Loss-of-function mutations in SLC30A8 protect against type 2 diabetes

Jason Flannick; Gudmar Thorleifsson; Nicola L Beer; Suzanne B R Jacobs; Niels Grarup; Noël P Burtt; Anubha Mahajan; Christian Fuchsberger; Gil Atzmon; Rafn Benediktsson; John Blangero; Don W Bowden; Ivan Brandslund; Julia Brosnan; Frank Burslem; John Chambers; Yoon Shin Cho; Cramer Christensen; Desirée A Douglas; Ravindranath Duggirala; Zachary Dymek; Yossi Farjoun; Timothy Fennell; Pierre Fontanillas; Tom Forsén; Stacey Gabriel; Benjamin Glaser; Daniel F Gudbjartsson; Craig Hanis; Torben Hansen; Astradur B Hreidarsson; Kristian Hveem; Erik Ingelsson; Bo Isomaa; Stefan Johansson; Torben Jørgensen; Marit Eika Jørgensen; Sekar Kathiresan; Augustine Kong; Jaspal Kooner; Jasmina Kravic; Markku Laakso; Jong-Young Lee; Lars Lind; Cecilia M Lindgren; Allan Linneberg; Gisli Masson; Thomas Meitinger; Rasmus Ribel-Madsen; Oluf Pedersen; Go-T2D Consortium

doi:10.1038/ng.2915

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes

Jason Flannick, Gudmar Thorleifsson, Nicola L Beer, Suzanne B R Jacobs, Niels Grarup, Noël P Burtt, Anubha Mahajan, Christian Fuchsberger, Gil Atzmon, Rafn Benediktsson, John Blangero, Don W Bowden, Ivan Brandslund, Julia Brosnan, Frank Burslem, John Chambers, Yoon Shin Cho, Cramer Christensen, Desirée A Douglas, Ravindranath DuggiralaZachary Dymek, Yossi Farjoun, Timothy Fennell, Pierre Fontanillas, Tom Forsén, Stacey Gabriel, Benjamin Glaser, Daniel F Gudbjartsson, Craig Hanis, Torben Hansen, Astradur B Hreidarsson, Kristian Hveem, Erik Ingelsson, Bo Isomaa, Stefan Johansson, Torben Jørgensen, Marit Eika Jørgensen, Sekar Kathiresan, Augustine Kong, Jaspal Kooner, Jasmina Kravic, Markku Laakso, Jong-Young Lee, Lars Lind, Cecilia M Lindgren, Allan Linneberg, Gisli Masson, Thomas Meitinger, Rasmus Ribel-Madsen, Oluf Pedersen, Go-T2D Consortium

308 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Nature Genetics
Volume	46
Issue number	4
Pages (from-to)	357-63
Number of pages	7
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.2915
Publication status	Published - Apr 2014

Keywords

Animals
Base Sequence
Blood Glucose
Cation Transport Proteins
Diabetes Mellitus, Type 2
Genetic Association Studies
Genotype
Humans
Ion Transport
Mice
Mice, Knockout
Molecular Sequence Data
Mutation, Missense
Proinsulin
Sequence Analysis, DNA

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.2915

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Flannick, J., 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., ... Go-T2D Consortium (2014). Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nature Genetics, 46(4), 357-63. https://doi.org/10.1038/ng.2915

Flannick, J, Thorleifsson, G, Beer, NL, Jacobs, SBR, Grarup, N, Burtt, NP, Mahajan, A, Fuchsberger, C, Atzmon, G, Benediktsson, R, Blangero, J, Bowden, DW, Brandslund, I, Brosnan, J, Burslem, F, Chambers, J, Cho, YS, Christensen, C, Douglas, DA, Duggirala, R, Dymek, Z, Farjoun, Y, Fennell, T, Fontanillas, P, Forsén, T, Gabriel, S, Glaser, B, Gudbjartsson, DF, Hanis, C, Hansen, T, Hreidarsson, AB, Hveem, K, Ingelsson, E, Isomaa, B, Johansson, S, Jørgensen, T, Jørgensen, ME, Kathiresan, S, Kong, A, Kooner, J, Kravic, J, Laakso, M, Lee, J-Y, Lind, L, Lindgren, CM, Linneberg, A, Masson, G, Meitinger, T, Ribel-Madsen, R, Pedersen, O & Go-T2D Consortium 2014, 'Loss-of-function mutations in SLC30A8 protect against type 2 diabetes', Nature Genetics, vol. 46, no. 4, pp. 357-63. https://doi.org/10.1038/ng.2915

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title = "Loss-of-function mutations in SLC30A8 protect against type 2 diabetes",

abstract = "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.",

keywords = "Animals, Base Sequence, Blood Glucose, Cation Transport Proteins, Diabetes Mellitus, Type 2, Genetic Association Studies, Genotype, Humans, Ion Transport, Mice, Mice, Knockout, Molecular Sequence Data, Mutation, Missense, Proinsulin, Sequence Analysis, DNA",

author = "Jason Flannick and Gudmar Thorleifsson and Beer, {Nicola L} and Jacobs, {Suzanne B R} and Niels Grarup and Burtt, {No{\"e}l P} and Anubha Mahajan and Christian Fuchsberger and Gil Atzmon and Rafn Benediktsson and John Blangero and Bowden, {Don W} and Ivan Brandslund and Julia Brosnan and Frank Burslem and John Chambers and Cho, {Yoon Shin} and Cramer Christensen and Douglas, {Desir{\'e}e A} and Ravindranath Duggirala and Zachary Dymek and Yossi Farjoun and Timothy Fennell and Pierre Fontanillas and Tom Fors{\'e}n and Stacey Gabriel and Benjamin Glaser and Gudbjartsson, {Daniel F} and Craig Hanis and Torben Hansen and Hreidarsson, {Astradur B} and Kristian Hveem and Erik Ingelsson and Bo Isomaa and Stefan Johansson and Torben J{\o}rgensen and J{\o}rgensen, {Marit Eika} and Sekar Kathiresan and Augustine Kong and Jaspal Kooner and Jasmina Kravic and Markku Laakso and Jong-Young Lee and Lars Lind and Lindgren, {Cecilia M} and Allan Linneberg and Gisli Masson and Thomas Meitinger and Rasmus Ribel-Madsen and Oluf Pedersen and {Go-T2D Consortium}",

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journal = "Nature: New biology",

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T1 - Loss-of-function mutations in SLC30A8 protect against type 2 diabetes

AU - Flannick, Jason

AU - Thorleifsson, Gudmar

AU - Beer, Nicola L

AU - Jacobs, Suzanne B R

AU - Grarup, Niels

AU - Burtt, Noël P

AU - Mahajan, Anubha

AU - Fuchsberger, Christian

AU - Atzmon, Gil

AU - Benediktsson, Rafn

AU - Blangero, John

AU - Bowden, Don W

AU - Brandslund, Ivan

AU - Brosnan, Julia

AU - Burslem, Frank

AU - Chambers, John

AU - Cho, Yoon Shin

AU - Christensen, Cramer

AU - Douglas, Desirée A

AU - Duggirala, Ravindranath

AU - Dymek, Zachary

AU - Farjoun, Yossi

AU - Fennell, Timothy

AU - Fontanillas, Pierre

AU - Forsén, Tom

AU - Gabriel, Stacey

AU - Glaser, Benjamin

AU - Gudbjartsson, Daniel F

AU - Hanis, Craig

AU - Hansen, Torben

AU - Hreidarsson, Astradur B

AU - Hveem, Kristian

AU - Ingelsson, Erik

AU - Isomaa, Bo

AU - Johansson, Stefan

AU - Jørgensen, Torben

AU - Jørgensen, Marit Eika

AU - Kathiresan, Sekar

AU - Kong, Augustine

AU - Kooner, Jaspal

AU - Kravic, Jasmina

AU - Laakso, Markku

AU - Lee, Jong-Young

AU - Lind, Lars

AU - Lindgren, Cecilia M

AU - Linneberg, Allan

AU - Masson, Gisli

AU - Meitinger, Thomas

AU - Ribel-Madsen, Rasmus

AU - Pedersen, Oluf

AU - Go-T2D Consortium

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N2 - 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.

AB - 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.

KW - Animals

KW - Base Sequence

KW - Blood Glucose

KW - Cation Transport Proteins

KW - Diabetes Mellitus, Type 2

KW - Genetic Association Studies

KW - Genotype

KW - Humans

KW - Ion Transport

KW - Mice

KW - Mice, Knockout

KW - Molecular Sequence Data

KW - Mutation, Missense

KW - Proinsulin

KW - Sequence Analysis, DNA

U2 - 10.1038/ng.2915

DO - 10.1038/ng.2915

M3 - Letter

C2 - 24584071

SN - 1061-4036

VL - 46

SP - 357

EP - 363

JO - Nature: New biology

JF - Nature: New biology

IS - 4

ER -

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes

Abstract

Keywords

UN SDGs

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