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. 2021 Oct 6;7(1):1–10. doi: 10.1001/jamacardio.2021.3728

Long-term Benefits and Harms Associated With Genetic Cholesteryl Ester Transfer Protein Deficiency in the General Population

Liv Tybjærg Nordestgaard 1,2, Mette Christoffersen 1, Bo Kobberø Lauridsen 1,3, Shoaib Afzal 2,4,5, Børge Grønne Nordestgaard 2,4,5,6, Ruth Frikke-Schmidt 1,2,5, Anne Tybjærg-Hansen 1,2,5,6,✉
PMCID: PMC8495609  PMID: 34613338

Key Points

Question

What is the balance between the long-term clinical benefits and harms associated with genetic cholesteryl ester transfer protein (CETP) deficiency?

Findings

This cohort study of the Danish general population found that genetic CETP deficiency was associated with lower risk of cardiovascular morbidity and mortality but higher risk of age-related macular degeneration (AMD). The lower risk of cardiovascular end points was associated with genetically lower levels of non–high density lipoprotein (HDL) cholesterol, while the higher risk of AMD was associated with genetically higher levels of HDL cholesterol.

Meaning

Despite a beneficial association between genetic CETP deficiency and cardiovascular outcomes, the increased risk of AMD may call into question the use of pharmacologic CETP inhibitors.

Abstract

Importance

The balance between the potential long-term clinical benefits and harms associated with genetic cholesteryl ester transfer protein (CETP) deficiency, mimicking pharmacologic CETP inhibition, is unknown.

Objective

To assess the relative benefits and harms associated with genetic CETP deficiency.

Design, Setting, and Participants

This study examined 2 similar prospective cohorts of the Danish general population, with data on a total of 102 607 participants collected from October 10, 1991, through December 7, 2018.

Exposures

Weighted CETP allele scores.

Main Outcomes and Measures

Incident cardiovascular mortality, ischemic heart disease, myocardial infarction, ischemic stroke, peripheral arterial disease, vascular dementia, Alzheimer disease, all-cause mortality, and age-related macular degeneration (AMD). The study first tested whether a CETP allele score was associated with morbidity and mortality, when scaled to genetically lower levels of non–high-density lipoprotein (HDL) cholesterol (ie, 17 mg/dL), corresponding to the reduction observed for anacetrapib vs placebo in the Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial. Second, the study assessed how much of the change in morbidity and mortality was associated with genetically lower levels of non-HDL cholesterol. Finally, the balance between the potential long-term clinical benefits and harms associated with genetic CETP deficiency was quantified. For AMD, the analyses also included higher levels of HDL cholesterol associated with genetic CETP deficiency.

Results

Of 102 607 individuals in the study, 56 559 (55%) were women (median age, 58 years [IQR, 47-67 years]). Multivariable adjusted hazard ratios showed that a genetically lower level of non-HDL cholesterol (ie, 17 mg/dL) was associated with a lower risk of cardiovascular mortality (hazard ratio [HR], 0.77 [95% CI, 0.62-0.95]), ischemic heart disease (HR, 0.80 [95% CI, 0.68-0.95]), myocardial infarction (HR, 0.72 [95% CI, 0.55-0.93]), peripheral arterial disease (HR, 0.80 [95% CI, 0.63-1.02]), and vascular dementia (HR, 0.38 [95% CI, 0.18-0.80]) and an increased risk of AMD (HR, 2.33 [95% CI, 1.63-3.30]) but was not associated with all-cause mortality (HR, 0.91 [95% CI, 0.81-1.02]), ischemic stroke (HR, 1.05 [95% CI, 0.81-1.36]), or Alzheimer disease (HR, 1.25 [95% CI, 0.89-1.76]). When scaled to a higher level of HDL cholesterol, the increased risk of AMD was even larger. A considerable fraction of the lower risk of cardiovascular end points was associated with genetically lower levels of non-HDL cholesterol, while the higher risk of AMD was associated with genetically higher levels of HDL cholesterol. Per 1 million person-years, the projected 1916 more AMD events associated with genetically higher levels of HDL cholesterol was similar to the 1962 fewer events of cardiovascular mortality and myocardial infarction combined associated with genetically lower levels of non-HDL cholesterol.

Conclusions and Relevance

This study suggests that genetic CETP deficiency, mimicking pharmacologic CETP inhibition, was associated with a lower risk of cardiovascular morbidity and mortality, but with a markedly higher risk of AMD.

This cohort study assesses the relative benefits and harms associated with genetic cholesteryl ester transfer protein deficiency.

Introduction

Cholesteryl ester transfer protein (CETP) plays a pivotal role in lipoprotein metabolism by facilitating the transfer of esterified cholesterol from high-density lipoprotein (HDL) to triglyceride-rich lipoproteins and low-density lipoprotein (LDL) in exchange for triglycerides.1 Cholesteryl ester transfer protein deficiency, both pharmacologic and genetic, is associated with an increase in HDL cholesterol, owing to a reduced rate of transfer of cholesteryl ester from HDL to triglyceride-rich lipoproteins and a concomitant decrease in non-HDL cholesterol (ie, the cholesterol content in triglyceride-rich lipoproteins, LDL, and lipoprotein[a]), leading to an overall antiatherogenic lipid profile.2

The Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial, to our knowledge, the largest of the CETP inhibitor clinical outcomes trials,3,4,5 demonstrated a 9% reduction in the composite primary end point of coronary death, myocardial infarction (MI), or coronary revascularization among participants treated with anacetrapib vs placebo.6 Further analysis suggested that the benefit associated with anacetrapib was mainly due to a mean reduction of 17 mg/dL in non-HDL cholesterol (to convert to millimoles per liter, multiply by 0.0259). Genetic studies of cardiovascular disease and/or all-cause mortality, including studies of truncating variants in CETP (OMIM 118470) and the use of mendelian randomization (MR), support that genetic CETP deficiency is associated with a lower risk of these end points.7,8,9,10,11 Several genome-wide association studies of age-related macular degeneration (AMD) have identified the CETP locus as a major locus for AMD in both European and Asian individuals and genetic variants associated with CETP deficiency (marked by high levels of HDL cholesterol) as genetic risk factors for AMD12,13,14,15 or “eye disease,”16 suggesting that AMD might be a long-term adverse effect of genetic and pharmacologic CETP deficiency. However, to date, no studies have assessed the balance between the potential long-term clinical benefits and harms associated with genetic and pharmacologic CETP deficiency, to our knowledge. Assessing this balance is clinically important because randomized clinical phase 2 trials of an additional CETP inhibitor, obicetrapib, have recently been registered in the US and in the EU.17,18,19

Therefore, to mimic the long-term effects and possible (on target) adverse effects of pharmacologic CETP inhibition, we first tested whether a CETP allele score weighted according to lower levels of non-HDL cholesterol was associated with cardiovascular mortality, ischemic heart disease (IHD), MI, ischemic stroke (IS), peripheral arterial disease (PAD), vascular dementia, Alzheimer disease, all-cause mortality, AMD, and the subgroups of dry and wet AMD among 102 607 individuals from the general population. Second, we determined hazard ratios (HRs) for the same end points scaled to a genetically lower level of non-HDL cholesterol (ie, 17 mg/dL), corresponding to the mean change observed with anacetrapib treatment vs placebo in the REVEAL trial. Third, we performed mediation analyses to assess how much of the change in morbidity and mortality conferred via genetic CETP deficiency was associated with lower levels of non-HDL cholesterol. Finally, to quantify the balance between the potential long-term clinical benefits and harms associated with genetic and pharmacological CETP deficiency, we assessed the projected change in the number of events of the individual end points per 17 mg/dL of genetically lower levels of non-HDL cholesterol in 100 000 individuals per 10 years of follow-up (1 million person-years). For AMD, we also scaled the analyses to a higher level of HDL cholesterol associated with genetic CETP deficiency.

Methods

Setting, Study Population, and Outcome

We included 102 607 White individuals of Danish descent from 2 similar prospective cohort studies of the Danish general population, the Copenhagen General Population Study (CGPS; N = 92 397) and the Copenhagen City Heart Study (CCHS; N = 10 210), with data collected from October 10, 1991, through December 7, 2018. We excluded individuals with prevalent IHD (n = 6067), including MI (n = 2358), IS (n = 3264), PAD (n = 1392), vascular dementia (n = 14), Alzheimer disease (n = 57), or AMD (n = 44) at baseline. Studies were approved by institutional review boards and Danish ethical committees (KF-100-2039/91 and H-KF-01-144/01) and conducted according to the Declaration of Helsinki.20 Written informed consent was obtained from all participants.

The CGPS was initiated in 2003 with ongoing enrollment. Individuals were selected based on the national Danish Civil Registration System to reflect the adult Danish population aged 20 to 100 years. Data were obtained from a questionnaire, a physical examination, and a blood test. We included 92 397 consecutive participants from this study in the present analysis. The median follow-up was 9 years (range, <1 year to 14 years).

The CCHS was initiated from 1976 to 1978, with follow-up examinations from 1981 to 1983, from 1991 to 1994, and from 2001 to 2003. Participants were recruited and examined as in the CGPS. We included all 10 210 consecutive participants in the 1991-1994 and 2001-2003 examinations in the present analysis. The median follow-up was 15 years (range, <1 year to 27 years).

The International Classification of Diseases, Eighth Revision and the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision were used for information on diagnoses. For a further description, see eMethods in the Supplement.

Genotyping and Other Covariates

We sequenced the core promoter, coding exons, and exon-intron boundaries of CETP in individuals with the lowest 2% (n = 190) and highest 2% (n = 190) of HDL cholesterol levels in the CCHS to increase the likelihood of identifying genetic variants with an association with HDL cholesterol levels in the general population.21,22,23,24,25,26 For the present study, genetic variants with a minor allele frequency greater than 0.01 were genotyped for 102 607 individuals in the CCHS and CGPS, and gene scores weighted according to non-HDL cholesterol or HDL cholesterol level were constructed using these variants (eFigure 1 in the Supplement).

A total of 84 252 individuals had genotypes available for 10 allelic variants in known non-HDL cholesterol genes: PCSK9 (OMIM 607786; rs11591147, rs148195424, rs562556, rs505151), HMGCR (OMIM 142910; rs17238484), LDLR (OMIM 606945; rs267607213, rs121908025), APOB (OMIM 107730; rs5742904), ABCG8 (OMIM 605460; rs11887534), and NPC1L1 (OMIM 608010; rs41279633).27,28 These variants were used to create an independent gene score weighted according to non-HDL cholesterol level (called the other score).

Sequencing was by Sanger sequencing, and genotyping was by TaqMan-based assays (Applied Biosystems) or by an allele-specific polymerase chain reaction system (KASPar; LGC Genomics Ltd). For other covariates, see the eMethods in the Supplement.

Statistical Analysis

Statistical analysis was performed with R, version 3.6.1 (R Group for Statistical Computing) or Stata SE, version 14 (StataCorp). We used the χ2 test, the Kruskal-Wallis test, or the Cuzick test for trend, the calculation of weighted allele scores across CETP variants and other variants, Cox proportional hazards regression, mediation analyses, instrumental variable analysis, and the calculation of the difference of absolute event rates using Poisson regression. Missing data on covariates (5746 of 1 436 498 [0.4%]) were imputed based on age, sex, and cohort. For an in-depth description of the statistical analyses and sensitivity analyses, see the eMethods in the Supplement.

Results

Of 102 607 individuals in the study, 56 559 (55%) were women (median age, 58 years [IQR, 47-67 years]). Eight genetic variants (rs4783961, rs4783962, rs1800776, rs708272, rs5883, rs11076176, rs5880, and rs5882) were used to construct a CETP allele score weighted according to lower levels of non-HDL cholesterol (eTable 1 and eTable 2A in the Supplement) or on higher levels of HDL cholesterol. The baseline characteristics of the study participants by tertiles of the CETP allele score weighted according to lower levels of non-HDL cholesterol are shown in the Table. For a detailed description, see the eResults, eFigure 1, and eFigure 2 in the Supplement.

Table. Characteristics of Study Participants by Tertiles of the CETP Allele Score (Weighted According to Non-HDL Cholesterol Levels) in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined.

Characteristic Tertile P value
First Second Third
No. of individuals (%) 32 694 (32) 30 784 (30) 39 129 (38)
Age, median (IQR), y 58 (47-67) 58 (47-67) 58 (47-67) .91
Female, No. (%) 18 085 (55) 16 873 (55) 21 601 (55) .41
BMI, median (IQR) 26 (23-28) 26 (23-28) 26 (23-28) .82
Hypertension, No. (%) 19 293 (59) 18 192 (59) 23 195 (59) .71
BP, median (IQR), mm Hg
Systolic 140 (126-155) 140 (126-155) 140 (126-155) .71
Diastolic 84 (76-90) 84 (76-90) 84 (76-90) .94
Type 1 and 2 diabetes, No. (%) 1256 (4) 1149 (4) 1556 (4) .17
Glucose, median (IQR), mg/dL 92 (85-103) 92 (85-103) 92 (85-103) .07
hsCRP, median (IQR), mg/dL 0.14 (0.10-0.24) 0.14 (0.11-0.24) 0.14 (0.10-0.24) .67
Smoking, No. (%) 6611 (20) 6425 (21) 8187 (21) .04
Alcohol consumption, No. (%) 5656 (17) 5187 (17) 6886 (18) .04
Physical inactivity, No. (%) 16 238 (50) 15 452 (50) 19 669 (50) .15
Postmenopausal, No. (%)a 12 148 (67) 11 357 (67) 14 511 (67) .95
HR therapy, No. (%)a 1956 (11) 1818 (11) 2332 (11) ≥.99
Lipid-lowering therapy, No. (%) 3513 (11) 3356 (11) 4003 (10) .009
Educational level <8 y, No. (%) 4396 (13) 4211 (14) 5372 (14) .68
APOE ɛ4 allele, No. (%) 939 (3) 789 (3) 1151 (3) .13
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Abbreviations: APOE, apolipoprotein E; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); BP, blood pressure; HDL, high-density lipoprotein; HR, hormone replacement; hsCRP, high-sensitivity C-reactive protein.

SI conversion factors: To convert glucose to millimoles per liter, multiply by 0.0555; and hsCRP to milligrams per liter, multiply by 10.

a

In women only.

Plasma Levels of Lipids, Lipoproteins, and Apolipoproteins

Associations of genetic variants in CETP with plasma levels of lipids, lipoproteins, and apolipoproteins are shown in eTable 3 in the Supplement for the individual variants included in the gene score and in eTable 4 in the Supplement for the tertiles of the weighted allele score. As expected from both pharmacologic and genetic CETP deficiency, lower levels of non-HDL cholesterol, reflecting lower levels of LDL cholesterol, cholesterol in triglyceride-rich lipoproteins, and cholesterol in lipoprotein(a), were associated with higher levels of HDL cholesterol, reflecting the inhibition of the transfer of cholesterol from HDL particles to LDL, triglyceride-rich lipoproteins, and lipoprotein(a) in exchange for triglycerides associated with CETP inhibition (non-HDL cholesterol and HDL cholesterol across tertiles of CETP allele score; eTable 4 in the Supplement).

Cardiovascular End Points, Alzheimer Disease, and Mortality

During a median follow-up of 8 to 9 years (range, <1 year to 26 years), 4376 participants died of cardiovascular disease, 7463 developed IHD, 3112 developed MI, 3172 developed IS, 3605 developed PAD, 367 developed vascular dementia, 1855 developed Alzheimer disease, and 15 251 died. The multivariable-adjusted HRs as a function of CETP allele score weighted according to non-HDL cholesterol levels for individuals in the third vs first tertile of the allele score showed a lower risk for cardiovascular mortality (HR, 0.91 [95% CI, 0.85-0.98]), IHD (HR, 0.92 [95% CI, 0.87-0.97]), MI (HR, 0.91 [95% CI, 0.84-0.99]), PAD (HR, 0.92 [95% CI, 0.85-1.00]), and vascular dementia (HR, 0.75 [95% CI, 0.58-0.95]); a directionally similar but not significant decrease for all-cause mortality (HR, 0.97 [95% CI, 0.93-1.01]); and no significant change for IS (HR, 1.01 [95% CI, 0.93-1.10]) or Alzheimer disease (HR, 1.07 [95% CI, 0.96-1.19]) (Figure 1).

Figure 1. Risk of Vascular End Points as a Function of CETP Weighted Allele Score in Tertiles.

Figure 1.

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Hazard ratios (HRs) and 95% CIs are from Cox proportional hazards regression models. The allele score was weighted according to the association with plasma levels of non–high-density lipoprotein cholesterol and the allele frequency of the CETP genetic variants in the Copenhagen studies. Adjustment was for age, sex, and cohort and multivariable for age, sex, cohort, body mass index, hypertension, type 1 and 2 diabetes, smoking, alcohol consumption, physical inactivity, menopausal status and hormonal therapy (only women), lipid-lowering therapy, and educational level.

Age-Related Macular Degeneration

During a median follow-up of 10 years (range, <1 year to 27 years), 1721 participants developed AMD, 993 developed dry AMD, and 1225 developed wet AMD. The multivariable adjusted HRs as a function of CETP allele score weighted according to non-HDL cholesterol levels for individuals in the third vs first tertile of the CETP allele score showed an increased risk for all AMD (HR, 1.24 [95% CI, 1.11-1.39]), dry AMD (HR, 1.41 [95% CI, 1.21-1.64]), and wet AMD (HR, 1.19 [95% CI, 1.04-1.36]) (Figure 2). The corresponding HRs as a function of CETP allele score weighted according to HDL cholesterol levels also showed an increased risk for all AMD (HR, 1.32 [95% CI, 1.18-1.49]), dry AMD (HR, 1.48 [95% CI, 1.26-1.73]), and wet AMD (HR, 1.28 [95% CI, 1.11-1.46]).

Figure 2. Risk of Age-Related Macular Degeneration (AMD) as a Function of CETP Weighted Allele Score in Tertiles.

Figure 2.

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Hazard ratios (HRs) and 95% CIs are from Cox regression models. The allele score was weighted according to the association with plasma non–high-density lipoprotein cholesterol (HDL-C) or HDL-C and the allele frequency of the CETP genetic variants in the Copenhagen studies. Adjustment was for age, sex, and cohort and multivariable for age, sex, cohort, body mass index, hypertension, type 1 and 2 diabetes, smoking, alcohol consumption, physical inactivity, menopausal status and hormonal therapy (only women), lipid-lowering therapy, and educational level.

Risk of All End Points per 17 mg/dL of Genetically Lower Levels of Non-HDL Cholesterol

Risk of all end points per 17 mg/dL of genetically lower levels of non-HDL cholesterol, corresponding to the mean reduction in the level of non-HDL cholesterol obtained with anacetrapib treatment compared with placebo in the REVEAL trial,6 by either CETP score or the “other score” on a continuous scale is shown in Figure 3. With the use of the CETP score, the multivariable-adjusted HRs showed a lower risk for cardiovascular mortality (HR, 0.77 [95% CI, 0.62-0.95]), IHD (HR, 0.80 [95% CI, 0.68-0.95]), MI (HR, 0.72 [95% CI, 0.55-0.93]), PAD (borderline; HR, 0.80 [95% CI, 0.63-1.02]), and vascular dementia (HR, 0.38 [95% CI, 0.18-0.80]); a directionally similar but not significant change for all-cause mortality (HR, 0.91 [95% CI, 0.81-1.02]); and no significant change for IS (HR, 1.05 [95% CI, 0.81-1.36]) or Alzheimer disease (HR, 1.25 [95% CI, 0.89-1.76]). There was an increased risk of all AMD (HR, 2.33 [95% CI, 1.63-3.30]), dry AMD (HR, 3.60 [95% CI, 2.21-5.70]), and wet AMD (HR, 1.87 [95% CI, 1.22-2.90]).

Figure 3. Risk of All End Points per 17-mg/dL Genetically Lower Level of Non–High-Density Lipoprotein (HDL) Cholesterol.

Figure 3.

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Hazard ratios (HRs) and 95% CIs are from Cox proportional hazards regression models. The allele score was weighted according to the association with plasma levels of non-HDL cholesterol and the allele frequency of the CETP genetic variants in the Copenhagen studies. Adjustment was for age, sex, cohort, body mass index, hypertension, type 1 and 2 diabetes, smoking, alcohol consumption, physical inactivity, menopausal status and hormonal therapy (only women), lipid-lowering therapy, and educational level. The other score was constructed using the following variants: PCSK9 (rs11591147, rs148195424, rs562556, and rs505151), HMGCR (rs17238484), LDLR (rs267607213 and rs121908025), APOB (rs5742904), ABCG8 (rs11887534), and NPC1L1 (rs41279633). AMD indicates age-related macular degeneration; CETP, cholesteryl ester transfer protein.

Results were similar for the other score (which was also weighted according to non-HDL cholesterol levels) for cardiovascular mortality (HR, 0.64 [95% CI, 0.42-0.97]), IHD (HR, 0.88 [95% CI, 0.80-0.97]), MI (HR, 0.88 [95% CI, 0.76-1.02]), IS (HR, 0.99 [95% CI, 0.84-1.16]), PAD (HR, 0.83 [95% CI, 0.73-0.94]), Alzheimer disease (HR, 1.01 [95% CI, 0.83-1.23]), and all-cause mortality (HR, 0.84 [95% CI, 0.68-1.03]) and directionally similar but not significant for vascular dementia (HR, 0.78 [95% CI, 0.55-1.13]) (Figure 3). In contrast to the CETP score, HRs for all AMD, dry AMD, and wet AMD were not increased for the other score (all AMD: HR, 1.13 [95% CI, 0.92-1.40]; dry AMD: HR, 1.00 [95% CI, 0.77-1.30]; and wet AMD: HR, 1.22 [95% CI, 0.94-1.60]). In summary, both genetic scores were associated with similar lower risks of cardiovascular end points, including cardiovascular mortality and all-cause mortality (borderline), were not associated with risk of IS or Alzheimer disease, and were discordant for risk of all AMD and both AMD subtypes, which were increased only for the CETP score.

Mediation Analyses

Lower levels of non-HDL cholesterol were associated with 8% (95% CI, 3%-34%) of the lower risk of cardiovascular mortality, 47% (95% CI, 25%-309%) of the lower risk of IHD, 39% (95% CI, 22%-234%) of the lower risk of MI, 33% (95% CI, 13%-306%) of the lower risk of PAD, and −1% (95% CI, −7% to 4%) of the lower risk of vascular dementia conferred via genetic CETP deficiency (eTable 5 in the Supplement). Of the corresponding increase in risk of AMD, levels of non-HDL cholesterol were associated with 0% (95% CI, −1% to 4%) of the risk of all AMD, 0% (95% CI, 0%-4%) of the risk of dry AMD, and 0% (95% CI, −5% to 4%) of the risk of wet AMD via genetic CETP deficiency. In contrast, mediation analyses via genetically higher levels of HDL cholesterol were associated with 18% (95% CI, 8%-35%) of the increased risk of all AMD, 13% (95% CI, 5%-25%) of the increased risk of dry AMD, and 25% (95% CI, 9%-72%) of the increased risk of wet AMD via genetic CETP deficiency. Taken together, these data suggest that, while a large fraction of the lower risk of cardiovascular end points conferred via genetic CETP deficiency is associated with lower levels of non-HDL cholesterol, the higher risk of AMD is associated with higher levels of HDL cholesterol.

Projected Difference in Events per 1 Million Person-Years

A 17-mg/dL lower level of non-HDL cholesterol, genetically assessed by CETP score, in 100 000 individuals per 10 years of follow-up (1 million person-years) corresponded to 1180 fewer events of cardiovascular mortality, 1428 fewer events of IHD, 782 fewer events of MI, 668 fewer events of PAD, and 331 fewer events of vascular dementia (Figure 4). In contrast, for the same reduction in genetically assessed levels of non-HDL cholesterol, there were 1286 more events of AMD, 1126 more events of dry AMD, and 666 more events of wet AMD. Furthermore, a 43-mg/dL genetically higher level of HDL cholesterol, corresponding to the mean increase in HDL cholesterol observed with anacetrapib vs placebo in the REVEAL trial,6 corresponded to even further increases to 1916 events for all types of AMD, 1750 events for dry AMD, and 953 events for wet AMD per 1 million person-years. In other words, the increase in the number of events of all AMD was similar to the 1962 fewer events of cardiovascular mortality and MI combined.

Figure 4. Difference in Events in 100 000 Individuals per 10 Years of Follow-up.

Figure 4.

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The CETP allele score was weighted according to the association with plasma non–high-density lipoprotein (HDL) cholesterol or HDL cholesterol and the allele frequency of the CETP genetic variants in the Copenhagen studies. Total events in 100 000 individuals for 10 years of follow-up (1 million person-years) and projected differences in events were calculated using Poisson regression and were adjusted for age, sex, and cohort. AMD indicates age-related macular degeneration; and CETP, cholesteryl ester transfer protein.

Sensitivity Analyses

With the use of external weights from the Global Lipids Genetics Consortium29 (eTable 2B in the Supplement) instead of internal weights in Cox proportional hazards regression analysis, the results were similar (eFigure 3 and eFigure 4 in the Supplement compared with Figure 1 and Figure 2). Because apolipoprotein B (apoB) is the major apolipoprotein on all lipoproteins causing atherosclerotic cardiovascular disease (LDL, triglyceride-rich lipoproteins, and lipoprotein[a]), and because both pharmacologic and genetic CETP inhibition lowers levels of apoB, we also assessed the risk of all end points using a CETP allele score weighted according to apoB levels. Results were similar when compared with the score weighted by levels of non-HDL cholesterol (eFigure 5 and eFigure 6 in the Supplement compared with Figure 1 and Figure 2). We further assessed the risk of all end points using a CETP allele score weighted according to HDL cholesterol levels. Results were similar when compared with the score weighted according to levels of non-HDL cholesterol (eFigure 7 in the Supplement).

On a continuous scale using restricted cubic splines, genetically lower levels of non-HDL cholesterol (a more negative score) were associated with a lower risk of cardiovascular mortality, IHD, MI, PAD, and vascular dementia but a higher risk of all AMD, dry AMD, and wet AMD (eFigure 8 in the Supplement compared with Figure 1 and Figure 2). Given the putative interaction previously described between CETP and HMGCR genetic scores on the risk of major cardiovascular events, we tested for interaction between the CETP-weighted allele score on a continuous scale and the other score on the risk of all end points and found no interaction (eFigure 9 in the Supplement).

Finally, in MR analyses using the inverse variance weighted method, a 17-mg/dL genetically lower level of non-HDL cholesterol or a 12-mg/dL genetically lower level of apoB (to convert to grams per liter, multiply by 0.01) was associated with a lower risk of cardiovascular mortality, IHD, MI, vascular dementia, and all-cause mortality and with a higher risk of AMD (eFigure 10 and eFigure 11 in the Supplement). A corresponding 43 mg/dL genetically higher level of HDL cholesterol was associated with a lower risk of cardiovascular mortality, vascular dementia, and all-cause mortality and with a higher risk of AMD (eFigure 12 in the Supplement). Results from the MR weighted method, Egger regression, and weighted mode were consistent and similar to the inverse variance weighted method for all end points, indicating a low risk of unmeasured pleiotropy and a reasonable likelihood that MR assumptions were fulfilled (eFigures 10, 11, and 12 in the Supplement).

Discussion

To date, no studies have directly quantified the balance between the potential long-term benefits and harms associated with genetic CETP deficiency, mimicking pharmacologic CETP inhibition, to our knowledge. In the present study of the general Danish population, long-term genetic CETP deficiency was associated with a lower absolute risk of cardiovascular mortality, IHD, MI, PAD, and vascular dementia but with a numerically similar higher absolute risk of AMD. Furthermore, while the reduction in cardiovascular events was associated mainly with genetically lower levels of non-HDL cholesterol, the increase in the number of events of AMD was associated with genetically higher levels of HDL cholesterol. These findings are novel and of potential clinical importance because they suggest that, although CETP may be a relevant drug target for reducing cardiovascular events, AMD might be a long-term adverse effect of pharmacologic CETP inhibition. The clinical relevance is further emphasized because randomized clinical phase 2 trials of an additional CETP inhibitor, obicetrapib, have recently been registered in the US and the EU.17,18,19

Previous studies have investigated associations of genetic variants in CETP with lipid traits alone,30,31 cardiovascular disease,7,9,10,11,32 cardiovascular disease and total mortality,8 or AMD individually,12,13,14,15,33,34,35,36 with the exception of a study of Chinese adults that showed a borderline increase in the risk of MI but a highly significant increase in the risk of eye disease.16 To our knowledge, the present study is the first to simultaneously assess the risk of cardiovascular mortality, IHD, MI, IS, PAD, dementia (including vascular dementia and Alzheimer disease), all-cause mortality, and AMD (including both dry and wet AMD).

To increase the clinical relevance of our findings, we scaled the genetic effect estimates for all end points to the corresponding effects observed for treatment with anacetrapib vs placebo in the REVEAL trial (a mean lower non-HDL cholesterol level of 17 mg/dL, which, in that study, was associated with a 9% reduction in the composite primary end point of coronary death, MI, or coronary revascularization).6 Furthermore, in mediation analyses, we found that 33% to 47% of the risk of IHD, MI, and PAD conferred via genetic CETP deficiency was associated with lower levels of non-HDL cholesterol, whereas 18% of the risk of AMD was associated with genetically higher levels of HDL cholesterol. Finally, when directly comparing the balance between the potential long-term clinical benefits and harms associated with genetic CETP deficiency for a similar reduction in levels of non-HDL cholesterol or an increase in levels of HDL cholesterol (for AMD only) per 1 million person-years, the projected 1916 more AMD events was similar to the 1962 fewer events of cardiovascular mortality and MI combined. Taken together, these results may call into question the use of long-term pharmacologic CETP inhibition.

The mechanism whereby genetic CETP deficiency reduces cardiovascular risk is probably straightforward. As shown in the present study and in randomized clinical trials (RCTs) of the more potent CETP inhibitors, both genetic CETP deficiency and pharmacologic CETP inhibition are associated with an increase in levels of HDL cholesterol, owing to a reduced rate of transfer of cholesteryl ester from HDL to mainly triglyceride-rich lipoproteins, and a concomitant decrease in levels of non-HDL cholesterol (ie, in the cholesterol content of triglyceride-rich lipoproteins, LDL, and lipoprotein[a]). These changes are associated with an overall antiatherogenic lipid profile and a lower risk of atherosclerotic cardiovascular disease. In the present study, we therefore used genetic variants spanning the core promoter and coding region of CETP that were associated with lower levels of non-HDL cholesterol and higher levels of HDL cholesterol, as a proxy for pharmacologic CETP inhibition.

In contrast, the mechanism whereby genetic CETP deficiency could increase the risk of AMD is speculative. When lipid-rich deposits accumulate between the retinal pigment epithelium and the Bruch membrane, transport of nutrients and metabolites across the Bruch membrane is compromised, damaging the photoreceptor layer and eventually leading to AMD.37,38 These lipid deposits are composed of esterified cholesterol-rich lipoprotein particles that are produced by the retinal pigment epithelium.37 The association between genetic CETP deficiency and risk of AMD might be explained by an involvement of CETP in the formation of these lipid-rich deposits in the eye.37 Genome-wide association studies of AMD have identified at least 4 genes (CETP, ABCA1 [OMIM 600046], APOE [OMIM 107741], and LIPC [OMIM 151670]) with well-established functions in the metabolism of HDL cholesterol.12,13 Additional studies suggest that increasing levels of HDL cholesterol, particularly via inhibition of CETP, may lead to an increased risk of AMD.15,36,39

In the first RCT of the CETP inhibitor torcetrapib (ILLUMINATE), there was an excess of deaths and cardiovascular disease attributed to off-target effects.3 The following 2 RCTs of dalcetrapib (dal-OUTCOMES)5 and evacetrapib (ACCELERATE)4 were stopped early owing to lack of efficacy in reducing cardiovascular events (futility). In the REVEAL trial,6 the most recent and largest of the RCTs of CETP inhibitors, anacetrapib reduced the primary composite end point of coronary death, MI, and coronary revascularization by 9%. The benefit associated with anacetrapib was largely explained by an 18% (17 mg/dL) reduction in levels of non-HDL cholesterol combined with sufficient statistical power, longer trial duration, and a lack of serious adverse events. However, the clinical development of anacetrapib did not proceed to the regulatory approval stage owing to concerns about the accumulation of the drug in adipose tissue.40,41 An additional CETP inhibitor, TA-8985, was well tolerated and had beneficial effects on lipid levels42 and has only recently been registered as obicetrapib in clinical phase 2 trials in the US and EU. See Armitage et al43 for a recent overview.

Although there is a well-recognized association between AMD and alleles at the CETP locus in individuals of different ethnicities,12,13,14,33,34,35 excess risk of AMD has not been reported in any CETP RCT to date, to our knowledge. However, a search of ClinicalTrials.gov and EU Clinical Trials Register did not reveal any trials of CETP inhibition that measured AMD as an outcome. Alternatively, the median follow-up times may have been too short, ranging from 12 to 31 months in ILLUMINATE, ACCELERATE, and dal-OUTCOMES to 4.1 years in REVEAL,3,4,5,6 for AMD to develop. In RCTs, treatment with CETP inhibitors was given in addition to statins, and although highly controversial, statin treatment might protect patients from AMD. Furthermore, the mean age at AMD diagnosis in our study was 72 years, while the mean age of study participants was 61 years in ILLUMINATE, 65 years in ACCELERATE, 60 years in dal-OUTCOMES, and 68 years in REVEAL. Furthermore, CETP inhibitors are small molecule inhibitors; therefore, the mode of action is not directly comparable to genetic CETP deficiency, which is lifelong and directly associated with regulation of the gene or the structure of the gene product. Finally, we cannot rule out that CETP inhibitors, as a drug class, may exert off-target effects that cannot be detected in a genetic study.

Limitations

This study has some limitations. All of the participants were White and of Danish descent. However, many of the associations between genetic variants in CETP, lipid traits, and disease end points have been confirmed in individuals of other ethnicities.14,30,31,34 Inferring clinical associations of CETP with levels of HDL cholesterol and non-HDL cholesterol and deriving conclusions from this analysis is subject to limitations, particularly because the associations are biologically correlated and do not account for unmeasured pleiotropy. However, sensitivity analyses using different MR methods suggested a low risk of unmeasured pleiotropy or other violations of MR assumptions.

Conclusions

This study suggests that genetic deficiency of CETP, mimicking pharmacologic CETP inhibition, was associated with a lower absolute risk of cardiovascular mortality, IHD, MI, PAD, and vascular dementia, but with an increased absolute risk of AMD of numerically similar magnitude. This finding suggests that AMD might be a harmful long-term adverse effect of pharmacologic CETP inhibition.

Supplement.

eMethods.

eResults.

eReferences.

eTable 1. Genetic Variants in CETP Used to Construct the Allele Scores in Copenhagen General Population Study and the Copenhagen City Heart Study Combined

eTable 2. Beta-Scores for the Individual CETP Genetic Variants in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined (Panel A) and in the Global Lipids Genetics Consortium (Panel B)

eTable 3. Lipid, Lipoprotein, and Apolipoprotein Levels as a Function of CETP Genotype for Each of the Included Variants in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined

eTable 4. Lipid, Lipoprotein, and Apolipoprotein Levels as a Function of CETP Allele Score (Weighted on Non-HDL Cholesterol) in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined

eTable 5. The Fraction of Risk of Morbidity or Mortality Explained by Lower Non-HDL Cholesterol or Higher HDL Cholesterol from Genetic CETP Deficiency

eFigure 1. Population-Based Sequencing of Individuals With the 2% Lowest and Highest HDL Cholesterol Levels in the Copenhagen City Heart Study

eFigure 2. Linkage Disequilibrium Plot for the Eight Genetic Variants in CETP Included in the Study

eFigure 3. Risk of Vascular End Points in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined as a Function of CETP Allele Score (Weighted on Non-HDL Cholesterol) in Tertiles Using External Weights

eFigure 4. Risk of Age-Related Macular Degeneration in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined as a Function of CETP Allele Score (Weighted on Non-HDL Cholesterol) in Tertiles Using External Weights

eFigure 5. Risk of Vascular End Points in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined as a Function of CETP Allele Score (Weighted on Apolipoprotein B) in Tertiles

eFigure 6. Risk of Age-Related Macular Degeneration in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined as a Function of CETP Allele Score (Weighted on Apolipoprotein B) in Tertiles

eFigure 7. Risk of all End Points per 0.44 mmol/L Genetically Lower Non-HDL Cholesterol and 1.12 mmol/L Genetically Higher HDL Cholesterol in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined

eFigure 8. Risk of all End Points as a Function of the CETP Allele Score (Weighted on Non-HDL Cholesterol) on a Continuous Scale in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined

eFigure 9. Risk of all End Points per 0.44 mmol/L Genetically Lower Non-HDL Cholesterol Stratified on PCSK9/HMGCR/LDLR/APOB/ABCG8/NPC1L1 Score in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined

eFigure 10. Causal Risk Estimates for All End Points per 0.44 mmol/L Genetically Lower Non-HDL Cholesterol in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined

eFigure 11. Causal Risk Estimates for all End Points per 12 mg/dL Genetically Lower Apolipoprotein B in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined

eFigure 12. Causal Risk Estimates for all End Points per 1.12 mmol/L Genetically Higher HDL Cholesterol in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined

Click here for additional data file. (665KB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement.

eMethods.

eResults.

eReferences.

eTable 1. Genetic Variants in CETP Used to Construct the Allele Scores in Copenhagen General Population Study and the Copenhagen City Heart Study Combined

eTable 2. Beta-Scores for the Individual CETP Genetic Variants in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined (Panel A) and in the Global Lipids Genetics Consortium (Panel B)

eTable 3. Lipid, Lipoprotein, and Apolipoprotein Levels as a Function of CETP Genotype for Each of the Included Variants in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined

eTable 4. Lipid, Lipoprotein, and Apolipoprotein Levels as a Function of CETP Allele Score (Weighted on Non-HDL Cholesterol) in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined

eTable 5. The Fraction of Risk of Morbidity or Mortality Explained by Lower Non-HDL Cholesterol or Higher HDL Cholesterol from Genetic CETP Deficiency

eFigure 1. Population-Based Sequencing of Individuals With the 2% Lowest and Highest HDL Cholesterol Levels in the Copenhagen City Heart Study

eFigure 2. Linkage Disequilibrium Plot for the Eight Genetic Variants in CETP Included in the Study

eFigure 3. Risk of Vascular End Points in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined as a Function of CETP Allele Score (Weighted on Non-HDL Cholesterol) in Tertiles Using External Weights

eFigure 4. Risk of Age-Related Macular Degeneration in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined as a Function of CETP Allele Score (Weighted on Non-HDL Cholesterol) in Tertiles Using External Weights

eFigure 5. Risk of Vascular End Points in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined as a Function of CETP Allele Score (Weighted on Apolipoprotein B) in Tertiles

eFigure 6. Risk of Age-Related Macular Degeneration in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined as a Function of CETP Allele Score (Weighted on Apolipoprotein B) in Tertiles

eFigure 7. Risk of all End Points per 0.44 mmol/L Genetically Lower Non-HDL Cholesterol and 1.12 mmol/L Genetically Higher HDL Cholesterol in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined

eFigure 8. Risk of all End Points as a Function of the CETP Allele Score (Weighted on Non-HDL Cholesterol) on a Continuous Scale in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined

eFigure 9. Risk of all End Points per 0.44 mmol/L Genetically Lower Non-HDL Cholesterol Stratified on PCSK9/HMGCR/LDLR/APOB/ABCG8/NPC1L1 Score in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined

eFigure 10. Causal Risk Estimates for All End Points per 0.44 mmol/L Genetically Lower Non-HDL Cholesterol in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined

eFigure 11. Causal Risk Estimates for all End Points per 12 mg/dL Genetically Lower Apolipoprotein B in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined

eFigure 12. Causal Risk Estimates for all End Points per 1.12 mmol/L Genetically Higher HDL Cholesterol in the Copenhagen General Population Study and the Copenhagen City Heart Study Combined

Click here for additional data file. (665KB, pdf)

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