Genetic study · N Engl J Med 2006
Cohen 2006
Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
The bottom line
People who naturally carry LDL-lowering PCSK9 gene variants from birth have a dramatically lower lifetime risk of coronary heart disease, supporting that lowering LDL-C, even modestly, over a lifetime substantially cuts cardiovascular risk.
Supports LDL causalityUS status: Not applicable
At a glance
- Medicine
- Presence of PCSK9 sequence variants (nonsense mutations in black subjects; a specific sequence variation in white subjects) associated with lifelong reduced LDL-C
- Compared with
- Subjects without the respective PCSK9 sequence variants (nonsense mutations in black subjects; the specific sequence variation in white subjects)
- People
- 12,887
- Who took part
- Participants in the Atherosclerosis Risk in Communities study: 3363 black subjects and 9524 white subjects examined for PCSK9 sequence variations
- Design
- Observational genetic association study (cohort analysis within the Atherosclerosis Risk in Communities study)
- Follow-up
- 15-year interval
- Main question
- Incidence of coronary heart disease (myocardial infarction, fatal CHD, or coronary revascularization) over a 15-year interval
Main result
Black subjects with PCSK9 nonsense mutations: 88 percent reduction in risk of CHD (hazard ratio, 0.11; 95 percent CI, 0.02 to 0.81; P=0.03). White subjects with the PCSK9 sequence variation: 47 percent reduction in risk of CHD (hazard ratio, 0.50; 95 percent CI, 0.32 to 0.79; P=0.003).
Effect on LDL cholesterol
28 percent reduction in mean LDL cholesterol (black subjects with nonsense mutations); 15 percent reduction in LDL cholesterol (white subjects with the sequence variation)
Other results
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Safety
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In the trial's own words
“Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P=0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P=0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003).”
Quoted from the abstract of N Engl J Med 2006, checked word for word against PubMed. PubMed 16554528 · Full paper (DOI)
Common questions
What did the Cohen 2006 trial find?
People who naturally carry LDL-lowering PCSK9 gene variants from birth have a dramatically lower lifetime risk of coronary heart disease, supporting that lowering LDL-C, even modestly, over a lifetime substantially cuts cardiovascular risk.
Who was in Cohen 2006?
12,887 people. Participants in the Atherosclerosis Risk in Communities study: 3363 black subjects and 9524 white subjects examined for PCSK9 sequence variations.
What was Cohen 2006's main result?
Black subjects with PCSK9 nonsense mutations: 88 percent reduction in risk of CHD (hazard ratio, 0.11; 95 percent CI, 0.02 to 0.81; P=0.03). White subjects with the PCSK9 sequence variation: 47 percent reduction in risk of CHD (hazard ratio, 0.50; 95 percent CI, 0.32 to 0.79; P=0.003).
How much did LDL cholesterol change in Cohen 2006?
28 percent reduction in mean LDL cholesterol (black subjects with nonsense mutations); 15 percent reduction in LDL cholesterol (white subjects with the sequence variation)
Related trials
- Ference 2016 (2016)Genetic mimicry shows that lowering LDL cholesterol via PCSK9 variants protects against cardiovascular events about as much as HMGCR (statin-target) variants, but both are linked to a smaller, additive increase in diabetes risk.
- Heart-2 (2026)A single intravenous dose of the base-editing drug VERVE-102 produced dose-dependent, durable reductions in PCSK9 and LDL cholesterol, with an acceptable early safety profile, in a small phase 1 trial.
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