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Meta-Analysis
. 2015 Mar 1;36(9):539-50.
doi: 10.1093/eurheartj/eht571. Epub 2014 Jan 27.

Mendelian Randomization of Blood Lipids for Coronary Heart Disease

Michael V Holmes  1 Folkert W Asselbergs  2 Tom M Palmer  3 Fotios Drenos  4 Matthew B Lanktree  5 Christopher P Nelson  6 Caroline E Dale  7 Sandosh Padmanabhan  8 Chris Finan  9 Daniel I Swerdlow  9 Vinicius Tragante  10 Erik P A van Iperen  11 Suthesh Sivapalaratnam  12 Sonia Shah  13 Clara C Elbers  14 Tina Shah  9 Jorgen Engmann  9 Claudia Giambartolomei  13 Jon White  13 Delilah Zabaneh  13 Reecha Sofat  9 Stela McLachlan  15 UCLEB consortiumPieter A Doevendans  16 Anthony J Balmforth  17 Alistair S Hall  17 Kari E North  18 Berta Almoguera  19 Ron C Hoogeveen  20 Mary Cushman  21 Myriam Fornage  22 Sanjay R Patel  23 Susan Redline  23 David S Siscovick  24 Michael Y Tsai  25 Konrad J Karczewski  26 Marten H Hofker  27 W Monique Verschuren  28 Michiel L Bots  29 Yvonne T van der Schouw  29 Olle Melander  30 Anna F Dominiczak  8 Richard Morris  31 Yoav Ben-Shlomo  32 Jackie Price  15 Meena Kumari  9 Jens Baumert  33 Annette Peters  33 Barbara Thorand  33 Wolfgang Koenig  34 Tom R Gaunt  35 Steve E Humphries  36 Robert Clarke  37 Hugh Watkins  38 Martin Farrall  38 James G Wilson  39 Stephen S Rich  40 Paul I W de Bakker  41 Leslie A Lange  42 George Davey Smith  35 Alex P Reiner  43 Philippa J Talmud  36 Mika Kivimäki  44 Debbie A Lawlor  35 Frank Dudbridge  7 Nilesh J Samani  6 Brendan J Keating  45 Aroon D Hingorani  9 Juan P Casas  46
Collaborators, Affiliations
Free PMC article
Meta-Analysis

Mendelian Randomization of Blood Lipids for Coronary Heart Disease

Michael V Holmes et al. Eur Heart J. .
Free PMC article

Abstract

Aims: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.

Methods and results: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75).

Conclusion: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.

Keywords: Aetiology; Epidemiology; Heart disease; Lipids; Mendelian randomization.

Figures

Figure 1
Figure 1
Meta-analysis pooled estimates of the association of the unrestricted and restricted allele scores with target and non-target lipid traits. Estimates were obtained from prospective cohorts genotyped using the ITMAT Broad Institute CARe consortium CardioChip array (detailed in Supplementary material online, Table S1). A lower limit of 0 was imposed on the R2 values. Mean diff, mean difference comparing top to bottom quintile of each allele score. R2 = proportion of variable of the lipid traits explained by each allele score. TG, triglycerides.
Figure 2
Figure 2
Meta-analysis pooled estimates for the effect of a 1 unit increase in blood lipid traits on coronary heart disease risk using instrumental variable analysis incorporating data from all studies. Estimates were derived incorporating data on the association between the allele scores and blood lipid traits only from prospective cohorts (in which most individuals were free from disease when lipid traits were measured) and applying this estimate to all studies with data on the association between the scores and coronary heart disease (including case–control studies). See Methods for further details. TG, triglycerides.
Figure 3
Figure 3
Meta-analysis pooled estimates for the effect of a 1 unit increase in blood lipid traits on combined incident/prevalent coronary heart disease risk using instrumental variable analysis with the unrestricted allele score, adjusted for non-target traits and statin use. Analysis was conducted in prospective cohorts with instrumental variables regression analysis. TG, triglycerides.
Figure 4
Figure 4
Meta-analysis pooled estimate for the effect of a 1 unit increase in blood lipid traits on carotid intima medial thickness. The four population-based prospective cohorts with carotid intima medial thickness traits were CHS, FHS, MESA, and Whitehall II (Supplementary material online, Table S4).

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