Association of Genetic Variants Related to Combined Exposure to Lower Low-Density Lipoproteins and Lower Systolic Blood Pressure With Lifetime Risk of Cardiovascular Disease | Cardiology | JAMA | JAMA Network
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1.
Baigent  C, Blackwell  L, Emberson  J,  et al; Cholesterol Treatment Trialists’ (CTT) Collaboration.  Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.  Lancet. 2010;376(9753):1670-1681. doi:10.1016/S0140-6736(10)61350-5PubMedGoogle ScholarCrossref
2.
Silverman  MG, Ference  BA, Im  K,  et al.  Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis.  JAMA. 2016;316(12):1289-1297. doi:10.1001/jama.2016.13985PubMedGoogle ScholarCrossref
3.
Ettehad  D, Emdin  CA, Kiran  A,  et al.  Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis.  Lancet. 2016;387(10022):957-967. doi:10.1016/S0140-6736(15)01225-8PubMedGoogle ScholarCrossref
4.
Cohen  JC, Boerwinkle  E, Mosley  TH  Jr, Hobbs  HH.  Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.  N Engl J Med. 2006;354(12):1264-1272. doi:10.1056/NEJMoa054013PubMedGoogle ScholarCrossref
5.
Ference  BA, Yoo  W, Alesh  I,  et al.  Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis.  J Am Coll Cardiol. 2012;60(25):2631-2639. doi:10.1016/j.jacc.2012.09.017PubMedGoogle ScholarCrossref
6.
Holmes  MV, Asselbergs  FW, Palmer  TM,  et al; UCLEB consortium.  Mendelian randomization of blood lipids for coronary heart disease.  Eur Heart J. 2015;36(9):539-550. doi:10.1093/eurheartj/eht571PubMedGoogle ScholarCrossref
7.
Ehret  GB, Munroe  PB, Rice  KM,  et al; International Consortium for Blood Pressure Genome-Wide Association Studies; CARDIoGRAM consortium; CKDGen Consortium; KidneyGen Consortium; EchoGen consortium; CHARGE-HF consortium.  Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.  Nature. 2011;478(7367):103-109. doi:10.1038/nature10405PubMedGoogle ScholarCrossref
8.
Ference  BA, Julius  S, Mahajan  N, Levy  PD, Williams  KA  Sr, Flack  JM.  Clinical effect of naturally random allocation to lower systolic blood pressure beginning before the development of hypertension.  Hypertension. 2014;63(6):1182-1188. doi:10.1161/HYPERTENSIONAHA.113.02734PubMedGoogle ScholarCrossref
9.
Ference  BA, Ginsberg  HN, Graham  I,  et al.  Low-density lipoproteins cause atherosclerotic cardiovascular disease, I; evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.  Eur Heart J. 2017;38(32):2459-2472. doi:10.1093/eurheartj/ehx144PubMedGoogle ScholarCrossref
10.
Packard  CJ, Weintraub  WS, Laufs  U.  New metrics needed to visualize the long-term impact of early LDL-C lowering on the cardiovascular disease trajectory.  Vascul Pharmacol. 2015;71:37-39. doi:10.1016/j.vph.2015.03.008PubMedGoogle ScholarCrossref
11.
Robinson  JG, Williams  KJ, Gidding  S,  et al.  Eradicating the burden of atherosclerotic cardiovascular disease by lowering apolipoprotein B lipoproteins earlier in life.  J Am Heart Assoc. 2018;7(20):e009778. doi:10.1161/JAHA.118.009778PubMedGoogle ScholarCrossref
12.
Sudlow  C, Gallacher  J, Allen  N,  et al.  UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age.  PLoS Med. 2015;12(3):e1001779. doi:10.1371/journal.pmed.1001779PubMedGoogle ScholarCrossref
13.
Manichaikul  A, Mychaleckyj  JC, Rich  SS, Daly  K, Sale  M, Chen  W-M.  Robust relationship inference in genome-wide association studies.  Bioinformatics. 2010;26(22):2867-2873. doi:10.1093/bioinformatics/btq559PubMedGoogle ScholarCrossref
14.
Liu  DJ, Peloso  GM, Yu  H,  et al; Charge Diabetes Working Group; EPIC-InterAct Consortium; EPIC-CVD Consortium; GOLD Consortium; VA Million Veteran Program.  Exome-wide association study of plasma lipids in >300,000 individuals.  Nat Genet. 2017;49(12):1758-1766. doi:10.1038/ng.3977PubMedGoogle ScholarCrossref
15.
Kraja  AT, Cook  JP, Warren  HR,  et al; Understanding Society Scientific Group; CHARGE EXOME BP, CHD Exome+, Exome BP, GoT2D:T2DGenes Consortia, The UK Biobank Cardio-Metabolic Traits Consortium Blood Pressure Working Group†.  New blood pressure-associated loci identified in meta-analyses of 475 000 individuals.  Circ Cardiovasc Genet. 2017;10(5):e001778. doi:10.1161/CIRCGENETICS.117.001778PubMedGoogle ScholarCrossref
16.
Liu  C, Kraja  AT, Smith  JA,  et al; CHD Exome+ Consortium; ExomeBP Consortium; GoT2DGenes Consortium; T2D-GENES Consortium; Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia; CKDGen Consortium.  Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.  Nat Genet. 2016;48(10):1162-1170. doi:10.1038/ng.3660PubMedGoogle ScholarCrossref
17.
Palmer  TM, Lawlor  DA, Harbord  RM,  et al.  Using multiple genetic variants as instrumental variables for modifiable risk factors.  Stat Methods Med Res. 2012;21(3):223-242. doi:10.1177/0962280210394459PubMedGoogle ScholarCrossref
18.
Lawlor  DA, Harbord  RM, Sterne  JA, Timpson  N, Davey Smith  G.  Mendelian randomization: using genes as instruments for making causal inferences in epidemiology.  Stat Med. 2008;27(8):1133-1163. doi:10.1002/sim.3034PubMedGoogle ScholarCrossref
19.
Ference  BA, Majeed  F, Penumetcha  R, Flack  JM, Brook  RD.  Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 × 2 factorial Mendelian randomization study.  J Am Coll Cardiol. 2015;65(15):1552-1561. doi:10.1016/j.jacc.2015.02.020PubMedGoogle ScholarCrossref
20.
Ference  BA, Robinson  JG, Brook  RD,  et al.  Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes.  N Engl J Med. 2016;375(22):2144-2153. doi:10.1056/NEJMoa1604304PubMedGoogle ScholarCrossref
21.
Ference  BA, Kastelein  JJP, Ginsberg  HN,  et al.  Association of genetic variants related to CETP inhibitors and statins with lipoprotein levels and cardiovascular risk.  JAMA. 2017;318(10):947-956. doi:10.1001/jama.2017.11467PubMedGoogle ScholarCrossref
22.
Nikpay  M, Goel  A, Won  HH,  et al.  A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease.  Nat Genet. 2015;47(10):1121-1130. doi:10.1038/ng.3396PubMedGoogle ScholarCrossref
23.
Bowden  J, Davey Smith  G, Burgess  S.  Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression.  Int J Epidemiol. 2015;44(2):512-525. doi:10.1093/ije/dyv080PubMedGoogle ScholarCrossref
24.
Ference  BA, Kastelein  JJP, Ray  KK,  et al.  Association of triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants with risk of coronary heart disease.  JAMA. 2019;321(4):364-373. doi:10.1001/jama.2018.20045PubMedGoogle ScholarCrossref
25.
Lewington  S, Whitlock  G, Clarke  R,  et al; Prospective Studies Collaboration.  Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths.  Lancet. 2007;370(9602):1829-1839. doi:10.1016/S0140-6736(07)61778-4PubMedGoogle ScholarCrossref
26.
Asia Pacific Cohort Studies Collaboration.  Joint effects of systolic blood pressure and serum cholesterol on cardiovascular disease in the Asia Pacific region.  Circulation. 2005;112(22):3384-3390. doi:10.1161/CIRCULATIONAHA.105.537472PubMedGoogle ScholarCrossref
27.
Di Angelantonio  E, Sarwar  N, Perry  P,  et al; Emerging Risk Factors Collaboration.  Major lipids, apolipoproteins, and risk of vascular disease.  JAMA. 2009;302(18):1993-2000. doi:10.1001/jama.2009.1619PubMedGoogle ScholarCrossref
28.
Allen  NB, Siddique  J, Wilkins  JT,  et al.  Blood pressure trajectories in early adulthood and subclinical atherosclerosis in middle age.  JAMA. 2014;311(5):490-497. doi:10.1001/jama.2013.285122PubMedGoogle ScholarCrossref
29.
Duncan  MS, Vasan  RS, Xanthakis  V.  Trajectories of blood lipid concentrations over the adult life course and risk of cardiovascular disease and all-cause mortality: observations from the Framingham Study over 35 years.  J Am Heart Assoc. 2019;8(11):e011433. doi:10.1161/JAHA.118.011433PubMedGoogle ScholarCrossref
Original Investigation
September 2, 2019

Association of Genetic Variants Related to Combined Exposure to Lower Low-Density Lipoproteins and Lower Systolic Blood Pressure With Lifetime Risk of Cardiovascular Disease

Author Affiliations
  • 1Centre for Naturally Randomized Trials, University of Cambridge, Cambridge, United Kingdom
  • 2MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
  • 3Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, Boston, Massachusetts
  • 4Department of Pharmacological and Biomolecular Sciences, University of Milan, Multimedica IRCCS, Milano, Italy
  • 5Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
  • 6School of Medicine, Trinity College, Dublin, Ireland
  • 7Department of Cardiology, University of Leipzig, Leipzig, Germany
  • 8Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 9Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
  • 10MRC Population Health Research Unit, Clinical Trial Service Unit, and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
  • 11MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
  • 12School of Public Health, Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, London, United Kingdom
  • 13Monash University, Melbourne, Australia
JAMA. 2019;322(14):1381-1391. doi:10.1001/jama.2019.14120
Key Points

Question  What is the association between genetic variants related to lower low-density lipoprotein cholesterol (LDL-C) levels and lower systolic blood pressure (SBP) with lifetime risk of cardiovascular disease?

Findings  In mendelian randomization analyses involving 438 952 participants, genetic variants related to lower LDL-C and lower SBP were significantly associated with independent, additive, and dose-dependent lower risk of cardiovascular disease. For example, participants with genetic variants associated with both 14-mg/dL lower LDL-C and 3-mm Hg lower SBP had an odds ratio of 0.61 for major coronary events (coronary death, myocardial infarction, or coronary revascularization).

Meaning  Lifelong genetic exposure to lower levels of low-density lipoprotein cholesterol and lower systolic blood pressure was associated with lower cardiovascular risk.

Abstract

Importance  The relationship between exposure to lower low-density lipoprotein cholesterol (LDL-C) and lower systolic blood pressure (SBP) with the risk of cardiovascular disease has not been reliably quantified.

Objective  To assess the association of lifetime exposure to the combination of both lower LDL-C and lower SBP with the lifetime risk of cardiovascular disease.

Design, Setting, and Participants  Among 438 952 participants enrolled in the UK Biobank between 2006 and 2010 and followed up through 2018, genetic LDL-C and SBP scores were used as instruments to divide participants into groups with lifetime exposure to lower LDL-C, lower SBP, or both. Differences in plasma LDL-C, SBP, and cardiovascular event rates between the groups were compared to estimate associations with lifetime risk of cardiovascular disease.

Exposures  Differences in plasma LDL-C and SBP compared with participants with both genetic scores below the median. Genetic risk scores higher than the median were associated with lower LDL-C and lower SBP.

Main Outcomes and Measures  Odds ratio (OR) for major coronary events, defined as coronary death, nonfatal myocardial infarction, or coronary revascularization.

Results  The mean age of the 438 952 participants was 65.2 years (range, 40.4-80.0 years), 54.1% were women, and 24 980 experienced a first major coronary event. Compared with the reference group, participants with LDL-C genetic scores higher than the median had 14.7-mg/dL lower LDL-C levels and an OR of 0.73 for major coronary events (95% CI, 0.70-0.75; P < .001). Participants with SBP genetic scores higher than the median had 2.9-mm Hg lower SBP and an OR of 0.82 for major coronary events (95% CI, 0.79-0.85, P < .001). Participants in the group with both genetic scores higher than the median had 13.9-mg/dL lower LDL-C, 3.1-mm Hg lower SBP, and an OR of 0.61 for major coronary events (95% CI, 0.59-0.64; P < .001). In a 4 × 4 factorial analysis, exposure to increasing genetic risk scores and lower LDL-C levels and SBP was associated with dose-dependent lower risks of major coronary events. In a meta-regression analysis, combined exposure to 38.67-mg/dL lower LDL-C and 10-mm Hg lower SBP was associated with an OR of 0.22 for major coronary events (95% CI, 0.17-0.26; P < .001), and 0.32 for cardiovascular death (95% CI, 0.25-0.40; P < .001).

Conclusions and Relevance  Lifelong genetic exposure to lower levels of low-density lipoprotein cholesterol and lower systolic blood pressure was associated with lower cardiovascular risk. However, these findings cannot be assumed to represent the magnitude of benefit achievable from treatment of these risk factors.

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