Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients--EUGENE2 study.
Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients--EUGENE2 study.
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DOI：
10.1371/journal.pone.0007236
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发表时间：
2009-09-30
期刊：
影响因子：
3.7
通讯作者：
EUGENE2 Consortium
中科院分区：
文献类型：
--
作者：
Boesgaard TW;Gjesing AP;Grarup N;Rutanen J;Jansson PA;Hribal ML;Sesti G;Fritsche A;Stefan N;Staiger H;Häring H;Smith U;Laakso M;Pedersen O;Hansen T;EUGENE2 Consortium
一项荟萃分析结合了三项全基因组关联研究的结果，随后进行了大规模复制，确定了六个新的2型糖尿病基因座。随后关于这些变体对β细胞功能和胰岛素敏感性估计的影响的研究尚未得出结论。我们检查了位于JAZF 1（rs 864745），THADA（rs7578597），TSPAN 8（rs7961581），ADAMTS 9（rs 4607103），NOTCH 2（rs 10923931）和CDC 123/CAMK 1D（rs 12779790）基因中或附近的这些变体与胰腺β细胞功能和胰岛素敏感性的相关性。口服和静脉内葡萄糖刺激的胰岛素释放（n = 849）和胰岛素敏感性（n = 596）估计从高胰岛素血症正葡萄糖钳夹在非糖尿病的后代2型糖尿病患者从5个欧洲人口进行了测量。 假设加性遗传模型，ADAMTS 9附近的rs 4607103的糖尿病相关主要C等位基因与高胰岛素正葡萄糖钳夹期间胰岛素刺激的葡萄糖摄取减少相关（p = 0.002）。 然而，静脉和口服葡萄糖后，C等位基因个体的血清胰岛素释放增加（分别为p= 0.003和p =0.01）。 一项荟萃分析结合了来自905名非糖尿病个体的钳夹和IVGTT数据，显示C风险等位基因与胰岛素敏感性降低（p = 0.003）和胰岛素释放增加（p = 0.002）相关。 内含子JAZF 1 rs 864745的主要T等位基因赋予增加的糖尿病风险与IVGTT期间增加的第2时相血清胰岛素释放（p = 0.03）和增加的空腹血清胰岛素水平（p = 0.001）相关。 其余的变异没有显示出与胰岛素反应、胰岛素敏感性或任何其他测量的数量性状的任何关联。目前的研究表明，ADAMTS 9附近的rs 4607103的C等位基因的致糖尿病的影响可能部分通过降低外周组织的胰岛素敏感性介导。
A meta-analysis combining results from three genome-wide association studies and followed by large-scale replication identified six novel type 2 diabetes loci. Subsequent studies of the effect of these variants on estimates of the beta-cell function and insulin sensitivity have been inconclusive. We examined these variants located in or near the JAZF1 (rs864745), THADA (rs7578597), TSPAN8 (rs7961581), ADAMTS9 (rs4607103), NOTCH2 (rs10923931) and the CDC123/CAMK1D (rs12779790) genes for associations with measures of pancreatic beta-cell function and insulin sensitivity. Oral and intravenous glucose stimulated insulin release (n = 849) and insulin sensitivity (n = 596) estimated from a hyperinsulinemic euglycemic clamp were measured in non-diabetic offspring of type 2 diabetic patients from five European populations. Assuming an additive genetic model the diabetes-associated major C-allele of rs4607103 near ADAMTS9 associated with reduced insulin-stimulated glucose uptake (p = 0.002) during a hyperinsulinemic euglycemic clamp. However, following intravenous and oral administration of glucose serum insulin release was increased in individuals with the C-allele (p = 0.003 and p = 0.01, respectively). A meta-analyse combining clamp and IVGTT data from a total of 905 non-diabetic individuals showed that the C-risk allele associated with decreased insulin sensitivity (p = 0.003) and increased insulin release (p = 0.002). The major T-allele of the intronic JAZF1 rs864745 conferring increased diabetes risk was associated with increased 2nd phase serum insulin release during an IVGTT (p = 0.03), and an increased fasting serum insulin level (p = 0.001). The remaining variants did not show any associations with insulin response, insulin sensitivity or any other measured quantitative traits. The present studies suggest that the diabetogenic impact of the C-allele of rs4607103 near ADAMTS9 may in part be mediated through decreased insulin sensitivity of peripheral tissues.
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影响因子：
30.8
作者：
Zeggini, Eleftheria;Scott, Laura J.;Saxena, Richa;Voight, Benjamin F.;Marchini, Jonathan L.;Hu, Tianle;de Bakker, Paul I. W.;Abecasis, Goncalo R.;Almgren, Peter;Andersen, Gitte;Ardlie, Kristin;Bostroem, Kristina Bengtsson;Bergman, Richard N.;Bonnycastle, Lori L.;Borch-Johnsen, Knut;Burtt, Noel P.;Chen, Hong;Chines, Peter S.;Daly, Mark J.;Deodhar, Parimal;Ding, Chia-Jen;Doney, Alex S. F.;Duren, William L.;Elliott, Katherine S.;Erdos, Michael R.;Frayling, Timothy M.;Freathy, Rachel M.;Gianniny, Lauren;Grallert, Harald;Grarup, Niels;Groves, Christopher J.;Guiducci, Candace;Hansen, Torben;Herder, Christian;Hitman, Graham A.;Hughes, Thomas E.;Isomaa, Bo;Jackson, Anne U.;Jorgensen, Torben;Kong, Augustine;Kubalanza, Kari;Kuruvilla, Finny G.;Kuusisto, Johanna;Langenberg, Claudia;Lango, Hana;Lauritzen, Torsten;Li, Yun;Lindgren, Cecilia M.;Lyssenko, Valeriya;Marvelle, Amanda F.;Meisinger, Christa;Midthjell, Kristian;Mohlke, Karen L.;Morken, Mario A.;Morris, Andrew D.;Narisu, Narisu;Nilsson, Peter;Owen, Katharine R.;Palmer, Colin N. A.;Payne, Felicity;Perry, John R. B.;Pettersen, Elin;Platou, Carl;Prokopenko, Inga;Qi, Lu;Qin, Li;Rayner, Nigel W.;Rees, Matthew;Roix, Jeffrey J.;Sandbaek, Anelli;Shields, Beverley;Sjogren, Marketa;Steinthorsdottir, Valgerdur;Stringham, Heather M.;Swift, Amy J.;Thorleifsson, Gudmar;Thorsteinsdottir, Unnur;Timpson, Nicholas J.;Tuomi, Tiinamaija;Tuomilehto, Jaakko;Walker, Mark;Watanabe, Richard M.;Weedon, Michael N.;Willer, Cristen J.;Illig, Thomas;Hveem, Kristian;Hu, Frank B.;Laakso, Markku;Stefansson, Kari;Pedersen, Oluf;Wareham, Nicholas J.;Barroso, Ines;Hattersley, Andrew T.;Collins, Francis S.;Groop, Leif;McCarthy, Mark I.;Boehnke, Michael;Altshuler, David
通讯作者：
Altshuler, David
影响因子：
3.7
作者：
Staiger, Harald;Machicao, Fausto;Kantartzis, Konstantinos;Schaefer, Silke A.;Kirchhoff, Kerstin;Guthoff, Martina;Silbernagel, Guenther;Stefan, Norbert;Fritsche, Andreas;Haering, Hans-Ulrich
通讯作者：
Haering, Hans-Ulrich
影响因子：
4.4
作者：
Clark, ME;Kelner, GS;Maki, RA
通讯作者：
Maki, RA
影响因子：
8.2
作者：
Boesgaard, T. W.;Zilinskaite, J.;Hansen, T.
通讯作者：
Hansen, T.
影响因子：
3.5
作者：
Sanghera, Dharambir K.;Been, Latonya;Ralhan, Sarju
通讯作者：
Ralhan, Sarju