Loss-of-function mutations in SLC30A8 protect against type 2 diabetes
Open accessAbstract
Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
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Data from patients with truncating gene variants suggest that reduced activity of ZnT8 is protective against T2DM.
“Although it was originally predicted that this variant increases T2DM risk, data from patients with truncating gene variants suggest that reduced activity of ZnT8 is actually protective (187).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [187]
Founder populations such as those from Finland and Iceland have provided multiple examples of otherwise rare risk alleles driven to higher frequency locally through drift and/or selection.
“Founder populations (such as those from Finland and Iceland) have provided multiple examples of otherwise rare risk alleles driven to higher frequency locally through drift and/or selection49–52.”
From A brief history of human disease genetics (2020) · cites this paper as [49]
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Self-citation
- Authors
- Go-T2D Consortium, Flannick, J., T2D-GENES Consortium, Thorleifsson, G., Beer, N. L., Jacobs, S. B. R., Grarup, N., Burtt, N. P., Mahajan, A., Fuchsberger, C., Atzmon, G., Benediktsson, R., Blangero, J., Bowden, D. W., Brandslund, I., Brosnan, J., Burslem, F., Chambers, J., Cho, Y. S., Christensen, C., Douglas, D. A., Duggirala, R., Dymek, Z., Farjoun, Y., Fennell, T., Fontanillas, P., Forsén, T., Gabriel, S., Glaser, B., Gudbjartsson, D. F., Hanis, C., Hansen, T., Hreidarsson, A. B., Hveem, K., Ingelsson, E., Isomaa, B., Johansson, S., Jørgensen, T., Jørgensen, M. E., Kathiresan, S., Kong, A., Kooner, J., Kravic, J., Laakso, M., Lee, J.-Y., Lind, L., Lindgren, C. M., Linneberg, A., Masson, G., Meitinger, T., Mohlke, K. L., Molven, A., Morris, A. P., Potluri, S., Rauramaa, R., Ribel-Madsen, R., Richard, A.-M., Rolph, T., Salomaa, V., Segrè, A. V., Skärstrand, H., Steinthorsdottir, V., Stringham, H. M., Sulem, P., Tai, E. S., Teo, Y. Y., Teslovich, T., Thorsteinsdottir, U., Trimmer, J. K., Tuomi, T., Tuomilehto, J., Vaziri-Sani, F., Voight, B. F., Wilson, J. G., Boehnke, M., McCarthy, M. I., Njølstad, P. R., Pedersen, O., Groop, L., Cox, D. R., Stefansson, K., & Altshuler, D.
- Affiliations
- Broad Institute (US)
- University of Copenhagen (DK)
- Centre for Human Genetics (GB)
- University of Michigan (US)
- Albert Einstein College of Medicine (US)
- National University Hospital of Iceland (IS)
- Texas Biomedical Research Institute (US)
- Wake Forest University Health Sciences (US)
- University of Southern Denmark (DK)
- Pfizer (United States) (US)
- National Health Service (GB)
- Hallym University (KR)
- Vejle Sygehus (DK)
- Lund University (SE)
- University of Helsinki (FI)
- deCODE Genetics (Iceland) (IS)
- The University of Texas Health Science Center at Houston (US)
- Norwegian University of Science and Technology (NO)
- Uppsala University (SE)
- Folkhälsans Forskningscentrum (FI)
- Haukeland University Hospital (NO)
- University of Eastern Finland (FI)
- Korea National Institute of Health (KR)
- Institut für Humangenetik (DE)
- University of North Carolina at Chapel Hill (US)
- Kuopio University Hospital (FI)
- Finnish Institute for Health and Welfare (FI)
- National University of Singapore (SG)
- Agency for Science, Technology and Research (SG)
- Universität für Weiterbildung Krems (AT)
- University of Mississippi Medical Center (US)
- Corresponding author
- Altshuler, David
- ORCID
- Flannick, Jason
- Beer, Nicola L
- Jacobs, Suzanne B R
- Grarup, Niels
- Burtt, Noël P
- Mahajan, Anubha
- Fuchsberger, Christian
- Atzmon, Gil
- Benediktsson, Rafn
- Blangero, John
- Brandslund, Ivan
- Chambers, John
- Cho, Yoon Shin
- Duggirala, Ravindranath
- Farjoun, Yossi
- Fontanillas, Pierre
- Gabriel, Stacey
- Gudbjartsson, Daniel F
- Hanis, Craig
- Hansen, Torben
- Hveem, Kristian
- Ingelsson, Erik
- Johansson, Stefan
- Jørgensen, Torben
- Jørgensen, Marit Eika
- Kathiresan, Sekar
- Kong, Augustine
- Kooner, Jaspal
- Laakso, Markku
- Lee, Jong-Young
- Lind, Lars
- Lindgren, Cecilia M
- Linneberg, Allan
- Meitinger, Thomas
- Mohlke, Karen L
- Molven, Anders
- Morris, Andrew P
- Rolph, Tim
- Salomaa, Veikko
- Segrè, Ayellet V
- Stringham, Heather M
- Sulem, Patrick
- Tai, E Shyong
- Tuomilehto, Jaakko
- Voight, Benjamin F
- Wilson, James G
- Boehnke, Michael
- McCarthy, Mark I
- Njølstad, Pål R
- Pedersen, Oluf
- Groop, Leif
- Cox, David R
- Altshuler, David
- Venue
- Nature Genetics
- Published
- 2014-03-02
- Volume
- 46
- Issue
- 4
- Pages
- 357-363
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC4051628
- OpenAlex
- W2132484969
- Cited by
- 492
- References
- 29
- Citations by year
- 2026: 21 · 2025: 24 · 2024: 27 · 2023: 21 · 2022: 25 · 2021: 32 · 2020: 35 · 2019: 45 · 2018: 48 · 2017: 51 · 2016: 59 · 2015: 65 · 2014: 36
- FWCI
- 46.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- VBN Forskningsportal (Aalborg Universitet) (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- WOS
- Funders
- Doris Duke Charitable Foundation
- Wellcome Trust (098017, 098381, WT098017, WT090367, WT098381, WT064890, WT090532, 090532)
- National Institute for Health and Care Research (NF-SI-0611-10099)
- Diabetes UK (11/0004348)
- Lunds Universitet
- Novo Nordisk Fonden (NNF13OC0005637)
- National Institutes of Health (n01hc95170-30-0-1, n01hc95171-31-0-1, 5rc2dk088389-02, n01hc95172-31-0-1)
- National Heart, Lung, and Blood Institute (N01 HC095171, N01 HC095172, N01 HC095170)
- National Human Genome Research Institute (U54HG003067, Z01HG000024, T32HG000040)
- National Cancer Institute (R13CA124293)
- National Institute of General Medical Sciences (T32GM007748)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01DK085526, U01DK085584, U01DK085501, R01DK072193, U01DK062370, U01DK085524, RC2-DK088389, U01DK085545, DK088389, R01DK098032, R01DK093757, R01DK062370)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- SLC30A8, zinc transporter 8, zinc transporters, type 2 diabetes, loss-of-function mutations, truncating mutations, haploinsufficiency, diabetes risk, glucose concentration, proinsulin, therapeutic target
- MeSH terms
- Zinc Transporter 8, Animals, Base Sequence, Blood Glucose, Diabetes Mellitus, Type 2, Genotype, Humans, Molecular Sequence Data, Proinsulin, Ion Transport, Sequence Analysis, DNA, Mice, Knockout, Mutation, Missense, Cation Transport Proteins, Mice, Genetic Association Studies
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