Cholesterol-lowering drug targets reduce risk of dementia: Mendelian randomization and meta-analyses of 1 million individuals

Abstract

Introduction: We tested whether genetically proxied non-high-density lipoprotein cholesterol (non-HDL-C)-lowering drug targets reduce risk of all-cause dementia.

Methods: We included 1,091,775 individuals from three prospective general population cohorts with individual-level data and two consortia with summary-level data. We selected genetic variants within HMGCR, NPC1L1, PCSK9, ANGPTL4, LPL, and CETP associated with non-HDL-C. These variants were used as exposures in Cox regression and one- and two-sample Mendelian randomization. Results were meta-analyzed.

Results: Meta-analysis of one-sample Mendelian randomization odds ratios per 1 mmol/L (39 mg/dL) lower non-HDL-C was 0.24 (0.18-0.31) for HMGCR, 0.18 (0.12-0.25) for NPC1L1, 0.97 (0.70-1.35) for PCSK9, 1.66 (0.52-5.36) for ANGPTL4, 1.41 (0.63-3.16) for LPL, and 0.30 (0.26-0.34) for CETP. Cox regression and two-sample Mendelian randomization results were mostly directionally consistent.

Discussion: Genetic lowering of non-HDL cholesterol via HMGCR, NPC1L1, and CETP reduces the risk of dementia. This reflects the effect of lifelong differences in non-HDL cholesterol on risk of dementia.

Highlights: Variants in HMGCR, NPC1L1, and CETP reduce the risk of dementia via non-high-density lipoprotein cholesterol (non-HDL-C). An effect of PCSK9, ANGPTL4, and LPL variants on dementia risk cannot be excluded. This reflects the effect of lifelong lower non-HDL-C on risk of dementia.

Keywords: Mendelian randomization; Niemann‐Pick C1‐like 1; atherosclerosis; cholesterol; cholesteryl ester transfer protein; dementia; genetics; lipid lowering; lipoproteins; β‐hydroxy β‐methylglutaryl‐CoA reductase.

FIGURE 1

Genetic instruments, cohorts, and endpoints in main analyses. A, Cox regression analyses in the CCHS + CGPS and UK Biobank. Selected variants were available in both the CCHS + CGPS and UK Biobank. Variants were excluded from main analyses if they were in linkage disequilibrium (thresholdr ² ≤ 0.05) or if there was a lack of association between the allele score and the positive control IHD in Cox regression analyses. B, The same variants were included in one‐sample Mendelian randomization analyses in the CCHS + CGPS and UK Biobank. C, The same variants were included in two‐sample Mendelian randomization analyses in the CCHS + CGPS, UK Biobank, FinnGen, and GLGC. ANGPTL4, angiopoietin like 4; CETP, cholesteryl ester transfer protein; CCHS, Copenhagen City Heart Study; CGPS, Copenhagen General Population Study; GLGC, Global Lipids Genetics Consortium; HMGCR, β‐hydroxy β‐methylglutaryl‐CoA reductase; IHD, ischemic heart disease; LPL, lipoprotein lipase; NPC1L1, Nieman pick C1‐like 1; PCSK9, proprotein convertase subtilisin/kexin type 9; SD, standard deviation. This figure was created with Biorender.com.

FIGURE 2

Meta‐analyses of Cox regression results: Risk of dementia and ischemic heart disease in CCHS + CGPS and UK Biobank. The allele scores were calculated based on the allele frequency of the variants in the CCHS + CGPS and UK Biobank. Change in the risk of dementia and ischemic heart disease is per 1 mmol/L (39 mg/dL) genetically lower non‐HDL cholesterol. Adjustment was for age and sex in CCHS + CGPS and for age, sex, and first 10 principal components in UK Biobank. Meta‐analyses for combined studies were performed using the “meta” R package. Heterogeneity tests for meta‐analyses: Q = 0.00–3.29 for HMGCR, 0.02–0.64 for NPC1L1, 0.82‐3.71 for PCSK9, 0.30–3.86 for ANGPTL4, 0.00–8.10 for LPL, and 0.16–4.37 for CETP. F statistics in CCHS + CGPS and the UK Biobank were 872 and 131 for HMGCR, 721 and 27 for NPC1L1, 238 and 428 for PCSK9, 47 and 28 for ANGPTL4, 104 and 158 for LPL, and 1795 and 94 for CETP, respectively. ANGPTL4, angiopoietin like 4; CETP, cholesteryl ester transfer protein; CCHS, Copenhagen City Heart Study; CGPS, Copenhagen General Population Study; CI, confidence interval; HDL‐C, high‐density lipoprotein cholesterol; HMGCR, β‐hydroxy β‐methylglutaryl‐CoA reductase; HR, hazard ratio; LPL, lipoprotein lipase; NPC1L1, Nieman pick C1‐like 1; PCSK9, proprotein convertase subtilisin/kexin type 9.

FIGURE 3

Meta‐analyses of one‐sample Mendelian randomization results: Risk of dementia and ischemic heart disease in CCHS + CGPS and UK Biobank. Individual genetic variants were used as instruments in the CCHS + CGPS and UK Biobank. Change in the risk of dementia and ischemic heart disease is per 1 mmol/L (39 mg/dL) genetically lower non‐HDL cholesterol. The Mendelian randomization estimates were derived using the OneSampleMR package. Meta‐analyses were performed using the meta R package. Heterogeneity tests for meta‐analyses: Q = 0.00–31.60 for HMGCR, 0.02–2.04 for NPC1L1, 2.1‐47.6 for PCSK9, 1.90–4.94 for ANGPTL4, 0.02–2.41 for LPL, and 0.20–4.92 for CETP. F statistics in CCHS + CGPS and the UK Biobank were 872 and 131 for HMGCR, 721 and 27 for NPC1L1, 238 and 428 for PCSK9, 47 and 28 for ANGPTL4, 104 and 158 for LPL, and mean F statistics were 1751 and 93 for CETP, respectively. CI, confidence interval; CCHS, Copenhagen City Heart Study; CGPS, Copenhagen General Population Study; ANGPTL4, angiopoietin like 4; CETP, cholesteryl ester transfer protein; HDL‐C, high‐density lipoprotein cholesterol; HMGCR, β‐hydroxy β‐methylglutaryl‐CoA reductase; HR, hazard ratio; LPL, lipoprotein lipase; MR, Mendelian randomization; NPC1L1, Nieman pick C1‐like 1; OR, odds ratio; PCSK9, proprotein convertase subtilisin/kexin type 9.

FIGURE 4

Meta‐analyses of two‐sample Mendelian randomization results: Risk of dementia and ischemic heart disease in CCHS + CGPS, UK Biobank, and FinnGen. Individual genetic variants were used as instruments in the CCHS + CGPS, UK Biobank, FinnGen, and GLGC. Change in the risk of dementia and ischemic heart disease is per 1 SD genetically lower non‐HDL cholesterol. The Mendelian randomization estimates were derived using the TwoSampleMR package. Meta‐analyses were performed using the meta R package. Results are from Wald ratio for drug target genes with one instrument and from weighted median analyses for drug targets with three variants. Heterogeneity tests for meta‐analyses: Q = 0.32–3.83 for HMGCR, 0.39–2.05 for NPC1L1, 0.26‐77.7 for PCSK9, 1.26–5.56 for ANGPTL4, 0.71–1.30 for LPL, and 9.19–21.15 for CETP. F statistics in GLGC were 268 for HMGCR, 62 for NPC1L1, the mean F statistic was 661 for PCSK9, 103 for ANGPTL4, 377 for LPL, and the mean F statistic was 219 for CETP, respectively. ANGPTL4, angiopoietin like 4; CETP, cholesteryl ester transfer protein; CI, confidence interval; HMGCR, β‐hydroxy β‐methylglutaryl‐CoA reductase; HR, hazard ratio; LPL, lipoprotein lipase; MR, Mendelian randomization; NPC1L1, Nieman pick C1‐like 1; OR, odds ratio; PCSK9, proprotein convertase subtilisin/kexin type 9; SD, standard deviation.