🚨 Publication alert: largest to date multiancestry exome analysis of body fat distribution discovers INHBE mutations associated with favorable adiposity and PROTECTION from diabetes! 🚨
Out today in @NatureComms
👇🧵 key takeaways below…
nature.com/articles/s4146…
Fat distribution: MAJOR BUT OVERLOOKED risk factor for diabetes & heart attacks globally
Storing⬆️fat in waist and⬇️in hips gives ⬆️⬆️⬆️risk – independent of overall body fat (👇)
🚨Lots of drug development in obesity; almost none for fat distribution
nature.com/articles/s4146…
Fat distribution is partly in our 🧬
nature.com/articles/s4146…
#exome #diabetes #obesity #NASH
Mutations in fat tissue genes ➡️ lipodystrophies
⬇️fat but⬆️diabetes
Counterintuitive but, calories not stored in adipose end up in liver, circulation (hyperlipidemia) & other undesirable places
academic.oup.com/edrv/article/3…
rcpjournals.org/content/clinme…
@StephenORahilly @DanielJDrucker
#GWAS ➡️ 100s common variants, often at adipose genes
nature.com/articles/natur…
jamanetwork.com/journals/jama/…
academic.oup.com/hmg/article/28…
nature.com/articles/s4146…
@amitvkhera @ceclindgren @saralpulit @saaket_agrawal
Inability to expand adipose to store excess calories➡️diabetes, 🫀 disease
Genetically⬆️WHR ➡️diabetes, 🫀 disease
diabetesjournals.org/diabetes/artic…
jamanetwork.com/journals/jama/…
nature.com/articles/ng.37…
@connoremdin @skathire @sguyenet @markmccarthyoxf @ethanjweiss @YaghootkarH @timfrayling
Note:
Mechanisms leading to ⬆️WHR
via ⬆️waist fat (abdominal obesity) OR
via ⬇️hip fat (subtle partial lipodystrophy)
can be distinct AND
both associated with ⬆️cardiometabolic risk
jamanetwork.com/journals/jama/…
Can we find possible new targets to ⬇️ this risk? 💉💊
Exome sequencing + 100,000s 👫+
multiple ancestries (diversity of 🧬 & environment)
= Proven recipe for new gene discovery
PROTECTIVE mutations ➡️ possible targets for therapy
It works!
science.org/doi/10.1126/sc…
nature.com/articles/s4158…
nejm.org/doi/full/10.10…
We analyzed exomes from >618,000 👫 of 5 ancestries from 🇬🇧🇲🇽🇸🇪
Largest & most ancestrally-diverse analysis for fat distribution thanks to @UIME_UNAM @Oxford_NDPH @GeisingerRsrch @lunduniversity @uk_biobank
➡️16 genes with rare coding variants associated with fat distribution
Discovered genes are enriched for:
➡️Mendelian lipodystrophy genes (PPARG, PLIN1)
➡️Genes expressed in ADIPOSE = critical energy-storing tissue
Association effects are:
➡️6-fold > than common variants
➡️Often stronger in women than men
⚡️ Rare mutations in liver-expressed INHBE associated with
➡️favorable fat distribution (lower WHR, larger hips)
➡️favorable metabolic profile (lower liver enzymes, lower triglycerides, lower HbA1c)
➡️~28% lower risk of type 2 diabetes!
Highlights & insights:
1⃣Dozens of rare coding variants with large effect on fat distribution
2⃣Enriched for lipodystrophy genes, adipose genes
3⃣INHBE LOF➡️favorable adiposity and diabetes protection➡️possible therapeutic target
And MORE – full story: nature.com/articles/s4146…
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