Those with DNA mutations inactivating APOB or PCSK9 genes have ⬇️ LDL-C and protection from🫀
disease.
We identify 801 carriers and observe
stable LDL-C reductions of ~47 mg/dL, corresponding to a 49% ⬇️🫀disease risk.
Details in @JamaCardio! jamanetwork.com/journals/jamac…
1/10🧵
disease.
We identify 801 carriers and observe
stable LDL-C reductions of ~47 mg/dL, corresponding to a 49% ⬇️🫀disease risk.
Details in @JamaCardio! jamanetwork.com/journals/jamac…
1/10🧵
2/10
In 2006, Cohen et al. reported PCSK9 mutations in Black individuals associated with an 89% ⬇️🫀disease risk, but this was based on only 1 event in carriers, resulting in a 95% CI ranging from 19 to 98%.
As an update from this work and other seminal observations…
In 2006, Cohen et al. reported PCSK9 mutations in Black individuals associated with an 89% ⬇️🫀disease risk, but this was based on only 1 event in carriers, resulting in a 95% CI ranging from 19 to 98%.
As an update from this work and other seminal observations…
3/10
… we used 🧬 and 🏥 data for 200K diverse individuals from @nih_nhbli and @uk_biobank cohorts to
update prevalence estimates of APOB and PCSK9 mutations and
their associated effect estimates for LDL-C and 🫀disease risk.
… we used 🧬 and 🏥 data for 200K diverse individuals from @nih_nhbli and @uk_biobank cohorts to
update prevalence estimates of APOB and PCSK9 mutations and
their associated effect estimates for LDL-C and 🫀disease risk.
4/10
We identified mutation carriers and noncarriers in 19K @nih_nhbli cohort participants.
At enrollment, we observed mean LDL-C of 80 mg/dL in carriers vs 128 mg/dL in noncarriers – a 49 mg/dL difference.
This diff in LDL-C was apparent early in age and stable over ⏰ time.
We identified mutation carriers and noncarriers in 19K @nih_nhbli cohort participants.
At enrollment, we observed mean LDL-C of 80 mg/dL in carriers vs 128 mg/dL in noncarriers – a 49 mg/dL difference.
This diff in LDL-C was apparent early in age and stable over ⏰ time.
5/10
Over a median follow-up time of 21.5 years, incident 🫀events occurred in 8.6% of carriers vs 16.0% of noncarriers,
corresponding to an adjusted 49% ⬇️🫀disease risk.
This lower risk was observed despite 8-fold more utilization of 💊 LLT in noncarriers than carriers.
Over a median follow-up time of 21.5 years, incident 🫀events occurred in 8.6% of carriers vs 16.0% of noncarriers,
corresponding to an adjusted 49% ⬇️🫀disease risk.
This lower risk was observed despite 8-fold more utilization of 💊 LLT in noncarriers than carriers.
6/10
Even in the context of other risk factors (e.g., 🚬), the estimated 10-year 🫀disease risk was:
2.7% in carriers who DO smoke 🚬
3.0% in noncarriers who do NOT smoke 🚭
These protective 🧬 mutations more than offset risk conferred by smoking, HTN, diabetes, and others!
Even in the context of other risk factors (e.g., 🚬), the estimated 10-year 🫀disease risk was:
2.7% in carriers who DO smoke 🚬
3.0% in noncarriers who do NOT smoke 🚭
These protective 🧬 mutations more than offset risk conferred by smoking, HTN, diabetes, and others!
7/10
We also predicted 🫀disease risk at 55, 65, and 75 years of age in 190K participants from the @uk_biobank.
While risk increased with age, carriers had 📉 lower predicted risk – almost half – than what was predicted for noncarriers.
We also predicted 🫀disease risk at 55, 65, and 75 years of age in 190K participants from the @uk_biobank.
While risk increased with age, carriers had 📉 lower predicted risk – almost half – than what was predicted for noncarriers.
8/10
Cumulative exposure to LDL-C (‘mg/dL-years’) is a primary driver of 🫀disease, which is rare when exposure is <5,000 mg/dL-years.
We estimate that individuals with protective 🧬mutation reach this point at age 50 vs 34 years for noncarriers.
Emphasis on ⬇️ LDL-C ASAP! 💊
Cumulative exposure to LDL-C (‘mg/dL-years’) is a primary driver of 🫀disease, which is rare when exposure is <5,000 mg/dL-years.
We estimate that individuals with protective 🧬mutation reach this point at age 50 vs 34 years for noncarriers.
Emphasis on ⬇️ LDL-C ASAP! 💊
9/10
0.4% of 209,537 individuals had an APOB or PCSK9🧬mutation and enjoyed ⬇️ LDL-C – about 50 mg/dL 📉 than noncarriers, corresponding to a 49% ⬇️🫀disease risk.
Further ⬇️🫀disease risk with further ⬇️ in LDL-C from therapies that achieve >>50% knockdown of APOB or PCSK9!
0.4% of 209,537 individuals had an APOB or PCSK9🧬mutation and enjoyed ⬇️ LDL-C – about 50 mg/dL 📉 than noncarriers, corresponding to a 49% ⬇️🫀disease risk.
Further ⬇️🫀disease risk with further ⬇️ in LDL-C from therapies that achieve >>50% knockdown of APOB or PCSK9!
10/10
Thanks to @nih_nhbli #BioDataCatalyst Fellows program for supporting this work, @nih_nhlbi #TOPMed program, @uk_biobank, and co-authors for invaluable contributions! 🤩🤝
And thanks to @JAMA_Cardio team and @AnnMarieNavar for their assistance and support! 🙏
Thanks to @nih_nhbli #BioDataCatalyst Fellows program for supporting this work, @nih_nhlbi #TOPMed program, @uk_biobank, and co-authors for invaluable contributions! 🤩🤝
And thanks to @JAMA_Cardio team and @AnnMarieNavar for their assistance and support! 🙏
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