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

Nat Genet

Authors	Jason Flannick Gudmar Thorleifsson Nicola Beer Suzanne Jacobs Niels Grarup Noel Burtt Anubha Mahajan Christian Fuchsberger Gil Atzmon Rafn Benediktsson John Blangero Don Bowden Ivan Brandslund Julia Brosnan Frank Burslem John Chambers Yoon Cho Cramer Christensen Desirée Douglas Ravindranath Duggirala Zachary Dymek Yossi Farjoun Timothy Fennell Pierre Fontanillas Tom Forsén Stacey Gabriel Benjamin Glaser Daniel Gudbjartsson Craig Hanis Torben Hansen Astradur Hreidarsson Kristian Hveem Erik Ingelsson Bo Isomaa Stefan Johansson Torben Jørgensen Marit Jørgensen Sekar Kathiresan Augustine Kong Jaspal Kooner Jasmina Kravic Markku Laakso Jong-Young Lee Lars Lind Cecilia Lindgren Allan Linneberg Gisli Masson Thomas Meitinger Karen Mohlke Anders Molven Andrew Morris Shobha Potluri Rainer Rauramaa Rasmus Ribel-Madsen Ann-Marie Richard Tim Rolph Veikko Salomaa Ayellet Segrè Hanna Skärstrand Valgerdur Steinthorsdottir Heather Stringham Patrick Sulem E Shyong Tai Yik Teo Tanya Teslovich Unnur Thorsteinsdottir Jeff Trimmer Tiinamaija Tuomi Jaakko Tuomilehto Fariba Vaziri-Sani Benjamin Voight James Wilson Michael Boehnke Mark McCarthy Pål Njølstad Oluf Pedersen Go-T2D Consortium T2D-GENES Consortium Leif Groop David Cox Kari Stefansson David Altshuler
Keywords	Animals Humans Mice Base Sequence Genotype Molecular Sequence Data Mice, Knockout Genetic Association Studies Sequence Analysis, DNA Blood Glucose Diabetes Mellitus, Type 2 Mutation, Missense Cation Transport Proteins Ion Transport Proinsulin
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.Lys34Serfs50) 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.
Year of Publication	2014
Journal	Nat Genet
Volume	46
Issue	4
Pages	357-63
Date Published	2014 Apr
ISSN	1546-1718
URL	http://dx.doi.org/10.1038/ng.2915
DOI	10.1038/ng.2915
PubMed ID	24584071
PubMed Central ID	PMC4051628
Links	PubMed Google Scholar DOI
Grant list	R01 DK093757 / DK / NIDDK NIH HHS / United States U01 DK085501 / DK / NIDDK NIH HHS / United States R13 CA124293 / CA / NCI NIH HHS / United States 098017 / Wellcome Trust / United Kingdom N01 HC095170 / HC / NHLBI NIH HHS / United States 5U01DK085526 / DK / NIDDK NIH HHS / United States U54 HG003067 / HG / NHGRI NIH HHS / United States U01 DK085524 / DK / NIDDK NIH HHS / United States U01 DK085545 / DK / NIDDK NIH HHS / United States R01 DK072193 / DK / NIDDK NIH HHS / United States U54HG003067 / HG / NHGRI NIH HHS / United States N01 HC095172 / HC / NHLBI NIH HHS / United States N01 HC095171 / HC / NHLBI NIH HHS / United States R01 DK062370 / DK / NIDDK NIH HHS / United States RC2 DK088389 / DK / NIDDK NIH HHS / United States 090532 / Wellcome Trust / United Kingdom U01 DK085526 / DK / NIDDK NIH HHS / United States U01 DK085584 / DK / NIDDK NIH HHS / United States DK088389 / DK / NIDDK NIH HHS / United States U01 DK062370 / DK / NIDDK NIH HHS / United States Z01 HG000024 / HG / NHGRI NIH HHS / United States 098381 / Wellcome Trust / United Kingdom T32 GM007748 / GM / NIGMS NIH HHS / United States