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

被引：355

作者：

Flannick, Jason ^{[1
,2
,3
]}

Thorleifsson, Gudmar ^{[4
]}

Beer, Nicola L. ^{[1
,5
]}

Jacobs, Suzanne B. R. ^{[1
]}

Grarup, Niels ^{[6
]}

Burtt, Noel P. ^{[1
]}

Mahajan, Anubha ^{[7
]}

Fuchsberger, Christian ^{[8
]}

Atzmon, Gil ^{[9
,10
]}

Benediktsson, Rafn ^{[11
]}

Blangero, John ^{[12
]}

Bowden, Don W. ^{[13
,14
,15
,16
]}

Brandslund, Ivan ^{[17
,18
]}

Brosnan, Julia ^{[19
]}

Burslem, Frank ^{[20
]}

Chambers, John ^{[21
,22
,23
]}

Cho, Yoon Shin ^{[24
]}

Christensen, Cramer ^{[25
]}

Douglas, Desiree A. ^{[26
]}

Duggirala, Ravindranath ^{[12
]}

Dymek, Zachary ^{[1
]}

Farjoun, Yossi ^{[1
]}

Fennell, Timothy ^{[1
]}

Fontanillas, Pierre ^{[1
]}

Forsen, Tom ^{[27
,28
]}

Gabriel, Stacey ^{[1
]}

Glaser, Benjamin ^{[29
,30
]}

Gudbjartsson, Daniel F. ^{[4
]}

Hanis, Craig ^{[31
]}

Hansen, Torben ^{[6
,32
]}

Hreidarsson, Astradur B. ^{[11
]}

Hveem, Kristian ^{[33
]}

Ingelsson, Erik ^{[7
,34
]}

Isomaa, Bo ^{[35
,36
]}

Johansson, Stefan ^{[37
,38
,39
]}

Jorgensen, Torben ^{[40
,41
,42
]}

Jorgensen, Marit Eika ^{[43
]}

Kathiresan, Sekar ^{[1
,44
,45
,46
]}

Kong, Augustine ^{[4
]}

Kooner, Jaspal ^{[22
,23
,47
]}

Kravic, Jasmina ^{[48
]}

Laakso, Markku ^{[49
,50
]}

Lee, Jong-Young ^{[51
]}

Lind, Lars ^{[52
]}

Lindgren, Cecilia M. ^{[1
,7
]}

Linneberg, Allan ^{[40
,41
,42
,53
]}

Masson, Gisli ^{[4
]}

Meitinger, Thomas ^{[54
]}

Mohlke, Karen L. ^{[55
]}

Molven, Anders ^{[37
,56
,57
]}

机构：

[1] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02141 USA

[2] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[3] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA

[4] Amgen Inc, deCODE Genet, Reykjavik, Iceland

[5] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[6] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn,Ctr Basic Metab Res, Copenhagen, Denmark

[7] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[8] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[9] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA

[10] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10467 USA

[11] Landspitali Univ Hosp, Dept Endocrinol & Metab, Reykjavik, Iceland

[12] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA

[13] Wake Forest Univ, Bowman Gray Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA

[14] Wake Forest Univ, Bowman Gray Sch Med, Ctr Diabet Res, Winston Salem, NC USA

[15] Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC USA

[16] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Winston Salem, NC USA

[17] Vejle Hosp, Dept Clin Biochem, Vejle, Denmark

[18] Univ Southern Denmark, Inst Reg Hlth Res, Odense, Denmark

[19] Pfizer Inc, Cardiovasc & Metab Dis Res Unit, Cambridge, MA USA

[20] Prescient Life Sci, Cardiovasc & Metab Dis Practice, London, England

[21] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England

[22] Univ London Imperial Coll Sci Technol & Med, Healthcare Natl Hlth Serv NHS Trust, London, England

[23] Ealing Hosp NHS Trust, Southall, Middx, England

[24] Hallym Univ, Dept Biomed Sci, Chunchon, South Korea

[25] Vejle Hosp, Dept Internal Med & Endocrinol, Vejle, Denmark

[26] Lund Univ, Dept Clin Sci, Unit Diabet & Celiac Dis, Malmo, Sweden

[27] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland

[28] Vaasa Hlth Care Ctr, Diabetes Care Unit, Vaasa, Finland

[29] Hadassah Hebrew Univ, Med Ctr, Endocrinol & Metab Serv, Jerusalem, Israel

[30] IDRG, Holon, Israel

[31] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77030 USA

[32] Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark

[33] Norwegian Univ Sci & Technol, Fac Med, Dept Publ Hlth, Levanger, Norway

[34] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden

[35] Folkhalsan Res Ctr, Helsinki, Finland

[36] Dept Social Serv & Hlth Care, Pietarsaari, Finland

[37] Univ Bergen, KG Jebsen Ctr Diabet Res, Dept Clin Sci, Bergen, Norway

[38] Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway

[39] Univ Bergen, Dept Biomed, Bergen, Norway

[40] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark

[41] Univ Copenhagen, Fac Hlth & Med, Copenhagen, Denmark

[42] Aalborg Univ, Fac Med, Aalborg, Denmark

[43] Steno Diabet Ctr, DK-2820 Gentofte, Denmark

[44] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[45] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Div Cardiol, Boston, MA 02114 USA

[46] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[47] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, NHLI, London, England

[48] Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden

[49] Univ Eastern Finland, Dept Med, Kuopio, Finland

[50] Kuopio Univ Hosp, SF-70210 Kuopio, Finland

来源：

NATURE GENETICS | 2014年 / 46卷 / 04期

基金：

欧洲研究理事会; 芬兰科学院; 英国惠康基金; 美国国家卫生研究院; 瑞典研究理事会;

关键词：

ZINC TRANSPORTER ZNT8; GENOME-WIDE ASSOCIATION; GLUCOSE-HOMEOSTASIS; COMMON VARIANTS; BETA-CELL; INSULIN; RARE; PATHOPHYSIOLOGY; EXPRESSION; RESPONSES;

D O I：

10.1038/ng.2915

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets1-3, 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) 4 and harbors a common variant (p. Trp325Arg) associated with T2D risk and glucose and proinsulin levels5-7. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 x 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 x 10(-4)). The two most common proteintruncating 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(8,9), and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts(10-15). 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.

引用

页码：357 / +

页数：8

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