Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/31696
Title: Human genetics uncovers MAP3K15 as an obesity-independent therapeutic target for diabetes.
Austin Authors: 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
Affiliation: Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Bioscience Metabolism, Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Discovery Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA, USA.
Faculty of Medicine, National Autonomous University of Mexico, Copilco Universidad, Coyoacán, 4360 Ciudad de México, Mexico.
Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, England, UK.
Emerging Innovations, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Translational Science and Experimental Medicine, Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Discovery Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Bioscience Metabolism, Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Medicine (University of Melbourne)
Issue Date: 18-Nov-2022
Date: 2022
Publication information: Science Advances 2022; 8(46)
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.
URI: https://ahro.austin.org.au/austinjspui/handle/1/31696
DOI: 10.1126/sciadv.add5430
ORCID: 0000-0002-4638-2433
0000-0002-8965-0813
0000-0003-4558-4698
0000-0002-8939-5445
0000-0001-8932-4631
0000-0002-3057-2654
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
0000-0002-8020-3275
0000-0003-0582-6429
0000-0001-9783-0956
0000-0002-1527-961X
Journal: Science Advances
Start page: eadd5430
PubMed URL: 36383675
ISSN: 2375-2548
Type: Journal Article
Subjects: Diabetes Mellitus, Type 2/genetics
Monocarboxylic Acid Transporters/genetics
Obesity/genetics
MAP Kinase Kinase Kinases/genetics
Appears in Collections:Journal articles

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