Mendelian Randomization of Blood Lipids for CHD
Mendelian Randomization of Blood Lipids for CHD
Across 17 studies with 62 199 individuals of European ancestry, there were 12 099 combined incident and prevalent CHD events of which 7339 were incident, and 9942 measures of cIMT, a non-invasive measure of atherosclerosis (Supplementary material online, Table S1http://eurheartj.oxfordjournals.org/content/suppl/2014/01/27/eht571.DC1). For the prospective cohorts, mean values of blood lipid traits, the proportion of individuals receiving lipid-lowering therapy, and whether samples were obtained when individuals were fasting are reported in Supplementary material online, Table S5http://eurheartj.oxfordjournals.org/content/suppl/2014/01/27/eht571.DC1. As expected, each SNP in the allele scores was associated individually with directionally concordant effects on the target lipid in prospective cohorts genotyped using the IBC CardioChip (Supplementary material online, Figure S10http://eurheartj.oxfordjournals.org/content/suppl/2014/01/27/eht571.DC1). There was a partial overlap of SNPs among the three unrestricted allele scores (Supplementary material online, Figure S3http://eurheartj.oxfordjournals.org/content/suppl/2014/01/27/eht571.DC1). By definition, SNPs in the restricted allele scores were non-overlapping.
The associations of each allele score for the target and non-target lipid traits are shown in Figure 1. The unrestricted allele scores consistently showed a larger magnitude of effect and explained more variance for the target lipid than the corresponding restricted allele scores. For example, the HDL-C unrestricted allele score was associated with higher HDL-C by 0.23 mmol/L (95% CI: 0.22, 0.24, comparing top to bottom quintiles of the allele score), explaining 3.8% of its variance. The comparable difference for the restricted HDL-C allele score was 0.08 mmol/L (95% CI: 0.07, 0.10), explaining only 0.3% of the variance. Corresponding values for triglycerides and LDL-C allele scores are presented in Figure 1. In addition to the association with the target lipid traits, each of the three unrestricted allele scores also showed association with non-target lipid traits (values reported in Figure 1). In contrast, the restricted allele scores consistently explained a smaller proportion of variance for non-target lipid traits. Stratification of the association of the allele scores with blood lipid traits by fasting status did not show heterogeneity in the estimates with the exception of the values for the restricted allele score for LDL-C; however, this did not influence the overall estimate (Supplementary material online, Figure S11http://eurheartj.oxfordjournals.org/content/suppl/2014/01/27/eht571.DC1).
(Enlarge Image)
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 R values. Mean diff, mean difference comparing top to bottom quintile of each allele score. R = proportion of variable of the lipid traits explained by each allele score. TG, triglycerides.
For LDL-C, in 16 cohort/case–control studies with 11 826 combined incident/prevalent CHD cases, a 1 mmol/L genetically instrumented increment in LDL-C gave an OR for CHD of 1.78 (95% CI: 1.58, 2.01) for the unrestricted, and 1.92 (95% CI: 1.68, 2.19) for the restricted allele score (Figure 2). For HDL-C, using the unrestricted allele score a 1 mmol/L genetically instrumented increment in HDL-C yielded an OR for CHD of 0.53 (95% CI: 0.40, 0.70), but the comparable estimate for the restricted allele score was 0.91 (95% CI: 0.42, 1.98). For triglycerides, a genetically instrumented 1 log-unit increment in triglycerides yielded similar estimates for CHD events: an OR of 1.62 (95% CI: 1.24, 2.11) for the unrestricted score and 1.61 (95% CI: 1.00, 2.59) for the restricted score. Estimates derived from instrumental variable analysis using incident-only CHD cases were comparable in effect size and direction to those from the analyses incorporating the combined incident and prevalent events (Figure 2). There was a similar inconsistency in the effect estimate of the unrestricted allele score for HDL-C and risk of incident-only CHD (OR: 0.68 per 1 mmol/L lower HDL-C; 95% CI: 0.47, 0.97) and that for the restricted HDL-C allele score with incident-only CHD (OR: 1.33; 95% CI: 0.49, 3.59).
(Enlarge Image)
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.
For each of the restricted and unrestricted allele scores, no difference was identified when the analysis was limited to fasted samples for the first stage of the instrumental variable analysis (Supplementary material online, Figure S12http://eurheartj.oxfordjournals.org/content/suppl/2014/01/27/eht571.DC1).
Sequential adjustment of the unrestricted LDL-C allele score for HDL-C, triglycerides, and statin use only moderately diminished the estimate for the association with CHD events (Figure 3), but comparable adjustments had more marked effects on the estimates for the HDL-C allele score. The association of the unrestricted HDL-C allele score with incident/prevalent CHD was shifted from an OR for CHD of 0.55 (95% CI: 0.38, 0.79) on unadjusted analysis to an OR of 0.79 (95% CI: 0.47, 1.32) with adjustment for triglycerides alone (Figure 3). In contrast, adjustment for LDL-C alone did not influence the estimate (OR: 0.52; 95% CI: 0.34, 0.78). When adjusted for triglycerides, LDL-C, and statin therapy, the OR for the association of the unrestricted HDL-C allele score with incident and prevalent CHD was 0.81 (95% CI: 0.44, 1.46), which was comparable with the estimates derived from the restricted allele score (OR: 0.91; 95% CI: 0.42, 1.98, Figure 2). For triglycerides, adjustment for HDL-C diminished the estimate for CHD risk from an OR of 1.38 (95% CI: 0.98, 1.94) for the unadjusted allele score to an OR of 0.97 (95% CI: 0.64. 1.49). Adjustment for LDL-C produced only a small alteration in the summary estimate for CHD risk: OR: 1.31 (95% CI: 0.86, 1.98). With adjustment for HDL-C, LDL-C, and statin use the OR estimate for the unrestricted triglyceride allele score with incident and prevalent CHD was 1.01 (95% CI: 0.59, 1.75).
(Enlarge Image)
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.
Only the LDL-C allele scores showed association with cIMT. A 1 mmol/L genetically instrumented increment in LDL-C was associated with higher cIMT by 2.49% (95% CI: 0.45, 4.57) and 3.81% (1.48, 6.19) for the unrestricted and restricted allele scores, respectively. Estimates for other lipid traits are provided in Figure 4.
(Enlarge Image)
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).
Results
Across 17 studies with 62 199 individuals of European ancestry, there were 12 099 combined incident and prevalent CHD events of which 7339 were incident, and 9942 measures of cIMT, a non-invasive measure of atherosclerosis (Supplementary material online, Table S1http://eurheartj.oxfordjournals.org/content/suppl/2014/01/27/eht571.DC1). For the prospective cohorts, mean values of blood lipid traits, the proportion of individuals receiving lipid-lowering therapy, and whether samples were obtained when individuals were fasting are reported in Supplementary material online, Table S5http://eurheartj.oxfordjournals.org/content/suppl/2014/01/27/eht571.DC1. As expected, each SNP in the allele scores was associated individually with directionally concordant effects on the target lipid in prospective cohorts genotyped using the IBC CardioChip (Supplementary material online, Figure S10http://eurheartj.oxfordjournals.org/content/suppl/2014/01/27/eht571.DC1). There was a partial overlap of SNPs among the three unrestricted allele scores (Supplementary material online, Figure S3http://eurheartj.oxfordjournals.org/content/suppl/2014/01/27/eht571.DC1). By definition, SNPs in the restricted allele scores were non-overlapping.
The associations of each allele score for the target and non-target lipid traits are shown in Figure 1. The unrestricted allele scores consistently showed a larger magnitude of effect and explained more variance for the target lipid than the corresponding restricted allele scores. For example, the HDL-C unrestricted allele score was associated with higher HDL-C by 0.23 mmol/L (95% CI: 0.22, 0.24, comparing top to bottom quintiles of the allele score), explaining 3.8% of its variance. The comparable difference for the restricted HDL-C allele score was 0.08 mmol/L (95% CI: 0.07, 0.10), explaining only 0.3% of the variance. Corresponding values for triglycerides and LDL-C allele scores are presented in Figure 1. In addition to the association with the target lipid traits, each of the three unrestricted allele scores also showed association with non-target lipid traits (values reported in Figure 1). In contrast, the restricted allele scores consistently explained a smaller proportion of variance for non-target lipid traits. Stratification of the association of the allele scores with blood lipid traits by fasting status did not show heterogeneity in the estimates with the exception of the values for the restricted allele score for LDL-C; however, this did not influence the overall estimate (Supplementary material online, Figure S11http://eurheartj.oxfordjournals.org/content/suppl/2014/01/27/eht571.DC1).
(Enlarge Image)
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 R values. Mean diff, mean difference comparing top to bottom quintile of each allele score. R = proportion of variable of the lipid traits explained by each allele score. TG, triglycerides.
For LDL-C, in 16 cohort/case–control studies with 11 826 combined incident/prevalent CHD cases, a 1 mmol/L genetically instrumented increment in LDL-C gave an OR for CHD of 1.78 (95% CI: 1.58, 2.01) for the unrestricted, and 1.92 (95% CI: 1.68, 2.19) for the restricted allele score (Figure 2). For HDL-C, using the unrestricted allele score a 1 mmol/L genetically instrumented increment in HDL-C yielded an OR for CHD of 0.53 (95% CI: 0.40, 0.70), but the comparable estimate for the restricted allele score was 0.91 (95% CI: 0.42, 1.98). For triglycerides, a genetically instrumented 1 log-unit increment in triglycerides yielded similar estimates for CHD events: an OR of 1.62 (95% CI: 1.24, 2.11) for the unrestricted score and 1.61 (95% CI: 1.00, 2.59) for the restricted score. Estimates derived from instrumental variable analysis using incident-only CHD cases were comparable in effect size and direction to those from the analyses incorporating the combined incident and prevalent events (Figure 2). There was a similar inconsistency in the effect estimate of the unrestricted allele score for HDL-C and risk of incident-only CHD (OR: 0.68 per 1 mmol/L lower HDL-C; 95% CI: 0.47, 0.97) and that for the restricted HDL-C allele score with incident-only CHD (OR: 1.33; 95% CI: 0.49, 3.59).
(Enlarge Image)
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.
For each of the restricted and unrestricted allele scores, no difference was identified when the analysis was limited to fasted samples for the first stage of the instrumental variable analysis (Supplementary material online, Figure S12http://eurheartj.oxfordjournals.org/content/suppl/2014/01/27/eht571.DC1).
Sequential adjustment of the unrestricted LDL-C allele score for HDL-C, triglycerides, and statin use only moderately diminished the estimate for the association with CHD events (Figure 3), but comparable adjustments had more marked effects on the estimates for the HDL-C allele score. The association of the unrestricted HDL-C allele score with incident/prevalent CHD was shifted from an OR for CHD of 0.55 (95% CI: 0.38, 0.79) on unadjusted analysis to an OR of 0.79 (95% CI: 0.47, 1.32) with adjustment for triglycerides alone (Figure 3). In contrast, adjustment for LDL-C alone did not influence the estimate (OR: 0.52; 95% CI: 0.34, 0.78). When adjusted for triglycerides, LDL-C, and statin therapy, the OR for the association of the unrestricted HDL-C allele score with incident and prevalent CHD was 0.81 (95% CI: 0.44, 1.46), which was comparable with the estimates derived from the restricted allele score (OR: 0.91; 95% CI: 0.42, 1.98, Figure 2). For triglycerides, adjustment for HDL-C diminished the estimate for CHD risk from an OR of 1.38 (95% CI: 0.98, 1.94) for the unadjusted allele score to an OR of 0.97 (95% CI: 0.64. 1.49). Adjustment for LDL-C produced only a small alteration in the summary estimate for CHD risk: OR: 1.31 (95% CI: 0.86, 1.98). With adjustment for HDL-C, LDL-C, and statin use the OR estimate for the unrestricted triglyceride allele score with incident and prevalent CHD was 1.01 (95% CI: 0.59, 1.75).
(Enlarge Image)
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.
Only the LDL-C allele scores showed association with cIMT. A 1 mmol/L genetically instrumented increment in LDL-C was associated with higher cIMT by 2.49% (95% CI: 0.45, 4.57) and 3.81% (1.48, 6.19) for the unrestricted and restricted allele scores, respectively. Estimates for other lipid traits are provided in Figure 4.
(Enlarge Image)
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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