APOC3 genetic variation, serum triglycerides, and risk of coronary artery disease in Asian Indians, Europeans, and other ethnic groups.
Aged
Alleles
Apolipoprotein C-III
/ genetics
Coronary Artery Disease
/ ethnology
Europe
/ epidemiology
Female
Genetic Association Studies
Genetic Variation
Genotype
Heterozygote
Humans
India
/ epidemiology
Male
Mendelian Randomization Analysis
Middle Aged
Mutation
Risk
Sequence Analysis, DNA
Triglycerides
/ blood
ApoC-III
Asian Indians
Coronary artery disease risk
Mendelian randomization
Rare and common variants
Triglyceride
Journal
Lipids in health and disease
ISSN: 1476-511X
Titre abrégé: Lipids Health Dis
Pays: England
ID NLM: 101147696
Informations de publication
Date de publication:
21 Sep 2021
21 Sep 2021
Historique:
received:
29
07
2021
accepted:
25
08
2021
entrez:
22
9
2021
pubmed:
23
9
2021
medline:
22
2
2022
Statut:
epublish
Résumé
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. 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. 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 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.
Sections du résumé
BACKGROUND
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
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
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
CONCLUSIONS
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.
Identifiants
pubmed: 34548093
doi: 10.1186/s12944-021-01531-8
pii: 10.1186/s12944-021-01531-8
pmc: PMC8456544
doi:
Substances chimiques
APOC3 protein, human
0
Apolipoprotein C-III
0
Triglycerides
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
113Subventions
Organisme : NHGRI NIH HHS
ID : NOT-HG-11-009
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01DK118427
Pays : United States
Organisme : NIH HHS
ID : R01DK082766
Pays : United States
Informations de copyright
© 2021. The Author(s).
Références
Curr Opin Lipidol. 2020 Dec;31(6):331-339
pubmed: 33027225
Atherosclerosis. 1996 Apr 26;122(1):105-15
pubmed: 8724117
Science. 2008 Dec 12;322(5908):1702-5
pubmed: 19074352
Nat Genet. 2016 Oct;48(10):1284-1287
pubmed: 27571263
J Clin Endocrinol Metab. 2004 Aug;89(8):3949-55
pubmed: 15292332
N Engl J Med. 2015 Jul 30;373(5):438-47
pubmed: 26222559
J Am Coll Cardiol. 2019 Jun 25;73(24):e285-e350
pubmed: 30423393
Am J Hum Genet. 2020 May 7;106(5):611-622
pubmed: 32275883
Nat Genet. 2011 Aug 28;43(10):984-9
pubmed: 21874001
Meta Gene. 2016 Apr 23;9:104-9
pubmed: 27331014
Circulation. 2000 Oct 17;102(16):1886-92
pubmed: 11034934
Int J Epidemiol. 2003 Feb;32(1):1-22
pubmed: 12689998
Circulation. 2010 Sep 21;122(12):1242-52
pubmed: 20733105
Atherosclerosis. 2003 Apr;167(2):293-302
pubmed: 12818412
Hum Mol Genet. 2008 Oct 15;17(R2):R151-5
pubmed: 18852204
PLoS Genet. 2011 Apr;7(4):e1001363
pubmed: 21490949
Circ Cardiovasc Genet. 2014 Jun;7(3):287-95
pubmed: 24795349
Genet Epidemiol. 2016 Nov;40(7):597-608
pubmed: 27625185
BMC Med Res Methodol. 2011 Oct 13;11:141
pubmed: 21995825
Curr Opin Lipidol. 2012 Jun;23(3):206-12
pubmed: 22510806
Arterioscler Thromb Vasc Biol. 2015 Aug;35(8):1880-8
pubmed: 26069232
Atherosclerosis. 2020 Oct;311:84-90
pubmed: 32949947
J Steroid Biochem Mol Biol. 2016 Apr;158:149-156
pubmed: 26704534
Atherosclerosis. 2017 Dec;267:49-60
pubmed: 29100061
Arch Med Res. 2007 May;38(4):444-51
pubmed: 17416293
Nature. 2010 Aug 5;466(7307):707-13
pubmed: 20686565
Bioinformatics. 2010 Sep 1;26(17):2190-1
pubmed: 20616382
Front Endocrinol (Lausanne). 2020 Sep 02;11:616
pubmed: 32982991
J Intern Med. 2012 Aug;272(2):185-96
pubmed: 22239554
Nature. 2018 Oct;562(7726):203-209
pubmed: 30305743
N Engl J Med. 2014 Jul 3;371(1):22-31
pubmed: 24941081
N Engl J Med. 2014 Jul 3;371(1):32-41
pubmed: 24941082
BMC Med Genet. 2007 Dec 20;8:80
pubmed: 18096054
Arterioscler Thromb Vasc Biol. 2003 May 1;23(5):853-8
pubmed: 12637336
Drug Saf. 2001;24(6):443-56
pubmed: 11368251
Bioinformatics. 2010 Sep 15;26(18):2336-7
pubmed: 20634204
J Am Soc Nephrol. 2016 Nov;27(11):3253-3265
pubmed: 27486138
Circulation. 1996 Nov 1;94(9):2159-70
pubmed: 8901667
BMC Med Genomics. 2018 Sep 14;11(Suppl 3):66
pubmed: 30255797
J Stroke Cerebrovasc Dis. 2020 Apr;29(4):104618
pubmed: 31973907
Eur Heart J. 2020 Jan 1;41(1):111-188
pubmed: 31504418
J Lipid Res. 2000 Nov;41(11):1760-71
pubmed: 11060345
Nature. 2017 Apr 12;544(7649):235-239
pubmed: 28406212
PLoS One. 2012;7(5):e37056
pubmed: 22623978
Diabetes. 2013 May;62(5):1746-55
pubmed: 23300278
Diabetologia. 2006 Nov;49(11):2580-8
pubmed: 16972045