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; Karen L. Mohlke; Anders Molven; Andrew P. Morris; Shobha Potluri; Rainer Rauramaa; Rasmus Ribel-Madsen; Ann Marie Richard; Tim Rolph; Veikko Salomaa; Ayellet V. Segrè; Hanna Skärstrand; Valgerdur Steinthorsdottir; Heather M. Stringham; Patrick Sulem; E. Shyong Tai; Yik Ying Teo; Tanya Teslovich; Unnur Thorsteinsdottir; Jeff K. Trimmer; Tiinamaija Tuomi; Jaakko Tuomilehto; Fariba Vaziri-Sani; Benjamin F. Voight; James G. Wilson; Michael Boehnke; Mark I. McCarthy; Pål R. Njølstad; Oluf Pedersen; Leif Groop; David R. Cox; Kari Stefansson; David Altshuler

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, Karen L. Mohlke, Anders Molven, Andrew P. Morris, Shobha Potluri, Rainer Rauramaa, Rasmus Ribel-Madsen, Ann Marie Richard, Tim Rolph, Veikko Salomaa, Ayellet V. Segrè, Hanna Skärstrand, Valgerdur Steinthorsdottir, Heather M. Stringham, Patrick Sulem, E. Shyong Tai, Yik Ying Teo, Tanya Teslovich, Unnur Thorsteinsdottir, Jeff K. Trimmer, Tiinamaija Tuomi, Jaakko Tuomilehto, Fariba Vaziri-Sani, Benjamin F. Voight, James G. Wilson, Michael Boehnke, Mark I. McCarthy, Pål R. Njølstad, Oluf Pedersen, Leif Groop, David R. Cox, Kari Stefansson, David Altshuler^*

^*Corresponding author for this work

Research output: Contribution to journal › Letter › peer-review

369 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)	357-363
Number of pages	7
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.2915
Publication status	Published - 1 Jan 2014

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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., ... Altshuler, D. (2014). Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nature Genetics, 46(4), 357-363. https://doi.org/10.1038/ng.2915

@article{ae07a4bf6ddb4ceebc1643d230f021fc,

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.",

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 Lee, {Jong Young} and Lars Lind and Lindgren, {Cecilia M.} and Allan Linneberg and Gisli Masson and Thomas Meitinger and Mohlke, {Karen L.} and Anders Molven and Morris, {Andrew P.} and Shobha Potluri and Rainer Rauramaa and Rasmus Ribel-Madsen and Richard, {Ann Marie} and Tim Rolph and Veikko Salomaa and Segr{\`e}, {Ayellet V.} and Hanna Sk{\"a}rstrand and Valgerdur Steinthorsdottir and Stringham, {Heather M.} and Patrick Sulem and Tai, {E. Shyong} and Teo, {Yik Ying} and Tanya Teslovich and Unnur Thorsteinsdottir and Trimmer, {Jeff K.} and Tiinamaija Tuomi and Jaakko Tuomilehto and Fariba Vaziri-Sani and Voight, {Benjamin F.} and Wilson, {James G.} and Michael Boehnke and McCarthy, {Mark I.} and Nj{\o}lstad, {P{\aa}l R.} and Oluf Pedersen and Leif Groop and Cox, {David R.} and Kari Stefansson and David Altshuler",

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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, JY, Lind, L, Lindgren, CM, Linneberg, A, Masson, G, Meitinger, T, Mohlke, KL, Molven, A, Morris, AP, Potluri, S, Rauramaa, R, Ribel-Madsen, R, Richard, AM, Rolph, T, Salomaa, V, Segrè, AV, Skärstrand, H, Steinthorsdottir, V, Stringham, HM, Sulem, P, Tai, ES, Teo, YY, Teslovich, T, Thorsteinsdottir, U, Trimmer, JK, Tuomi, T, Tuomilehto, J, Vaziri-Sani, F, Voight, BF, Wilson, JG, Boehnke, M, McCarthy, MI, Njølstad, PR, Pedersen, O, Groop, L, Cox, DR, Stefansson, K & Altshuler, D 2014, 'Loss-of-function mutations in SLC30A8 protect against type 2 diabetes', Nature Genetics, vol. 46, no. 4, pp. 357-363. https://doi.org/10.1038/ng.2915

TY - JOUR

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 - Mohlke, Karen L.

AU - Molven, Anders

AU - Morris, Andrew P.

AU - Potluri, Shobha

AU - Rauramaa, Rainer

AU - Ribel-Madsen, Rasmus

AU - Richard, Ann Marie

AU - Rolph, Tim

AU - Salomaa, Veikko

AU - Segrè, Ayellet V.

AU - Skärstrand, Hanna

AU - Steinthorsdottir, Valgerdur

AU - Stringham, Heather M.

AU - Sulem, Patrick

AU - Tai, E. Shyong

AU - Teo, Yik Ying

AU - Teslovich, Tanya

AU - Thorsteinsdottir, Unnur

AU - Trimmer, Jeff K.

AU - Tuomi, Tiinamaija

AU - Tuomilehto, Jaakko

AU - Vaziri-Sani, Fariba

AU - Voight, Benjamin F.

AU - Wilson, James G.

AU - Boehnke, Michael

AU - McCarthy, Mark I.

AU - Njølstad, Pål R.

AU - Pedersen, Oluf

AU - Groop, Leif

AU - Cox, David R.

AU - Stefansson, Kari

AU - Altshuler, David

PY - 2014/1/1

Y1 - 2014/1/1

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.

U2 - 10.1038/ng.2915

DO - 10.1038/ng.2915

M3 - Letter

C2 - 24584071

AN - SCOPUS:84897407583

SN - 1061-4036

VL - 46

SP - 357

EP - 363

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

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

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