The Influence of Rare Genetic Variation in SLC30A8 on Diabetes Incidence and β-Cell Function
Open accessAbstract
CONTEXT/OBJECTIVE: The variant rs13266634 in SLC30A8, encoding a β-cell-specific zinc transporter, is associated with type 2 diabetes. We aimed to identify other variants in SLC30A8 that increase diabetes risk and impair β-cell function, and test whether zinc intake modifies this risk. DESIGN/OUTCOME: We sequenced exons in SLC30A8 in 380 Diabetes Prevention Program (DPP) participants and identified 44 novel variants, which were genotyped in 3445 DPP participants and tested for association with diabetes incidence and measures of insulin secretion and processing. We examined individual common variants and used gene burden tests to test 39 rare variants in aggregate. RESULTS: We detected a near-nominal association between a rare-variant genotype risk score and diabetes risk. Five common variants were associated with the oral disposition index. Various methods aggregating rare variants demonstrated associations with changes in oral disposition index and insulinogenic index during year 1 of follow-up. We did not find a clear interaction of zinc intake with genotype on diabetes incidence. CONCLUSIONS: Individual common and an aggregate of rare genetic variation in SLC30A8 are associated with measures of β-cell function in the DPP. Exploring rare variation may complement ongoing efforts to uncover the genetic influences that underlie complex diseases.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin
(2002) · New England Journal of Medicine · doi:10.1056/nejmoa012512 · Cited by 19,011 · see citing works
Rare-Variant Association Testing for Sequencing Data with the Sequence Kernel Association Test
Wu, M. C., Lee, S., Cai, T., Li, Y., Boehnke, M., & Lin, X. (2011) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.05.029 · Cited by 2,317 · see citing works
New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk
DIAGRAM Consortium, Dupuis, J., GIANT Consortium, Global BPgen Consortium, Anders Hamsten on behalf of Procardis Consortium, the MAGIC investigators, Langenberg, C., Prokopenko, I., Saxena, R., Soranzo, N., et al. (2010) · Nature Genetics · doi:10.1038/ng.520 · Cited by 2,166 · see citing works
Li, B., & Leal, S. M. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.06.024 · Cited by 1,527 · see citing works
Dietary factors influencing zinc absorption.
Lönnerdal, B. (2000) · Journal of NutriLife · doi:10.1093/jn/130.5.1378s · Cited by 1,003 · see citing works
Seltzer, H. S., Allen, E. W., Herron, A. L., & Brennan, M. T. (1967) · Journal of Clinical Investigation · doi:10.1172/jci105534 · Cited by 819 · see citing works
(1999) · Diabetes Care · doi:10.2337/diacare.22.4.623 · Cited by 725 · see citing works
Utzschneider, K. M., Prigeon, R. L., Faulenbach, M. V., Tong, J., Carr, D. B., Boyko, E. J., Leonetti, D. L., McNeely, M. J., Fujimoto, W. Y., & Kahn, S. E. (2009) · Diabetes Care · doi:10.2337/dc08-1478 · Cited by 572 · see citing works
Self-citationChimienti, F., Devergnas, S., Favier, A. E., & Seve, M. (2004) · Diabetes · doi:10.2337/diabetes.53.9.2330 · Cited by 470 · see citing works
The genetics of type 2 diabetes: what have we learned from GWAS?
Billings, L. K., & Florez, J. C. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05838.x · Cited by 386 · see citing works
Self-citationNicolson, T. J., Bellomo, E. A., Wijesekara, N., Loder, M. K., Baldwin, J. M., Gyulkhandanyan, A. V., Koshkin, V., Tarasov, A. I., Carzaniga, R., Kronenberger, K., et al. (2009) · Diabetes · doi:10.2337/db09-0551 · Cited by 372 · see citing works
Chimienti, F., Devergnas, S., Pattou, F., Schuit, F., Garcia-Cuenca, R., Vandewalle, B., Kerr-Conte, J., Van Lommel, L., Grunwald, D., Favier, A., et al. (2006) · Journal of Cell Science · doi:10.1242/jcs.03164 · Cited by 349 · see citing works
Wijesekara, N., Dai, F. F., Hardy, A. B., Raeisi‐Giglou, P., Bhattacharjee, A., Koshkin, V., Chimienti, F., Gaisano, H. Y., Rutter, G. A., & Wheeler, M. B. (2010) · Diabetologia · doi:10.1007/s00125-010-1733-9 · Cited by 302 · see citing works
Kirchhoff, K., Machicao, F. E., Haupt, A., Schäfer, S., Tschritter, O., Staiger, H., Stefan, N., Häring, H.-U., & Fritsche, A. (2008) · Diabetologia · doi:10.1007/s00125-008-0926-y · Cited by 264 · see citing works
Ingelsson, E., Langenberg, C., Hivert, M., Prokopenko, I., Lyssenko, V., Dupuis, J., Mägi, R., Sharp, S. J., Jackson, A., Assimes, T. L., et al. (2010) · Diabetes · doi:10.2337/db09-1568 · Cited by 254 · see citing works
Self-citationDeletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion
Pound, L. D., Sarkar, S. A., Benninger, R. K. P., Wang, Y., Suwanichkul, A., Shadoan, M. K., Printz, R. L., Oeser, J. K., Lee, C. E., Piston, D. W., et al. (2009) · Biochemical Journal · doi:10.1042/bj20090530 · Cited by 167 · see citing works
Extension of Type 2 Diabetes Genome-Wide Association Scan Results in the Diabetes Prevention Program
Moore, A. F., Jablonski, K. A., McAteer, J. B., Saxena, R., Pollin, T. I., Franks, P. W., Hanson, R. L., Shuldiner, A. R., Knowler, W. C., Altshuler, D., et al. (2008) · Diabetes · doi:10.2337/db08-0284 · Cited by 101 · see citing works
Self-citationTotal Zinc Intake May Modify the Glucose-Raising Effect of a Zinc Transporter (SLC30A8) Variant
Kanoni, S., Nettleton, J. A., Hivert, M., Ye, Z., van Rooij, F. J. A., Shungin, D., Sonestedt, E., Ngwa, J. S., Wojczynski, M. K., Lemaître, R. N., et al. (2011) · Diabetes · doi:10.2337/db11-0176 · Cited by 99 · see citing works
Self-citationDietary intake in the Diabetes Prevention Program cohort: baseline and 1-year post-randomization
Mayer‐Davis, E. J., Sparks, K. C., Km, H., Costacou, T., Lovejoy, J. C., Regensteiner, J. G., Hoskin, M. A., Kriska, A. M., & Bray, G. A. (2004) · Annals of Epidemiology · doi:10.1016/j.annepidem.2004.02.004 · Cited by 91 · see citing works
Self-citationMajithia, A. R., Jablonski, K. A., McAteer, J. B., Mather, K. J., Goldberg, R. B., Kahn, S. E., & Florez, J. C. (2011) · Diabetologia · doi:10.1007/s00125-011-2234-1 · Cited by 26 · see citing works
Self-citationKanoni, S., Nettleton, J. A., Hivert, M.-F., Ye, Z., van Rooij, F. J., Shungin, D., Sonestedt, E., Ngwa, J. S., Wojczynski, M. K., Lemaître, R. N., et al. (2011) · Apollo (University of Cambridge) · doi:10.17863/cam.17974 · Cited by 3 · see citing works
Self-citation
Flagged first, then by citations
11 of the 32 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Khan, I. A., Jahan, P., Hasan, Q. A., & Rao, P. (2018) · Diabetes & Metabolic Syndrome Clinical Research & Reviews · doi:10.1016/j.dsx.2018.11.035 · Cited by 117 · see citing works
Gene‐lifestyle interaction on risk of type 2 diabetes: A systematic review
Dietrich, S., Jacobs, S., Zheng, J., Meidtner, K., Schwingshackl, L., & Schulze, M. B. (2019) · Obesity Reviews · doi:10.1111/obr.12921 · Cited by 95 · see citing works
Genetic and inflammatory factors underlying gestational diabetes mellitus: a review
Ray, G. W., Zeng, Q., Kusi, P., Zhang, H., Shao, T., Yang, T., Wei, Y., Li, M., Che, X., & Guo, R. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1399694 · Cited by 76 · see citing works
The β Cell in Diabetes: Integrating Biomarkers With Functional Measures
Kahn, S. E., Chen, Y., Esser, N., Taylor, A. J., van Raalte, D. H., Zraika, S., & Verchere, C. B. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnab021 · Cited by 69 · see citing works
Self-citationMather, K. J., KIM, C., Christophi, C., Aroda, V. R., Knowler, W. C., EDELSTEIN, S., Florez, J. C., Labrie, F., Kahn, S. E., Goldberg, R. B., et al. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-2328 · Cited by 61 · see citing works
Self-citationFu, J., Han, L., Zhao, Y., Li, G., Zhu, Y., Yu, L. J., Li, M., Gao, S., & Willi, S. M. (2018) · Clinical Nutrition · doi:10.1016/j.clnu.2018.08.039 · Cited by 46 · see citing works
Importance of Zinc Transporter 8 Autoantibody in the Diagnosis of Type 1 Diabetes in Latin Americans
Gomes, K. F. B., Semzezem, C., Batista, R., Fukui, R. T., Santos, A. S., Correia, M. R. S., Passos‐Bueno, M. R., & da Silva, M. E. R. (2017) · Scientific Reports · doi:10.1038/s41598-017-00307-4 · Cited by 38 · see citing works
Association between SLC30A8 rs13266634 Polymorphism and Type 2 Diabetes Risk: A Meta-Analysis
Cheng, L. (2015) · Medical Science Monitor · doi:10.12659/msm.894052 · Cited by 37 · see citing works
Fu, J., Hou, C., Li, L., Feng, D., Li, G., Li, M., Li, C., Gao, S., & Li, M. (2016) · Cardiovascular Diabetology · doi:10.1186/s12933-016-0461-y · Cited by 33 · see citing works
Genetic Variations as Modifying Factors to Dietary Zinc Requirements—A Systematic Review
Day, K., Adamski, M. M., Dordevic, A. L., & Murgia, C. (2017) · Nutrients · doi:10.3390/nu9020148 · Cited by 33 · see citing works
Does Zinc Really “Metal” with Diabetes? The Epidemiologic Evidence
Manuel Ruz, O., Fernando Carrasco, N., Sánchez, A., Pérez, Á., & Rojas, P. (2016) · Current Diabetes Reports · doi:10.1007/s11892-016-0803-x · Cited by 20 · see citing works
The Contribution of Low-Frequency and Rare Coding Variation to Susceptibility to Type 2 Diabetes
Flannick, J. A. (2019) · Current Diabetes Reports · doi:10.1007/s11892-019-1142-5 · Cited by 15 · see citing works
GADA and anti‐ZnT8 complicate the outcome of phenotypic type 2 diabetes of adults
Haller‐Kikkatalo, K., Pruul, K., Kisand, K., Nemvalts, V., Reimand, K., & Uibo, R. (2015) · European Journal of Clinical Investigation · doi:10.1111/eci.12404 · Cited by 14 · see citing works
Type 2 Diabetes Prevention: Implications of Hemoglobin A1c Genetics
Leong, A., & Meigs, J. B. (2015) · The Review of Diabetic Studies · doi:10.1900/rds.2015.12.351 · Cited by 12 · see citing works
Billings, L. K., Jablonski, K. A., Pan, Q., Florez, J. C., Franks, P. W., Goldberg, R. B., Hivert, M.-F., Kahn, S. E., Knowler, W. C., Lee, C. G., et al. (2024) · Diabetes · doi:10.2337/db23-0761 · Cited by 11 · see citing works
Self-citationGenetic Polymorphisms and Zinc Status: Implications for Supplementation in Metabolic Diseases
Virgili, F., Ambra, R., McCormack, J. M., Simpson, E. E. A., Ciarapica, D., Barnaba, L., Azzini, E., & Polito, A. (2018) · Current Pharmaceutical Design · doi:10.2174/1381612824666181016155903 · Cited by 11 · see citing works
Complete loss of SLC30A8 in humans improves glucose metabolism and beta cell function
Lamarche, L. B., Koch, C., Khalid, S., Khan, M. Z., Zessis, R., Clement, M. E., Denning, D. P., Goldfine, A. B., Splawski, I., Abbasi, A., et al. (2025) · Diabetologia · doi:10.1007/s00125-025-06530-3 · Cited by 10 · see citing works
Self-citationMartínez-Morata, I., Dennehy, K., Chepurny, O. G., Delibaşı, T., Schilling, K., Navas‐Acién, A., & Muayed, M. E. (2025) · Journal of Trace Elements in Medicine and Biology · doi:10.1016/j.jtemb.2025.127733 · Cited by 6 · see citing works
Gene-Diet Interactions in Type 2 Diabetes
Cornelis, M. C. (2014) · Current Nutrition Reports · doi:10.1007/s13668-014-0095-1 · Cited by 6 · see citing works
ГЕНЕТИЧНІ МАРКЕРИ ЦУКРОВОГО ДІАБЕТУ 2 ТИПУ
Musiienko, V., & Марущак, М. І. (2020) · Medical and Clinical Chemistry · doi:10.11603/mcch.2410-681x.2019.v.i4.10688 · Cited by 5 · see citing works
SLC30A8: A Complex Road from Association to Function
Flannick, J. A., & Lowe, W. L. (2016) · Springer eBooks · doi:10.1007/978-3-319-01574-3_18 · Cited by 2 · see citing works
Khadra, K. M. A., Wahsha, M. A., & Al-Najjar, T. H. (2025) · Biomedical & Pharmacology Journal · doi:10.13005/bpj/3182 · Cited by 1 · see citing works
Brunke-Reese, D., Ssentongo, P., Ssentongo, A. E., Phillips, B. E., Pauli, E. M., Berg, A. S., Kelleher, S. L., & Soybel, D. I. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-02588 · Cited by 1 · see citing works
Complete loss of SLC30A8 in humans improves glucose metabolism and beta cell functionPreprint
Lamarche, L. B., Koch, C., Khalid, S., Zaman, M., Zessis, R., Clement, M. E., Denning, D. P., Goldfine, A. B., Abbasi, A., Harrow, J., et al. (2024) · medRxiv · doi:10.1101/2024.04.05.24305397 · Cited by 1 · see citing works
Self-citationNutrigenetics of Type 2 Diabetes
Qi, L., & Franks, P. W. (2016) · Springer eBooks · doi:10.1007/978-3-319-01574-3_26
Self-citationPinhas‐Hamiel, O., Zeitler, P. S., & Kelsey, M. M. (2017) · Contemporary Endocrinology · doi:10.1007/978-3-319-68192-4_24
Ghafouri-Taleghani, F., & Bahadoran, Z. (2026) · Current nutrition reports · doi:10.1007/s13668-026-00762-4 · Cited by 1 · see citing works
- Authors
- Billings, L. K., Jablonski, K. A., Ackerman, R. J., Taylor, A., Fanelli, R. R., McAteer, J. B., Guiducci, C., Delahanty, L. M., Dabelea, D., Kahn, S. E., Franks, P. W., Hanson, R. L., Maruthur, N. M., Shuldiner, A. R., Mayer-Davis, E. J., Knowler, W. C., Florez, J. C., & for the Diabetes Prevention Program Research Group, R.
- Affiliations
- Endeavor Health (US)
- George Washington University (US)
- Center for Human Genetic Research (L.K.B., R.J.A., A.T., R.R.F., J.B.M., J.C.F.)
- Broad Institute (US)
- Harvard University (US)
- Colorado School of Public Health (US)
- University of Washington (US)
- National Institutes of Health (US)
- Johns Hopkins University (US)
- University of Maryland, Baltimore (US)
- Department of Nutrition (E.J.M.-D.), University of North Carolina, Gillings School of Global Public Health, Chapel Hill, North Carolina 27599
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2014-05-01
- Volume
- 99
- Issue
- 5
- Pages
- E926-E930
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC4010688
- OpenAlex
- W2059497041
- Cited by
- 27
- References
- 32
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2021: 1 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 4 · 2015: 4 · 2014: 1
- FWCI
- 2.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK072041, L30 DK089944, 1-L30-DK-089944-01, P30DK079637, U01DK048489, P30DK017047, T32DK007028)
- 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, rare variants, type 2 diabetes, beta-cell function, zinc transporters, zinc intake, oral disposition index, insulinogenic index, gene burden, rs13266634, Diabetes Prevention Program, insulin secretion
- MeSH terms
- Zinc Transporter 8, Insulin Secretion, Adult, Alleles, Diabetes Mellitus, Type 2, Female, Gene Frequency, Humans, Insulin, Male, Middle Aged, Incidence, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Cation Transport Proteins, Insulin-Secreting Cells, Genetic Association Studies
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
