Loss-of-function mutations in SLC30A8 protect against type 2 diabetes
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Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. / Flannick, Jason; Thorleifsson, Gudmar; Beer, Nicola L; Jacobs, Suzanne B R; Grarup, Niels; Burtt, Noël P; Mahajan, Anubha; Fuchsberger, Christian; Atzmon, Gil; Benediktsson, Rafn; Blangero, John; Bowden, Don W; Brandslund, Ivan; Brosnan, Julia; Burslem, Frank; Chambers, John; Cho, Yoon Shin; Christensen, Cramer; Douglas, Desirée A; Duggirala, Ravindranath; Dymek, Zachary; Farjoun, Yossi; Fennell, Timothy; Fontanillas, Pierre; Forsén, Tom; Gabriel, Stacey; Glaser, Benjamin; Gudbjartsson, Daniel F; Hanis, Craig; Hansen, Torben; Hreidarsson, Astradur B; Hveem, Kristian; Ingelsson, Erik; Isomaa, Bo; Johansson, Stefan; Jørgensen, Torben; Jørgensen, Marit Eika; Kathiresan, Sekar; Kong, Augustine; Kooner, Jaspal; Kravic, Jasmina; Laakso, Markku; Lee, Jong-Young; Lind, Lars; Lindgren, Cecilia M; Linneberg, Allan; Masson, Gisli; Meitinger, Thomas; Ribel-Madsen, Rasmus; Pedersen, Oluf; Go-T2D Consortium.
In: Nature Genetics, Vol. 46, No. 4, 04.2014, p. 357-63.Research output: Contribution to journal › Letter › Research › peer-review
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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 - Ribel-Madsen, Rasmus
AU - Pedersen, Oluf
AU - Go-T2D Consortium
PY - 2014/4
Y1 - 2014/4
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
VL - 46
SP - 357
EP - 363
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 4
ER -
ID: 117883107