Thread by @jsdron

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🧵

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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.

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.

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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.

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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!

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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.

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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! 💊

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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!

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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! 🙏