1. Epidemiology and Global Health
  2. Evolutionary Biology

Investigating pleiotropic effects of statins on ischemic heart disease in the UK Biobank using Mendelian randomisation

  1. CM Schooling  Is a corresponding author
  2. JV Zhao
  3. SL Au Yeung
  4. GM Leung
  1. School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, China
  2. City University of New York, Graduate School of Public Health and Health Policy, United States
https://doi.org/10.7554/eLife.58567
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  1. CM Schooling
  2. JV Zhao
  3. SL Au Yeung
  4. GM Leung
(2020)
Investigating pleiotropic effects of statins on ischemic heart disease in the UK Biobank using Mendelian randomisation
eLife 9:e58567.
https://doi.org/10.7554/eLife.58567
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2 figures, 4 tables and 2 additional files

Figures

Figure 1
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Directed acyclic graph showing the well-established protective effects of lipid modifiers and anti-inflammatories on IHD (solid lines) and possible additional pathways (dashed lines) investigated here.

Green indicates a lowering effect, red indicates an increasing effect.

Figure 2
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Schematic diagram showing the well-established protective effects of lipid modifiers on IHD (solid green lines) in the context of additional relevant pathways (green protective, red harmful) from an evolutionary biology perspective.

(Key: GnRH: gonadotropin releasing hormone, RBC: red blood cell, LDL: low density lipoprotein).

Tables

Table 1
Sex-specific Mendelian randomization estimates (where possible) for effects of genetically mimicked statins, PCSK9 inhibitor and ezetimibe (in effect sizes of LDL-cholesterol) on testosterone (effect size) in men and women using the UK Biobank .
Mendelian Randomization estimates
Therapy# SNPsMethodBeta95% CIP valueMR-Egger intercept p-value
MenStatin1Inverse variance weighted−0.15−0.23 to −0.060.001
Statin6Inverse variance weighted−0.15−0.23 to −0.070.0005
PCSK9 inhibitor3Inverse variance weighted0.04−0.11 to 0.180.63
PCSK9 inhibitor3Weighted median0.07−0.13 to 0.270.29
PCSK9 inhibitor3MR-Egger0.340.09 to 0.600.01−0.01 (0.01)
PCSK9 inhibitor7Inverse variance weighted0.05−0.05 to 0.150.29
ezetimibe1Inverse variance weighted0.04−0.15 to 0.230.68
ezetimibe3Inverse variance weighted0.05−0.12 to 0.220.55
ezetimibe3Weighted median0.03−0.13 to 0.180.72
ezetimibe3MR-Egger0.24−0.52 to 1.00.54−0.01 (0.52)
WomenStatin1Inverse variance weighted0.04−0.06 to 0.140.45
Statin6Inverse variance weighted0.03−0.07 to 0.130.52
PCSK9 inhibitor3Inverse variance weighted0.01−0.11 to 0.140.85
PCSK9 inhibitor3Weighted median0.01−0.13 to 0.150.91
PCSK9 inhibitor3MR-Egger0.09−0.38 to 0.560.71−0.003 (0.74)
PCSK9 inhibitor7Inverse variance weighted−0.004−0.14 to 0.130.95
ezetimibe1Inverse variance weighted0.18−0.05 to 0.400.12
ezetimibe3Inverse variance weighted0.12−0.08 to 0.310.24

  1. One statin SNP is rs12916, and six statin SNPs additionally included rs5909, rs10066707, rs17238484, rs2006760 and rs2303152 taking into account their correlations.

    Three PCSK9 inhibitor SNPs are rs11206510, rs2149041 and rs7552841, and 7 PCSK9 inhibitor SNPs additionally included rs10888897, rs2479394, rs2479409 and, rs562556 taking into account all their correlations.

  2. One ezetimibe SNP is rs2073547 (proxied by rs10260606), and three ezetimibe SNPs additionally included rs7791240 and rs217386 taking into account all their correlations.

    The unit of LDL-cholesterol is approximately 0.83 mm/L. An effect size of testosterone is approximately, 0.23 nmol/L in women (Haring et al., 2012) and 3.1 nmol/L in men (Mohr et al., 2005).

Table 2
Mendelian randomization estimates for effects of genetically mimicked statins (effect sizes of LDL-cholesterol) and of genetically predicted testosterone (effect size) on IHD in men and women using the UK Biobank.
Mendelian randomization estimates
Exposure# SNPsMethodOR95% CIP valueMR-Egger intercept p-value
MenStatin mimic1Inverse variance weighted0.550.38 to 0.790.001
Statin mimic6Inverse variance weighted0.540.33 to 0.890.02
Testosterone125Inverse variance weighted1.111.04 to 1.190.003
Testosterone125Weighted median1.181.06 to 1.310.002
Testosterone125MR-Egger1.100.98 to 1.230.090.01 (0.84)
WomenStatin mimic1Inverse variance weighted0.870.59 to 1.270.46
Statin mimic6Inverse variance weighted0.790.54 to 1.130.20
Testosterone254Inverse variance weighted0.960.89 to 1.030.29
Testosterone254Weighted median1.030.92 to 1.140.63
Testosterone254MR-Egger1.080.94 to 1.230.27−0.004 (0.05)

  1. One statin SNP is rs12916, and six statin SNPs additionally included rs5909, rs10066707, rs17238484, rs2006760 and rs2303152 taking into account all their correlations. The unit of LDL-cholesterol is approximately 0.83 mm/L. An effect size of testosterone is approximately, 0.23 nmol/L in women (Haring et al., 2012) and 3.1 nmol/L in men (Mohr et al., 2005).

Table 2—source data 1

Genetic associations for men.

https://cdn.elifesciences.org/articles/58567/elife-58567-table2-data1-v2.csv
Table 2—source data 2

genetic associations for women.

https://cdn.elifesciences.org/articles/58567/elife-58567-table2-data2-v2.csv
Table 3
Multivariable Mendelian randomization estimates for effects of genetically mimicked statins (effect sizes of LDL-cholesterol) and of testosterone (effect size) together on IHD in men and women using the UK Biobank.
Mendelian randomization estimates
SexExposuresInstrumented byAdjusted forMethodOR95% CIP valueMR-Egger intercept p-value
MenStatin mimic1 Statin SNP on LDL-cholesterolTestosteroneInverse variance weighted1.050.74 to 1.470.79
Testosterone125 SNPs on testosteronestatinInverse variance weighted1.111.04 to 1.200.003
Statin mimic1 Statin SNP on LDL-cholesterolTestosteroneMR-Egger0.730.48 to 1.110.14
Testosterone125 SNPs on testosteronestatinMR-Egger1.091.02 to 1.170.020.005
Statin mimic6 Statin SNPs on LDL-cholesterolTestosteroneInverse variance weighted1.020.72 to 1.430.91
Testosterone125 SNPs on testosteronestatinInverse variance weighted1.111.04 to 1.200.003
WomenStatin mimic1 Statin SNP on LDL-cholesterolTestosteroneInverse variance weighted0.980.75 to 1.160.53
Testosterone254 SNPs on testosteronestatinInverse variance weighted0.960.90 to 1.040.33
Statin mimic1 Statin SNP on LDL-cholesterolTestosteroneMR-Egger0.720.55 to 0.940.02
Testosterone254 SNPs on testosteronestatinMR-Egger0.960.89 to 1.030.270.001
Statin mimic6 Statin SNPs on LDL-cholesterolTestosteroneInverse variance weighted0.920.74 to 1.160.49
Testosterone254 SNPs on testosteronestatinInverse variance weighted0.970.90 to 1.040.36

  1. One statin SNP is rs12916, and six statin SNPs additionally included rs5909, rs10066707, rs17238484, rs2006760 and rs2303152 taking into account all their correlations. The unit of LDL-cholesterol is approximately 0.83 mm/L. An effect size of testosterone is approximately, 0.23 nmol/L in women (Haring et al., 2012) and 3.1 nmol/L in men (Mohr et al., 2005).

Table 4
Mendelian randomization inverse variance weighted estimates for genetically mimicked effects of the anti-inflammatory anakinra raising IL-1Ra (effect size) (Swerdlow et al., 2012) on testosterone (effect size) and ischemic heart disease and for genetically mimicked effects of tocilizumab raising serum IL-6r (ng/ml) (Rafiq et al., 2007) on testosterone in men and women using the UK Biobank .
TherapyTargetOutcome# SNPsMeasureEstimate95% CIp-value
MenAnakinraIL-1Ratestosterone2beta0.0220.01 to 0.040.002
IHD2OR1.081.01 to 1.150.017
TocilizumabIL-6rtestosterone1beta0.003−0.06 to 0.130.96
WomenAnakinraIL-1Ratestosterone2beta−0.01−0.04 to 0.010.24
IHD2OR0.990.91 to 1.080.86
TocilizumabIL-6rtestosterone1beta0.002−0.02 to 0.020.84

  1. SNPs mimicking anakinra are rs6743376 and rs1542176.

    The SNP mimicking tocilizumab is rs7529229.

  2. An effect size of testosterone is approximately, 0.23 nmol/L in women (Haring et al., 2012) and 3.1 nmol/L in men (Mohr et al., 2005).

Additional files

Supplementary file 1

Associations of SNPs mimicking effects of lipid modifiers with LDL-cholesterol.

(a) SNP-specific estimates for SNPs mimicking effects of statins, PCSK9 inhibitor and ezetimibe on LDL-cholesterol (effect size) in women and men from the UK Biobank, and for comparison estimates for both sexes together from the Global Lipids Genetics Consortium (GLGC) (Willer et al., 2013). (b) SNP-specific estimates for anakinra and tocilizumab SNPs on IL1-Ra (Interleukin 1 Genetics Consortium, 2015) and IL-6 (Swerdlow et al., 2012) respectively.

https://cdn.elifesciences.org/articles/58567/elife-58567-supp1-v2.docx
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https://cdn.elifesciences.org/articles/58567/elife-58567-transrepform-v2.pdf

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  1. CM Schooling
  2. JV Zhao
  3. SL Au Yeung
  4. GM Leung
(2020)
Investigating pleiotropic effects of statins on ischemic heart disease in the UK Biobank using Mendelian randomisation
eLife 9:e58567.
https://doi.org/10.7554/eLife.58567