APOC3 genetic variation, serum triglycerides, and risk of coronary artery disease in Asian Indians, Europeans, and other ethnic groups.

Publisher: BioMed Central Country of Publication: England NLM ID: 101147696 Publication Model: Electronic Cited Medium: Internet ISSN: 1476-511X (Electronic) Linking ISSN: 1476511X NLM ISO Abbreviation: Lipids Health Dis Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2002-

Genetic Variation*; Apolipoprotein C-III/*genetics ; Coronary Artery Disease/*genetics; Aged ; Alleles ; Coronary Artery Disease/ethnology ; Europe/epidemiology ; Female ; Genetic Association Studies ; Genotype ; Heterozygote ; Humans ; India/epidemiology ; Male ; Mendelian Randomization Analysis ; Middle Aged ; Mutation ; Risk ; Sequence Analysis, DNA ; Triglycerides/blood

Background: Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk.
Methods: We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD.
Results: One rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10 ^- 424 . Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042).
Conclusions: Our results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk.
(© 2021. The Author(s).)

Curr Opin Lipidol. 2020 Dec;31(6):331-339. (PMID: 33027225)
Atherosclerosis. 1996 Apr 26;122(1):105-15. (PMID: 8724117)
Science. 2008 Dec 12;322(5908):1702-5. (PMID: 19074352)
Nat Genet. 2016 Oct;48(10):1284-1287. (PMID: 27571263)
J Clin Endocrinol Metab. 2004 Aug;89(8):3949-55. (PMID: 15292332)
N Engl J Med. 2015 Jul 30;373(5):438-47. (PMID: 26222559)
J Am Coll Cardiol. 2019 Jun 25;73(24):e285-e350. (PMID: 30423393)
Am J Hum Genet. 2020 May 7;106(5):611-622. (PMID: 32275883)
Nat Genet. 2011 Aug 28;43(10):984-9. (PMID: 21874001)
Meta Gene. 2016 Apr 23;9:104-9. (PMID: 27331014)
Circulation. 2000 Oct 17;102(16):1886-92. (PMID: 11034934)
Int J Epidemiol. 2003 Feb;32(1):1-22. (PMID: 12689998)
Circulation. 2010 Sep 21;122(12):1242-52. (PMID: 20733105)
Atherosclerosis. 2003 Apr;167(2):293-302. (PMID: 12818412)
Hum Mol Genet. 2008 Oct 15;17(R2):R151-5. (PMID: 18852204)
PLoS Genet. 2011 Apr;7(4):e1001363. (PMID: 21490949)
Circ Cardiovasc Genet. 2014 Jun;7(3):287-95. (PMID: 24795349)
Genet Epidemiol. 2016 Nov;40(7):597-608. (PMID: 27625185)
BMC Med Res Methodol. 2011 Oct 13;11:141. (PMID: 21995825)
Curr Opin Lipidol. 2012 Jun;23(3):206-12. (PMID: 22510806)
Arterioscler Thromb Vasc Biol. 2015 Aug;35(8):1880-8. (PMID: 26069232)
Atherosclerosis. 2020 Oct;311:84-90. (PMID: 32949947)
J Steroid Biochem Mol Biol. 2016 Apr;158:149-156. (PMID: 26704534)
Atherosclerosis. 2017 Dec;267:49-60. (PMID: 29100061)
Arch Med Res. 2007 May;38(4):444-51. (PMID: 17416293)
Nature. 2010 Aug 5;466(7307):707-13. (PMID: 20686565)
Bioinformatics. 2010 Sep 1;26(17):2190-1. (PMID: 20616382)
Front Endocrinol (Lausanne). 2020 Sep 02;11:616. (PMID: 32982991)
J Intern Med. 2012 Aug;272(2):185-96. (PMID: 22239554)
Nature. 2018 Oct;562(7726):203-209. (PMID: 30305743)
N Engl J Med. 2014 Jul 3;371(1):22-31. (PMID: 24941081)
N Engl J Med. 2014 Jul 3;371(1):32-41. (PMID: 24941082)
BMC Med Genet. 2007 Dec 20;8:80. (PMID: 18096054)
Arterioscler Thromb Vasc Biol. 2003 May 1;23(5):853-8. (PMID: 12637336)
Drug Saf. 2001;24(6):443-56. (PMID: 11368251)
Bioinformatics. 2010 Sep 15;26(18):2336-7. (PMID: 20634204)
J Am Soc Nephrol. 2016 Nov;27(11):3253-3265. (PMID: 27486138)
Circulation. 1996 Nov 1;94(9):2159-70. (PMID: 8901667)
BMC Med Genomics. 2018 Sep 14;11(Suppl 3):66. (PMID: 30255797)
J Stroke Cerebrovasc Dis. 2020 Apr;29(4):104618. (PMID: 31973907)
Eur Heart J. 2020 Jan 1;41(1):111-188. (PMID: 31504418)
J Lipid Res. 2000 Nov;41(11):1760-71. (PMID: 11060345)
Nature. 2017 Apr 12;544(7649):235-239. (PMID: 28406212)
PLoS One. 2012;7(5):e37056. (PMID: 22623978)
Diabetes. 2013 May;62(5):1746-55. (PMID: 23300278)
Diabetologia. 2006 Nov;49(11):2580-8. (PMID: 16972045)

212945/Z/18/Z United Kingdom WT_ Wellcome Trust; G0700931 United Kingdom MRC_ Medical Research Council; G0601966 United Kingdom MRC_ Medical Research Council; R01DK118427 United States DK NIDDK NIH HHS; NOT-HG-11-009 United States HG NHGRI NIH HHS; R01DK082766 United States NH NIH HHS

Keywords: ApoC-III; Asian Indians; Coronary artery disease risk; Mendelian randomization; Rare and common variants; Triglyceride

0 (APOC3 protein, human)
0 (Apolipoprotein C-III)
0 (Triglycerides)

Date Created: 20210922 Date Completed: 20220221 Latest Revision: 20240214

20240214

PMC8456544

10.1186/s12944-021-01531-8

34548093