Thread by @Niek_verweij

Our discovery of mutations in the CIDEB gene that protect against liver disease is published in @NEJM, leading to possible #RNAi therapeutics for NASH by Regeneron & Alnylam. 🚨
nejm.org/doi/full/10.10…

A short summary of the key findings 🧬🧵↓

Liver disease is a big unsolved problem:

1⃣ 1 in 3 adults globally have fatty liver, often due to #obesity.

2⃣ Liver inflammation due to fat (NASH) is becoming #1 cause of liver transplant.

3⃣No approved therapies.

Where can we find possible NASH targets?

➡️In our DNA!

Studies of common genetic variants found PNPLA3 (2008 - risk-increasing, rb.gy/rgyped) and HSD17B13 (2018 – protective, rb.gy/mn2rce) variants associated with liver disease that are now potential #RNAi therapeutics currently in development.

Strengths of multiancestry #exome sequencing in 100,000s people:

1⃣) Rare mutations effects often >>> common variant effects (rb.gy/xlgk96)

2⃣) protective mutations ➡️potential therapeutic targets, e.g. ANGPTL3 rb.gy/y2bjcn, GPR75 rb.gy/f9cftm

Can we find rare mutations in humans with large protective effect on liver disease?

Yes, it turns out, we can!

In >540K exomes, 1 in 700 people with a broken copy of CIDEB had 50% lower risk of nonalcoholic liver disease, cirrhosis and other liver diseases (alcoholic, viral).

CIDEB associations appear a few times larger than HSD17B13 ones. bit.ly/3biYQhQ
Powered by sequencing in @uk_biobank @GeisingerRsrch and more.

Validation is a key for large-scale human genetics.
Important: CIDEB associations validate across different ancestries.

We studied 5 ancestry groups, but European analysis still the largest: we need to do better as a field!
#DiversityInGenomics #BreaktheBias #DEI

Importantly CIDEB mutations show the largest protection of liver disease in obese people, also lower liver inflammation in bariatric surgery patients from @GeisingerRsrch: A very important finding because #obesity is THE #1 risk factor for #NASH.

For more on obesity genetics: @Nature @ScienceMagazine @StephenORahilly @DanielJDrucker @doc_locke
nature.com/articles/43185
nature.com/articles/natur…
science.org/doi/10.1126/sc…
science.org/doi/10.1126/sc…

On the biology side: CIDE-family proteins are known to enable buildup of fat droplets within cells. We experimentally showed that in liver cells, silencing CIDEB with siRNA prevents fat buildup and formation of larger lipid droplets.
Lipid droplets play a central role in NASH!

The amazing thing of @RegeneronDNA is that we now “pass the baton” to our colleagues and top-notch medicine developers to drive the CIDEB program forward.

And now back at it: unearthing protective human genetics that may lead to new medicines.Stay tuned!
bit.ly/3biYQhQ