 2021. 237: 71-78. https://doi.org/10.1016/j.jpeds.2021.06.010
  23. Suhre K, Wallaschofski H, Raffler J, et al. A genome-wide association study of metabolic traits in human urine. Nat Genet. 2011. 43: 565-569. https://doi.org/10.1038/ng.837
  24. Tam V, Patel N, Turcotte M, et al. Benefits and limitations of genome-wide association studies. Nat Rev Genet. 2019. 20: 467-484. https://doi.org/10.1038/s41576-019-0127-1
  25. Visscher PM, Wray NR, Zhang Q, et al. 10 Years of GWAS Discovery: Biology, Function, and Translation. Am J Hum Genet. 2017. 101: 5-22. https://doi.org/10.1016/j.ajhg.2017.06.005