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

Flannick, Jason (author)
Thorleifsson, Gudmar (author)
Lind, Lars (author)
Uppsala universitet,Kardiovaskulär epidemiologi
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Jacobs, Suzanne B R (author)
Grarup, Niels (author)
Burtt, Noël P (author)
Mahajan, Anubha (author)
Fuchsberger, Christian (author)
Atzmon, Gil (author)
Benediktsson, Rafn (author)
Blangero, John (author)
Bowden, Don W (author)
Brandslund, Ivan (author)
Brosnan, Julia (author)
Burslem, Frank (author)
Chambers, John (author)
Cho, Yoon Shin (author)
Christensen, Cramer (author)
Douglas, Desiree (author)
Lund University,Lunds universitet,Celiaki och diabetes,Forskargrupper vid Lunds universitet,Cellpatologi, Malmö,Celiac Disease and Diabetes Unit,Lund University Research Groups,Cell Pathology, Malmö
Duggirala, Ravindranath (author)
Dymek, Zachary (author)
Farjoun, Yossi (author)
Fennell, Timothy (author)
Fontanillas, Pierre (author)
Forsén, Tom (author)
Gabriel, Stacey (author)
Glaser, Benjamin (author)
Gudbjartsson, Daniel F (author)
Hanis, Craig (author)
Hansen, Torben (author)
Hreidarsson, Astradur B (author)
Hveem, Kristian (author)
Ingelsson, Erik (author)
Uppsala universitet,Science for Life Laboratory, SciLifeLab,Molekylär epidemiologi
Isomaa, Bo (author)
Johansson, Stefan (author)
Jørgensen, Torben (author)
Jørgensen, Marit Eika (author)
Kathiresan, Sekar (author)
Kong, Augustine (author)
Kooner, Jaspal (author)
Kravic, Jasmina (author)
Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups
Laakso, Markku (author)
Lee, Jong-Young (author)
Lind, Lars (author)
Lindgren, Cecilia M (author)
Linneberg, Allan (author)
Masson, Gisli (author)
Meitinger, Thomas (author)
Mohlke, Karen L (author)
Molven, Anders (author)
Morris, Andrew P (author)
Potluri, Shobha (author)
Rauramaa, Rainer (author)
Ribel-Madsen, Rasmus (author)
Richard, Ann-Marie (author)
Rolph, Tim (author)
Salomaa, Veikko (author)
Segrè, Ayellet V (author)
Skärstrand, Hanna (author)
Lund University,Lunds universitet,Celiaki och diabetes,Forskargrupper vid Lunds universitet,Celiac Disease and Diabetes Unit,Lund University Research Groups
Steinthorsdottir, Valgerdur (author)
Stringham, Heather M (author)
Sulem, Patrick (author)
Tai, E Shyong (author)
Teo, Yik Ying (author)
Teslovich, Tanya (author)
Thorsteinsdottir, Unnur (author)
Trimmer, Jeff K (author)
Tuomi, Tiinamaija (author)
Tuomilehto, Jaakko (author)
Vaziri Sani, Fariba (author)
Lund University,Lunds universitet,Celiaki och diabetes,Forskargrupper vid Lunds universitet,Celiac Disease and Diabetes Unit,Lund University Research Groups
Voight, Benjamin F (author)
Wilson, James G (author)
Boehnke, Michael (author)
McCarthy, Mark I (author)
Njølstad, Pål R (author)
Pedersen, Oluf (author)
Groop, Leif (author)
Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups
Cox, David R (author)
Stefansson, Kari (author)
Altshuler, David (author)
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 (creator_code:org_t)
2014-03-02
2014
English.
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 46:4, s. 357-357
  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

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By the author/editor
Flannick, Jason
Thorleifsson, Gu ...
Lind, Lars
Jacobs, Suzanne ...
Grarup, Niels
Burtt, Noël P
show more...
Mahajan, Anubha
Fuchsberger, Chr ...
Atzmon, Gil
Benediktsson, Ra ...
Blangero, John
Bowden, Don W
Brandslund, Ivan
Brosnan, Julia
Burslem, Frank
Chambers, John
Cho, Yoon Shin
Christensen, Cra ...
Douglas, Desiree
Duggirala, Ravin ...
Dymek, Zachary
Farjoun, Yossi
Fennell, Timothy
Fontanillas, Pie ...
Forsén, Tom
Gabriel, Stacey
Glaser, Benjamin
Gudbjartsson, Da ...
Hanis, Craig
Hansen, Torben
Hreidarsson, Ast ...
Hveem, Kristian
Ingelsson, Erik
Isomaa, Bo
Johansson, Stefa ...
Jørgensen, Torbe ...
Jørgensen, Marit ...
Kathiresan, Seka ...
Kong, Augustine
Kooner, Jaspal
Kravic, Jasmina
Laakso, Markku
Lee, Jong-Young
Lindgren, Cecili ...
Linneberg, Allan
Masson, Gisli
Meitinger, Thoma ...
Mohlke, Karen L
Molven, Anders
Morris, Andrew P
Potluri, Shobha
Rauramaa, Rainer
Ribel-Madsen, Ra ...
Richard, Ann-Mar ...
Rolph, Tim
Salomaa, Veikko
Segrè, Ayellet V
Skärstrand, Hann ...
Steinthorsdottir ...
Stringham, Heath ...
Sulem, Patrick
Tai, E Shyong
Teo, Yik Ying
Teslovich, Tanya
Thorsteinsdottir ...
Trimmer, Jeff K
Tuomi, Tiinamaij ...
Tuomilehto, Jaak ...
Vaziri Sani, Far ...
Voight, Benjamin ...
Wilson, James G
Boehnke, Michael
McCarthy, Mark I
Njølstad, Pål R
Pedersen, Oluf
Groop, Leif
Cox, David R
Stefansson, Kari
Altshuler, David
show less...
About the subject
MEDICAL AND HEALTH SCIENCES
MEDICAL AND HEAL ...
and Clinical Medicin ...
and Endocrinology an ...
MEDICAL AND HEALTH SCIENCES
MEDICAL AND HEAL ...
and Basic Medicine
and Medical Genetics
Articles in the publication
Nature Genetics
By the university
Lund University
Uppsala University

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