APOE and KLF14 Genetic Variants Are Sex-specific for Low High-density Lipoprotein Cholesterol Identified by a Genome-wide Association Study

Overview

Journal Genet Mol Biol

Specialty Genetics

Date 2022 Mar 3

PMID 35238325

Authors

Ying-Hui Lee

Ya-Sian Chang

Chih-Chang Hsieh

Rong-Tsorng Wang

Jan-Gowth Chang

Chung-Jen Chen

Shun-Jen Chang

Affiliations

Soon will be listed here.

Abstract

To demonstrate the loci that relate to high-density lipoprotein cholesterol (HDL-C) levels and genetic sex heterogeneity, we enrolled 41,526 participants aged between 30 and 70 years old from the Taiwan Biobank in a genome-wide association study. We applied the Manhattan plot to display the p-values estimated for the relationships between loci and low HDL-C. A total of 160 variants were significantly associated with low HDL-C. The genotype TT of rs1364422 located in the KLF14 gene has 1.30 (95% CI=1.20 - 1.42) times the risk for low-HDL compared to genotype CC in females (log(-p) =8.98). Moreover, the genes APOC1, APOE, PVRL2, and TOMM40 were associated significantly with low-HDL-C in males only. Excluding the variants with high linkage disequilibrium, we revealed the rs429358 located in APOE as the major genetic variant for lowering HDL-C, in which genotype CT has 1.24 (95% CI= 1.16 - 1.32) times the risk. In addition, we also examine 12 genes related to HDL-C in both sexes, including LPL, ABCA1, APOA5, BUD13, ZPR1, ALDH1A2, LIPC, CETP, HERPUD1, LIPG, ANGPTL8, and DOCK6. In conclusion, low-HDL-C is a genetic and sex-specific phenotype, and we discovered that the APOE and KLF14 are specific to low-HDL-C for men and women, respectively.

Citing Articles

Biochemical Activation and Regulatory Functions of Trans-Regulatory KLF14 and Its Association with Genetic Polymorphisms.

Akash M, Rasheed S, Rehman K, Ibrahim M, Imran M, Assiri M Metabolites. 2023; 13(2).

PMID: 36837818 PMC: 9962810. DOI: 10.3390/metabo13020199.

References

Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray K, Thompson A . Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009; 302(18):1993-2000. PMC: 3284229. DOI: 10.1001/jama.2009.1619. View

Chen X, Li S, Yang Y, Yang X, Liu Y, Hu W . Genome-wide association study validation identifies novel loci for atherosclerotic cardiovascular disease. J Thromb Haemost. 2012; 10(8):1508-14. DOI: 10.1111/j.1538-7836.2012.04815.x. View

Weintraub A, Li C, Zamudio A, Sigova A, Hannett N, Day D . YY1 Is a Structural Regulator of Enhancer-Promoter Loops. Cell. 2017; 171(7):1573-1588.e28. PMC: 5785279. DOI: 10.1016/j.cell.2017.11.008. View

Small K, Todorcevic M, Civelek M, El-Sayed Moustafa J, Wang X, Simon M . Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition. Nat Genet. 2018; 50(4):572-580. PMC: 5935235. DOI: 10.1038/s41588-018-0088-x. View

Chung S, Gebre A, Seo J, Shelness G, Parks J . A novel role for ABCA1-generated large pre-beta migrating nascent HDL in the regulation of hepatic VLDL triglyceride secretion. J Lipid Res. 2010; 51(4):729-42. PMC: 2842152. DOI: 10.1194/jlr.M900083. View

Williams P . Quantile-Dependent Expressivity and Gene-Lifestyle Interactions Involving High-Density Lipoprotein Cholesterol. Lifestyle Genom. 2020; 14(1):1-19. PMC: 8116986. DOI: 10.1159/000511421. View

Willer C, Schmidt E, Sengupta S, Peloso G, Gustafsson S, Kanoni S . Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013; 45(11):1274-1283. PMC: 3838666. DOI: 10.1038/ng.2797. View

Liu M, Chung S, Shelness G, Parks J . Hepatic ABCA1 deficiency is associated with delayed apolipoprotein B secretory trafficking and augmented VLDL triglyceride secretion. Biochim Biophys Acta Mol Cell Biol Lipids. 2017; 1862(10 Pt A):1035-1043. PMC: 6726374. DOI: 10.1016/j.bbalip.2017.07.001. View

Cilingiroglu M, Ballantyne C . Endothelial lipase and cholesterol metabolism. Curr Atheroscler Rep. 2004; 6(2):126-30. DOI: 10.1007/s11883-004-0101-y. View

10.

Teslovich T, Musunuru K, Smith A, Edmondson A, Stylianou I, Koseki M . Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010; 466(7307):707-13. PMC: 3039276. DOI: 10.1038/nature09270. View

11.

Lin E, Kuo P, Liu Y, Yang A, Kao C, Tsai S . Association and interaction of APOA5, BUD13, CETP, LIPA and health-related behavior with metabolic syndrome in a Taiwanese population. Sci Rep. 2016; 6:36830. PMC: 5101796. DOI: 10.1038/srep36830. View

12.

Pruim R, Welch R, Sanna S, Teslovich T, Chines P, Gliedt T . LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010; 26(18):2336-7. PMC: 2935401. DOI: 10.1093/bioinformatics/btq419. View

13.

Soro A, Jauhiainen M, Ehnholm C, Taskinen M . Determinants of low HDL levels in familial combined hyperlipidemia. J Lipid Res. 2003; 44(8):1536-44. DOI: 10.1194/jlr.M300069-JLR200. View

14.

Brooks M, Dziembowski A, Quevillon-Cheruel S, Henriot V, Faux C, Van Tilbeurgh H . Structure of the yeast Pml1 splicing factor and its integration into the RES complex. Nucleic Acids Res. 2008; 37(1):129-43. PMC: 2615620. DOI: 10.1093/nar/gkn894. View

15.

Goldberg I . Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis. J Lipid Res. 1996; 37(4):693-707. View

16.

Shahvazian E, Mahmoudi M, Yazd E, Gharibi S, Moghimi B, HosseinNia P . The KLF14 Variant is Associated with Type 2 Diabetes and HbA Level. Biochem Genet. 2021; 59(2):574-588. DOI: 10.1007/s10528-020-10015-w. View

17.

von Eckardstein A, Schulte H, Assmann G . Risk for diabetes mellitus in middle-aged Caucasian male participants of the PROCAM study: implications for the definition of impaired fasting glucose by the American Diabetes Association. Prospective Cardiovascular Münster. J Clin Endocrinol Metab. 2000; 85(9):3101-8. DOI: 10.1210/jcem.85.9.6773. View

18.

Braeckman L, De Bacquer D, Rosseneu M, De Backer G . Apolipoprotein E polymorphism in middle-aged Belgian men: phenotype distribution and relation to serum lipids and lipoproteins. Atherosclerosis. 1996; 120(1-2):67-73. DOI: 10.1016/0021-9150(95)05681-5. View

19.

Wang H, Guo Y, Lu H, Luo Y, Hu W, Liang W . Krüppel-like factor 14 deletion in myeloid cells accelerates atherosclerotic lesion development. Cardiovasc Res. 2021; 118(2):475-488. PMC: 8803076. DOI: 10.1093/cvr/cvab027. View

20.

Laks R, Araujo L, Filho C, Cendoroglo M . The importance of HDL-C and CRP in cardiovascular risk evaluation in longevous elderly individuals. Einstein (Sao Paulo). 2016; 9(3):397-403. DOI: 10.1590/S1679-45082011RW1953. View