Abstract
Sequence variants affecting blood lipids and coronary artery disease (CAD) may enhance understanding of the atherogenicity of lipid fractions. Using a large resource of whole-genome sequence data, we examined rare and low-frequency variants for association with non-HDL cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides in up to 119,146 Icelanders. We discovered 13 variants with large effects (within ANGPTL3, APOB, ABCA1, NR1H3, APOA1, LIPC, CETP, LDLR, and APOC1) and replicated 14 variants. Five variants within PCSK9, APOA1, ANGPTL4, and LDLR associate with CAD (33,090 cases and 236,254 controls). We used genetic risk scores for the lipid fractions to examine their causal relationship with CAD. The non-HDL cholesterol genetic risk score associates most strongly with CAD (P = 2.7 × 10−28), and no other genetic risk score associates with CAD after accounting for non-HDL cholesterol. The genetic risk score for non-HDL cholesterol confers CAD risk beyond that of LDL cholesterol (P = 5.5 × 10−8), suggesting that targeting atherogenic remnant cholesterol may reduce cardiovascular risk.
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Acknowledgements
The authors thank all the individuals who participated in this study and whose contribution made this work possible. We also thank our valued colleagues who contributed to the data collection and phenotypic characterization of clinical samples as well as to the genotyping and analysis of the whole-genome association data. Funding was provided by deCODE Genetics/Amgen and at Emory by NIH grants UL1RR025008 from the Clinical and Translational Science Award program, R01HL089650-02, and Emory Neuroscience NINDS Core Facilities grant P30NS055077.
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A.H., S.G., G. Thorleifsson, U.T., D.F.G., H.H., and K.S. conceived and designed the study. D.F.G. developed statistical tools. E.H. and G.M. contributed to bioinformatic analysis. A.S., A.M., A.J., and H.K. performed experiments. A.H., G. Thorleifsson, D.F.G., A.O., and G.S. performed statistical analysis. T.R., I.J., I.O., G.I.E., O.S., M.S.D., D.K., F.A., D.W.S., L.K., A.A.Q., A.I.L., R.S.P., S.S.H., I.J.G., V.S., and G. Thorgeirsson contributed to data acquisition. A.H., S.G., G. Thorleifsson, P.S., I.O., G. Thorgeirsson, U.T., D.F.G., H.H., and K.S. analyzed and interpreted the data. All authors reviewed and approved the manuscript. K.S. supervised the study.
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A.H., S.G., G. Thorleifsson, E.H., A.S., A.M., A.J., H.K., P.S., A.O., G.S., V.S., T.R., G.M., I.J., U.T., D.F.G., H.H. and K.S. are all employees of deCODE Genetics/Amgen, Inc.
Integrated supplementary information
Supplementary Figure 1 Pedigrees of families with APOB p.Gln725* mutation and APOB p.Gly1829Glufs8 mutation
(a,b) Pedigrees of families with APOB p.Gln725* mutation. (c) Pedigree of family with APOB p.Gly1829Glufs8 mutation. Squares denote male family members, circles denote female family members, and symbols with slashes denote deceased family members. Values below symbols are non-HDL cholesterol (above) and LDL cholesterol (below) in mmol/L for family members with available lipid information. The pedigrees have been simplified to maintain confidentiality.
Supplementary Figure 2 A schematic illustration of the lipid metabolism genes harboring mutations described in this study.
Cholesterol and triglycerides (TG) are transferred together by triglyceride-rich lipoproteins, including very low-density lipoprotein (VLDL), intermediate-density lipoproteins (IDL), chylomicrons, and chylomicron remnants. Apolipoprotein B, encoded by APOB, is an essential structural component of VLDL, IDL, LDL, and chylomicrons. The APOA1 gene encodes apolipoprotein A-I, the major protein component of HDL particles that have a key role in reverse cholesterol transport. Apolipoprotein C-I, encoded by APOC1, is associated with both HDL and triglyceride-rich lipoproteins, inhibits cholesteryl ester transfer protein (CETP), and hinders hepatic clearance of triglyceride-rich lipoproteins. ATP-binding cassette transporter (ABCA1) mediates the efflux of cholesterol and phospholipids to lipid-poor apolipoprotein A-1 to form nascent pre-β-HDL. Triglycerides from triglyceride-rich lipoproteins are hydrolyzed into free fatty acids by lipoprotein lipase (LPL). Angiopoietin-like 3 (encoded by the ANGPTL3 gene) inhibits LPL. CETP and hepatic lipase (encoded by LIPC) are central in lipoprotein remodeling. CETP facilitates transfer of cholesteryl ester (CE) from HDL to triglyceride-rich lipoproteins in exchange for triglycerides. Hepatic lipase (LIPC) remodels large lipoprotein particles into smaller and denser particles. IDL is converted to LDL by the action of hepatic lipase (LIPC). LDL is taken up by liver and other tissues in an endocytotic process that involves the LDL receptor (LDLR). Liver X receptor, encoded by the NR1H3 gene, is a cholesterol sensor that induces transcription of multiple genes that protect cells from cholesterol overload.
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Supplementary Text and Figures
Supplementary Figures 1 and 2, and Supplementary Note. (PDF 670 kb)
Supplementary Table 1
The association of rare and low-frequency coding variants with lipid traits, with and without covariate adjustment. (XLSX 23 kb)
Supplementary Table 2
The association of rare and low-frequency variants with blood lipids and coronary artery disease. (XLSX 16 kb)
Supplementary Table 3
Replication of the lipid association signals in populations from the Netherlands and Iran. (XLSX 17 kb)
Supplementary Table 4
The association of APOC3 loss-of-function mutations with coronary artery disease. (XLSX 10 kb)
Supplementary Table 5
Summary-level Mendelian randomization of lipid fractions and CAD using modified methods proposed by Do et al. (XLSX 11 kb)
Supplementary Table 6
Summary-level Mendelian randomization of lipid fractions and CAD extending the framework proposed by Bowden et al. to include multiple exposures. (XLSX 11 kb)
Supplementary Table 7
The total number of Icelandic individuals used in the study for each trait. (XLSX 10 kb)
Supplementary Table 8
The association of modified genetic risk scores with coronary artery disease. (XLSX 10 kb)
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Helgadottir, A., Gretarsdottir, S., Thorleifsson, G. et al. Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease. Nat Genet 48, 634–639 (2016). https://doi.org/10.1038/ng.3561
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DOI: https://doi.org/10.1038/ng.3561
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