Human genetics uncovers <i>MAP3K15</i> as an obesity-independent therapeutic target for diabetes-Reference-Cited by-同舟云学术

Human genetics uncovers MAP3K15 as an obesity-independent therapeutic target for diabetes

Published:2022-11-18 Issue:46 Volume:8 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Nag Abhishek¹^ORCID,Dhindsa Ryan S.²^ORCID,Mitchell Jonathan¹,Vasavda Chirag²^ORCID,Harper Andrew R.¹,Vitsios Dimitrios¹^ORCID,Ahnmark Andrea³^ORCID,Bilican Bilada⁴^ORCID,Madeyski-Bengtson Katja⁴,Zarrouki Bader³,Zoghbi Anthony W.²,Wang Quanli²,Smith Katherine R.¹^ORCID,Alegre-Díaz Jesus⁵^ORCID,Kuri-Morales Pablo⁵^ORCID,Berumen Jaime⁵^ORCID,Tapia-Conyer Roberto⁵^ORCID,Emberson Jonathan⁶^ORCID,Torres Jason M.⁶^ORCID,Collins Rory⁶^ORCID,Smith David M.⁷^ORCID,Challis Benjamin⁸^ORCID,Paul Dirk S.¹^ORCID,Bohlooly-Y Mohammad⁴,Snowden Mike⁹,Baker David¹⁰^ORCID,Fritsche-Danielson Regina¹¹^ORCID,Pangalos Menelas N.¹²^ORCID,Petrovski Slavé¹¹³^ORCID

Affiliation:

1. Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.

2. Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA, USA.

3. Bioscience Metabolism, Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

4. Discovery Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

5. Faculty of Medicine, National Autonomous University of Mexico, Copilco Universidad, Coyoacán, 4360 Ciudad de México, Mexico.

6. Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, England, UK.

7. Emerging Innovations, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.

8. Translational Science and Experimental Medicine, Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.

9. Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.

10. Bioscience Metabolism, Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.

11. Early CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

12. BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.

13. Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, Australia.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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