Study analysis · European Journal of Preventive Cardiology · 2023
Cholesterol-lowering PCSK9 genes may cut heart risk but raise relative odds of severe lung problems—including 261% higher relative odds of fatal COPD flare-ups.
In 100,000+ Chinese adults, genes mimicking PCSK9 cholesterol drugs were linked to lower heart disease risk but higher relative odds of lung infections, asthma, and COPD flare-ups; absolute risks weren't reported.
Overview
What the study found
The study in plain English — the bottom line, every takeaway we extracted, and what to do with them.
In simple terms
This study looked at people's genes and their health over many years. It found that certain gene changes linked to lower cholesterol are also linked to fewer heart problems but more lung infections. But it can't prove that a medicine that mimics these genes would cause the same effects.
What’s the bottom line?
Scientists studied genes that lower cholesterol in a similar way to PCSK9 inhibitor drugs. In over 100,000 Chinese adults, these genes lowered heart and blood vessel risks, but they were also linked to more lung infections, asthma, and COPD problems.
How strong is this study?
The study is very large and followed people for a long time, and it checked its findings in another country. That makes the links more reliable, but it's still not a randomized drug trial, so we can't be sure about cause and effect.
0 / 100
- COI disclosureconflicts of interest not disclosed
- Data availabilitydata not shared
- Code availabilitycode not shared
25 / 100
- Randomizationnot randomized
- Blindingblinding unclear
- Control groupno control group
- Sample size (n=100706)+20/20
- Follow-upno follow-up reported
100 / 100
77 / 100
- P-values+15/15
- Effect size+20/20
- Confidence intervals+15/15
- Pre-registrationnot pre-registered
Each component is scored out of 100 and then capped by the study design — a case series cannot reach the ceiling a randomised trial can, however well it is reported.
Where it sits
RCT reviewsReviews of RCTs (Meta-analyses)
Max 100Randomized TrialsRandomized Trials
Max 90Reviews of Cohort StudiesReviews of Cohort Studies
Max 85Cohort StudiesCohort Studies
Max 72Reviews of Case-Control StudiesReviews of Case-Control Studies
Max 63Case-Control StudiesCase-Control Studies
Max 58Cross-Sectional & Case SeriesCross-Sectional & Case Series
Max 50Expert OpinionExpert Opinion
Max 548 / 100
Probability of being correct
Groups of people are followed over time to see who develops an outcome. Strong for identifying risk factors and associations, but cannot prove causation as firmly as RCTs.
This design cannot establish causation — the findings describe an association, not a cause. Observational cohort with genetic instruments; randomization to genotype is not randomization to treatment; potential confounding, pleiotropy, and linkage disequilibrium; cannot prove that PCSK9 inhibition causes respiratory outcomes.
COI Unknown
Could not determine conflict of interest status
No conflict of interest or funding statements were present in the provided text; the study appears to be an academic analysis of the China Kadoorie Biobank and UK Biobank, but COI/funding information cannot be determined from the available excerpt.
The provided text is truncated and lacks a Conflict of Interest, Funding, or Author Contributions section. No author affiliations or financial relationships are listed. The study uses data from China Kadoorie Biobank and UK Biobank, with assays by Beckman Coulter and Nightingale Health Ltd, but no author-level COI is disclosed.
Key takeaways
- 01
For a 1-SD lower LDL cholesterol (about 27.4 mg/dL), the PCSK9 gene score was linked to 39% lower relative odds of carotid plaque (OR 0.61) and 20% lower relative odds of major occlusive vascular events and ischaemic stroke (OR 0.80).
- 02
It was also linked to 38% higher relative odds of COPD hospitalisation (OR 1.38), 91% higher relative odds of any COPD exacerbation (OR 1.91), 261% higher relative odds of fatal COPD exacerbation (OR 3.61), 87% higher relative odds of URTI in pooled analysis (OR 1.87), and 17% higher relative odds of asthma (OR 1.17).
- 03
Absolute risk increases were not reported in this study.
- 04
The study did not give absolute risks, so it cannot say how many extra or fewer cases per 1,000 people would occur.
- 05
The respiratory risks were strongest in people who already had COPD, especially fatal exacerbations.
- 06
A separate LDL-C gene score was not linked to these lung outcomes, suggesting the signal may be specific to PCSK9 rather than cholesterol lowering itself.
Surprising findings
- The PCSK9 genetic score was linked to 261% higher relative odds of fatal COPD exacerbation among people with pre-existing COPD (OR 3.61).The effect size is large for a genetic variant, and it appears only in those with existing COPD, not in prevalent COPD itself.
- A polygenic LDL-C score was not associated with COPD hospitalisation, COPD exacerbation, or URTI, while the PCSK9 score was.It suggests the respiratory risks are specific to PCSK9 rather than LDL-C lowering itself, contradicting the idea that all LDL-lowering is equivalent.
- The PCSK9 genetic score was not associated with prevalent COPD at baseline (OR 0.96; P=0.75), but was associated with worse outcomes once COPD existed.The genes don't seem to cause COPD, but may make existing COPD more dangerous—a distinction with clinical implications.
Practical takeaways
If you have COPD and are on or considering a PCSK9 inhibitor, discuss respiratory symptoms with your doctor—but do not stop any medication without medical advice.
This study is observational, genetic, and did not report absolute risks. It does not prove that PCSK9 inhibitors cause lung problems.
low confidenceWhen reading headlines about relative risks, ask: what is the absolute risk increase? How many extra cases per 1,000 people?
The study did not provide absolute risk differences, so this information is currently missing.
medium confidenceClinicians may consider monitoring respiratory symptoms in patients with existing COPD who are treated with PCSK9 inhibitors, pending further data.
This is a hypothesis-generating finding, not a guideline change. Large trials with respiratory endpoints are needed.
low confidenceWhy this study matters
Heart protection confirmed in East Asians
A PCSK9 genetic score scaled to 1 SD lower LDL-C (about 27.4 mg/dL) was associated with 39% lower relative odds of carotid plaque (OR 0.61) and 20% lower relative odds of major occlusive vascular events and ischaemic stroke (OR 0.80). Absolute risk differences were not reported.
Most PCSK9 genetic data comes from European populations. This suggests the cardiovascular benefit likely extends to East Asian populations, who often have lower baseline LDL-C levels.
A hidden lung signal: COPD hospitalisation
The same PCSK9 genetic score was linked to 38% higher relative odds of COPD hospitalisation (OR 1.38; 95% CI 1.08–1.76; P=0.0089). Absolute risk difference was not reported.
Cholesterol drugs are usually discussed for heart risk, not lung risk. This could change how doctors monitor patients on PCSK9 inhibitors.
Fatal COPD flare-ups: 3.6x relative odds
Among people with pre-existing COPD, the PCSK9 genetic score was linked to 91% higher relative odds of any exacerbation (OR 1.91; 95% CI 1.12–3.24) and 261% higher relative odds of fatal exacerbation (OR 3.61; 95% CI 1.71–7.60). Absolute risks were not reported.
People with COPD may be a vulnerable group if these genetic findings translate to drugs. It raises questions about screening and monitoring.
Not all LDL lowering is equal
A polygenic LDL-C score excluding the PCSK9 locus was not associated with COPD hospitalisation, COPD exacerbation, or URTI. Heterogeneity P-values were 0.013 for URTI and 0.0012 for fatal COPD exacerbation when compared with the PCSK9 score.
This challenges the assumption that lowering LDL-C by any means has identical effects. The mechanism may be PCSK9-specific rather than LDL-C itself.
URTI and asthma signals pooled across biobanks
In trans-ancestry meta-analysis with UK Biobank, the PCSK9 genetic score was associated with 87% higher relative odds of upper respiratory tract infection (pooled OR 1.87; 95% CI 1.38–2.54) and 17% higher relative odds of asthma (pooled OR 1.17; 95% CI 1.04–1.30). Absolute risk differences were not reported.
Common infections and asthma affect millions. Even modest relative increases could matter at population scale if they translate to drugs.
Replication gaps keep this hypothesis-generating
COPD exacerbation findings were not replicated in UK Biobank using a different PCSK9 variant, and the HUNT biobank in Norway showed null associations with asthma and COPD. Prevalent COPD was not associated with the PCSK9 score (OR 0.96; 95% CI 0.73–1.26).
Science is uncertain. This study alone should not make anyone change medications. It highlights the need for more research.
Want the whole report?
Detailed mode opens the full scientific breakdown — every score component, the methodology, conflicts of interest, the evidence analysis behind each claim, and the raw study data.
Overview
What the study found
The study in plain English — the bottom line, every takeaway we extracted, and what to do with them.
Not medical advice. For informational purposes only. Always consult a healthcare professional. Terms
Scientists studied genes that lower cholesterol in a similar way to PCSK9 inhibitor drugs. In over 100,000 Chinese adults, these genes lowered heart and blood vessel risks, but they were also linked to more lung infections, asthma, and COPD problems.
Research results
For a 1-SD lower LDL cholesterol (about 27.4 mg/dL), the PCSK9 gene score was linked to 39% lower relative odds of carotid plaque (OR 0.61) and 20% lower relative odds of major occlusive vascular events and ischaemic stroke (OR 0.80). It was also linked to 38% higher relative odds of COPD hospitalisation (OR 1.38), 91% higher relative odds of any COPD exacerbation (OR 1.91), 261% higher relative odds of fatal COPD exacerbation (OR 3.61), 87% higher relative odds of URTI in pooled analysis (OR 1.87), and 17% higher relative odds of asthma (OR 1.17). Absolute risk increases were not reported in this study.
What this means - more context
The study did not give absolute risks, so it cannot say how many extra or fewer cases per 1,000 people would occur. The respiratory risks were strongest in people who already had COPD, especially fatal exacerbations. A separate LDL-C gene score was not linked to these lung outcomes, suggesting the signal may be specific to PCSK9 rather than cholesterol lowering itself.
To use PCSK9 genetic variants in the China Kadoorie Biobank and UK Biobank to mimic PCSK9 inhibition and identify unexpected vascular and non-vascular effects.
In a prospective cohort of over 100,000 Chinese adults, a PCSK9 genetic score scaled to 1 SD lower LDL-C (about 27.4 mg/dL) was associated with lower relative odds of carotid plaque (OR 0.61, 39% lower), major occlusive vascular events (OR 0.80, 20% lower), and ischaemic stroke (OR 0.80, 20% lower). However, it was also associated with higher relative odds of COPD hospitalisation (OR 1.38, 38% higher), fatal COPD exacerbation among people with pre-existing COPD (OR 3.61, 261% higher), URTI (pooled OR 1.87, 87% higher), and asthma (pooled OR 1.17, 17% higher). A polygenic LDL-C score was not associated with COPD hospitalisation, COPD exacerbation, or URTI. Absolute risk differences were not reported.
Methods Used
Prospective China Kadoorie Biobank cohort with >100,000 genotyped participants; PCSK9 genetic score from three variants including loss-of-function rs151193009; logistic regression scaled to 1 SD lower directly measured LDL-C; electronic record linkage for disease outcomes; meta-analyses with UK Biobank where applicable.
Main Finding
PCSK9 genetic score scaled to 1 SD lower LDL-C (about 27.4 mg/dL) was associated with lower relative odds of atherosclerotic vascular disease—carotid plaque OR 0.61 (39% lower), major occlusive vascular events OR 0.80 (20% lower), and ischaemic stroke OR 0.80 (20% lower)—but higher relative odds of respiratory diseases—COPD hospitalisation OR 1.38 (38% higher), fatal COPD exacerbation OR 3.61 (261% higher), URTI pooled OR 1.87 (87% higher), and asthma pooled OR 1.17 (17% higher). Absolute risk differences were not reported in this study.
Confidence Level
Moderate. Large prospective biobank with genetic instruments and some replication, but genetic associations are observational, absolute risks were not reported, and key respiratory findings are hypothesis-generating with incomplete replication.
Study Flags
Red Flags
- •Absolute risk differences not reported
- •Findings are hypothesis-generating; COPD exacerbation was not replicated in UK Biobank and HUNT showed null asthma/COPD associations
- •Lifelong genetic exposure may not translate to therapeutic PCSK9 inhibition because of limited tissue penetration and short trial follow-up
Surprising Findings
The PCSK9 genetic score was linked to 261% higher relative odds of fatal COPD exacerbation among people with pre-existing COPD (OR 3.61).
The effect size is large for a genetic variant, and it appears only in those with existing COPD, not in prevalent COPD itself.
Practical Takeaways
If you have COPD and are on or considering a PCSK9 inhibitor, discuss respiratory symptoms with your doctor—but do not stop any medication without medical advice.
RCT reviewsReviews of RCTs (Meta-analyses)
Max 100Randomized TrialsRandomized Trials
Max 90Reviews of Cohort StudiesReviews of Cohort Studies
Max 85Cohort StudiesCohort Studies
Max 72Reviews of Case-Control StudiesReviews of Case-Control Studies
Max 63Case-Control StudiesCase-Control Studies
Max 58Cross-Sectional & Case SeriesCross-Sectional & Case Series
Max 50Expert OpinionExpert Opinion
Max 548 / 100
Probability of being correct
Groups of people are followed over time to see who develops an outcome. Strong for identifying risk factors and associations, but cannot prove causation as firmly as RCTs.
Human Cohort Study
Subject
Moderate probability
on the GRADE evidence scale
This study looked at people's genes and their health over many years. It found that certain gene changes linked to lower cholesterol are also linked to fewer heart problems but more lung infections. But it can't prove that a medicine that mimics these genes would cause the same effects.
Strengths
- Large prospective cohort with >100,000 genotyped participants
- Use of functional PCSK9 loss-of-function variant and genetic score
- Replication in UK Biobank and trans-ancestry meta-analysis
Weaknesses
- Observational design cannot establish causation
- Genetic instruments may be subject to pleiotropy
- PCSK9 genetic score explains only 1.2% of LDL-C variance
Methodology
Evidence Keywords
Statistical Reporting
Not medical advice. For informational purposes only. Always consult a healthcare professional. Terms
Scientists studied genes that lower cholesterol in a similar way to PCSK9 inhibitor drugs. In over 100,000 Chinese adults, these genes lowered heart and blood vessel risks, but they were also linked to more lung infections, asthma, and COPD problems.
Research results
For a 1-SD lower LDL cholesterol (about 27.4 mg/dL), the PCSK9 gene score was linked to 39% lower relative odds of carotid plaque (OR 0.61) and 20% lower relative odds of major occlusive vascular events and ischaemic stroke (OR 0.80). It was also linked to 38% higher relative odds of COPD hospitalisation (OR 1.38), 91% higher relative odds of any COPD exacerbation (OR 1.91), 261% higher relative odds of fatal COPD exacerbation (OR 3.61), 87% higher relative odds of URTI in pooled analysis (OR 1.87), and 17% higher relative odds of asthma (OR 1.17). Absolute risk increases were not reported in this study.
What this means - more context
The study did not give absolute risks, so it cannot say how many extra or fewer cases per 1,000 people would occur. The respiratory risks were strongest in people who already had COPD, especially fatal exacerbations. A separate LDL-C gene score was not linked to these lung outcomes, suggesting the signal may be specific to PCSK9 rather than cholesterol lowering itself.
To use PCSK9 genetic variants in the China Kadoorie Biobank and UK Biobank to mimic PCSK9 inhibition and identify unexpected vascular and non-vascular effects.
In a prospective cohort of over 100,000 Chinese adults, a PCSK9 genetic score scaled to 1 SD lower LDL-C (about 27.4 mg/dL) was associated with lower relative odds of carotid plaque (OR 0.61, 39% lower), major occlusive vascular events (OR 0.80, 20% lower), and ischaemic stroke (OR 0.80, 20% lower). However, it was also associated with higher relative odds of COPD hospitalisation (OR 1.38, 38% higher), fatal COPD exacerbation among people with pre-existing COPD (OR 3.61, 261% higher), URTI (pooled OR 1.87, 87% higher), and asthma (pooled OR 1.17, 17% higher). A polygenic LDL-C score was not associated with COPD hospitalisation, COPD exacerbation, or URTI. Absolute risk differences were not reported.
Methods Used
Prospective China Kadoorie Biobank cohort with >100,000 genotyped participants; PCSK9 genetic score from three variants including loss-of-function rs151193009; logistic regression scaled to 1 SD lower directly measured LDL-C; electronic record linkage for disease outcomes; meta-analyses with UK Biobank where applicable.
Main Finding
PCSK9 genetic score scaled to 1 SD lower LDL-C (about 27.4 mg/dL) was associated with lower relative odds of atherosclerotic vascular disease—carotid plaque OR 0.61 (39% lower), major occlusive vascular events OR 0.80 (20% lower), and ischaemic stroke OR 0.80 (20% lower)—but higher relative odds of respiratory diseases—COPD hospitalisation OR 1.38 (38% higher), fatal COPD exacerbation OR 3.61 (261% higher), URTI pooled OR 1.87 (87% higher), and asthma pooled OR 1.17 (17% higher). Absolute risk differences were not reported in this study.
Confidence Level
Moderate. Large prospective biobank with genetic instruments and some replication, but genetic associations are observational, absolute risks were not reported, and key respiratory findings are hypothesis-generating with incomplete replication.
Study Flags
Red Flags
- •Absolute risk differences not reported
- •Findings are hypothesis-generating; COPD exacerbation was not replicated in UK Biobank and HUNT showed null asthma/COPD associations
- •Lifelong genetic exposure may not translate to therapeutic PCSK9 inhibition because of limited tissue penetration and short trial follow-up
Surprising Findings
The PCSK9 genetic score was linked to 261% higher relative odds of fatal COPD exacerbation among people with pre-existing COPD (OR 3.61).
The effect size is large for a genetic variant, and it appears only in those with existing COPD, not in prevalent COPD itself.
Practical Takeaways
If you have COPD and are on or considering a PCSK9 inhibitor, discuss respiratory symptoms with your doctor—but do not stop any medication without medical advice.
RCT reviewsReviews of RCTs (Meta-analyses)
Max 100Randomized TrialsRandomized Trials
Max 90Reviews of Cohort StudiesReviews of Cohort Studies
Max 85Cohort StudiesCohort Studies
Max 72Reviews of Case-Control StudiesReviews of Case-Control Studies
Max 63Case-Control StudiesCase-Control Studies
Max 58Cross-Sectional & Case SeriesCross-Sectional & Case Series
Max 50Expert OpinionExpert Opinion
Max 548 / 100
Probability of being correct
Groups of people are followed over time to see who develops an outcome. Strong for identifying risk factors and associations, but cannot prove causation as firmly as RCTs.
Human Cohort Study
Subject
Moderate probability
on the GRADE evidence scale
This study looked at people's genes and their health over many years. It found that certain gene changes linked to lower cholesterol are also linked to fewer heart problems but more lung infections. But it can't prove that a medicine that mimics these genes would cause the same effects.
Strengths
- Large prospective cohort with >100,000 genotyped participants
- Use of functional PCSK9 loss-of-function variant and genetic score
- Replication in UK Biobank and trans-ancestry meta-analysis
Weaknesses
- Observational design cannot establish causation
- Genetic instruments may be subject to pleiotropy
- PCSK9 genetic score explains only 1.2% of LDL-C variance
Methodology
Evidence Keywords
Statistical Reporting
Scoring
How strong is this study?
The study is very large and followed people for a long time, and it checked its findings in another country. That makes the links more reliable, but it's still not a randomized drug trial, so we can't be sure about cause and effect.
0 / 100
- COI disclosureconflicts of interest not disclosed
- Data availabilitydata not shared
- Code availabilitycode not shared
25 / 100
- Randomizationnot randomized
- Blindingblinding unclear
- Control groupno control group
- Sample size (n=100706)+20/20
- Follow-upno follow-up reported
100 / 100
77 / 100
- P-values+15/15
- Effect size+20/20
- Confidence intervals+15/15
- Pre-registrationnot pre-registered
Each component is scored out of 100 and then capped by the study design — a case series cannot reach the ceiling a randomised trial can, however well it is reported.
Where it sits
RCT reviewsReviews of RCTs (Meta-analyses)
Max 100Randomized TrialsRandomized Trials
Max 90Reviews of Cohort StudiesReviews of Cohort Studies
Max 85Cohort StudiesCohort Studies
Max 72Reviews of Case-Control StudiesReviews of Case-Control Studies
Max 63Case-Control StudiesCase-Control Studies
Max 58Cross-Sectional & Case SeriesCross-Sectional & Case Series
Max 50Expert OpinionExpert Opinion
Max 548 / 100
Probability of being correct
Groups of people are followed over time to see who develops an outcome. Strong for identifying risk factors and associations, but cannot prove causation as firmly as RCTs.
This design cannot establish causation — the findings describe an association, not a cause. Observational cohort with genetic instruments; randomization to genotype is not randomization to treatment; potential confounding, pleiotropy, and linkage disequilibrium; cannot prove that PCSK9 inhibition causes respiratory outcomes.
COI Unknown
Could not determine conflict of interest status
No conflict of interest or funding statements were present in the provided text; the study appears to be an academic analysis of the China Kadoorie Biobank and UK Biobank, but COI/funding information cannot be determined from the available excerpt.
The provided text is truncated and lacks a Conflict of Interest, Funding, or Author Contributions section. No author affiliations or financial relationships are listed. The study uses data from China Kadoorie Biobank and UK Biobank, with assays by Beckman Coulter and Nightingale Health Ltd, but no author-level COI is disclosed.
Standing
Who’s using this study?
The videos and claims on this site that lean on this study, and the researchers who wrote it.
1 video from Dr Brad Stanfield cite this study, drawing 1 claim from it.
- Very strong evidence
Randomized or controlled trials support this claim, alongside consistent supporting evidence.
Evidence
Authored by
184 researchersIf this is your work, this is how we attribute it on Fit Body Science. Michael V. Holmes is listed as the lead author.