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Comment
. 2014 Sep 2;20(3):387-9.
doi: 10.1016/j.cmet.2014.08.007.

APOC3, coronary disease, and complexities of Mendelian randomization

Jonathan C Cohen  1 , Stefan Stender  2 , Helen H Hobbs  3
Affiliations
Comment

APOC3, coronary disease, and complexities of Mendelian randomization

Jonathan C Cohen et al. Cell Metab. .

Abstract

Two new studies report that triglyceride (TG)-lowering mutations in APOC3 reduce coronary heart disease (CHD) (Crosby et al., 2014; Jørgensen et al., 2014). Here, we explore limitations of using Mendelian randomization to evaluate CHD risk, including potential confounding by the widespread use of statin therapy.

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Figures

Figure 1
Figure 1. Genetic and Pharmacological Reduction in LDL-C and Coronary Heart Disease
(A) Reduction in CHD risk associated with genetic variants (blue circles) and pharmacological agents (green circles) that lower plasma levels of LDL-C. Genetic variations that reduce plasma LDL-C levels are associated with a greater reduction in CHD compared to that seen in statin trials. The sources of the data shown in this figure are as follows: APOB rs754523 (PMID: 18193043), LDLR rs2228671 (PMID: 18714375), ABCG8 rs4245791 (PMID: 24657701), and PCSK9 (PMID: 16554528). The red circle represents the CHD reduction (~46%) that is predicted for a loss-of-function mutation in APOC3 (R19X) (Crosby et al., 2014; Pollin et al., 2008). WOSCOPS, The West of Scotland Coronary Prevention Study (PMID: 7566020); CARE, Cholesterol and Recurrent Events Trial (PMID: 8801446); HPS, Heart Protection Study (PMID: 12114036); 4S, The Scandinavian Simvastatin Survival Study (PMID: 7968073). (B) Effects of APOC3 loss-of-function variants on circulating lipid and lipoprotein levels and on CHD. Proven causal links are indicated by blue arrows. Question marks indicate where causality has not been established. The red X indicates no causal relationship. IDL, intermediate density lipoprotein; CR, chylomicron remnant.
See this image and copyright information in PMC

Comment on

  • Loss-of-function mutations in APOC3, triglycerides, and coronary disease.
    TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute; Crosby J, Peloso GM, Auer PL, Crosslin DR, Stitziel NO, Lange LA, Lu Y, Tang ZZ, Zhang H, Hindy G, Masca N, Stirrups K, Kanoni S, Do R, Jun G, Hu Y, Kang HM, Xue C, Goel A, Farrall M, Duga S, Merlini PA, Asselta R, Girelli D, Olivieri O, Martinelli N, Yin W, Reilly D, Speliotes E, Fox CS, Hveem K, Holmen OL, Nikpay M, Farlow DN, Assimes TL, Franceschini N, Robinson J, North KE, Martin LW, DePristo M, Gupta N, Escher SA, Jansson JH, Van Zuydam N, Palmer CN, Wareham N, Koch W, Meitinger T, Peters A, Lieb W, Erbel R, Konig IR, Kruppa J, Degenhardt F, Gottesman O, Bottinger EP, O'Donnell CJ, Psaty BM, Ballantyne CM, Abecasis G, Ordovas JM, Melander O, Watkins H, Orho-Melander M, Ardissino D, Loos RJ, McPherson R, Willer CJ, Erdmann J, Hall AS, Samani NJ, Deloukas P, Schunkert H, Wilson JG, Kooperberg C, Rich SS, Tracy RP, Lin DY, Altshuler D, Gabriel S, Nickerson DA, Jarvik GP, Cupples LA, Reiner AP, Boerwinkle E, Kathiresan S. TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute, et al. N Engl J Med. 2014 Jul 3;371(1):22-31. doi: 10.1056/NEJMoa1307095. Epub 2014 Jun 18. N Engl J Med. 2014. PMID: 24941081 Free PMC article.
  • Loss-of-function mutations in APOC3 and risk of ischemic vascular disease.
    Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Jørgensen AB, et al. N Engl J Med. 2014 Jul 3;371(1):32-41. doi: 10.1056/NEJMoa1308027. Epub 2014 Jun 18. N Engl J Med. 2014. PMID: 24941082

References

    1. Crosby J, Peloso GM, Auer PL, Crosslin DR, Stitziel NO, Lange LA, Lu Y, Tang ZZ, Zhang H, Hindy G, et al. TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute N Engl J Med. 2014;371:22–31. - PubMed
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    1. Frikke-Schmidt R, Nordestgaard BG, Stene MC, Sethi AA, Remaley AT, Schnohr P, Grande P, Tybjaerg-Hansen A. JAMA. 2008;299:2524–2532. - PubMed
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    1. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. N Engl J Med. 2014;371:32–41. - PubMed

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