Austin Health

Title
Human genetics uncovers MAP3K15 as an obesity-independent therapeutic target for diabetes.
Publication Date
2022-11-18
Author(s)
Nag, Abhishek
Dhindsa, Ryan S
Mitchell, Jonathan
Vasavda, Chirag
Harper, Andrew R
Vitsios, Dimitrios
Ahnmark, Andrea
Bilican, Bilada
Madeyski-Bengtson, Katja
Zarrouki, Bader
Zoghbi, Anthony W
Wang, Quanli
Smith, Katherine R
Alegre-Díaz, Jesus
Kuri-Morales, Pablo
Berumen, Jaime
Tapia-Conyer, Roberto
Emberson, Jonathan
Torres, Jason M
Collins, Rory
Smith, David M
Challis, Benjamin
Paul, Dirk S
Bohlooly-Y, Mohammad
Snowden, Mike
Baker, David
Fritsche-Danielson, Regina
Pangalos, Menelas N
Petrovski, Slavé
Type of document
Journal Article
OrcId
0000-0002-4638-2433
0000-0002-8965-0813
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0000-0003-4558-4698
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0000-0002-8939-5445
0000-0001-8932-4631
0000-0002-3057-2654
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0000-0002-0329-5938
0000-0001-9390-3871
0000-0002-0704-9507
0000-0001-6707-3317
0000-0003-3814-2904
0000-0001-7792-9422
0000-0002-7537-7035
0000-0001-8288-8602
0000-0001-6831-280X
0000-0002-1130-2851
0000-0002-8230-0116
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0000-0002-8020-3275
0000-0003-0582-6429
0000-0001-9783-0956
0000-0002-1527-961X
DOI
10.1126/sciadv.add5430
Abstract
We performed collapsing analyses on 454,796 UK Biobank (UKB) exomes to detect gene-level associations with diabetes. Recessive carriers of nonsynonymous variants in MAP3K15 were 30% less likely to develop diabetes (P = 5.7 × 10-10) and had lower glycosylated hemoglobin (β = -0.14 SD units, P = 1.1 × 10-24). These associations were independent of body mass index, suggesting protection against insulin resistance even in the setting of obesity. We replicated these findings in 96,811 Admixed Americans in the Mexico City Prospective Study (P < 0.05)Moreover, the protective effect of MAP3K15 variants was stronger in individuals who did not carry the Latino-enriched SLC16A11 risk haplotype (P = 6.0 × 10-4). Separately, we identified a Finnish-enriched MAP3K15 protein-truncating variant associated with decreased odds of both type 1 and type 2 diabetes (P < 0.05) in FinnGen. No adverse phenotypes were associated with protein-truncating MAP3K15 variants in the UKB, supporting this gene as a therapeutic target for diabetes.
Link
Citation
Science Advances 2022; 8(46)
Jornal Title
Science Advances
ISSN
2375-2548

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