Novel meta-analysis-derived type 2 diabetes risk loci do not determine prediabetic phenotypes.
Novel meta-analysis-derived type 2 diabetes risk loci do not determine prediabetic phenotypes.
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DOI：
10.1371/journal.pone.0003019
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发表时间：
2008-08-20
期刊：
影响因子：
3.7
通讯作者：
Haering, Hans-Ulrich
中科院分区：
文献类型：
--
作者：
Staiger, Harald;Machicao, Fausto;Kantartzis, Konstantinos;Schaefer, Silke A.;Kirchhoff, Kerstin;Guthoff, Martina;Silbernagel, Guenther;Stefan, Norbert;Fritsche, Andreas;Haering, Hans-Ulrich
全基因组关联（GWA）研究发现了一系列新的2型糖尿病危险位点。它们中的大多数随后被证明影响胰腺β细胞的胰岛素分泌。最近，一项对GWA数据的荟萃分析揭示了9个在2型糖尿病发病机制中仍未明确作用的额外风险位点。通过对2型糖尿病风险增加的受试者进行彻底表型分析，我们评估了9种最新遗传变异与糖尿病前期主要特征（即肥胖、胰岛素分泌受损和胰岛素抵抗）之间的关系。对报道的候选单核苷酸多态性（snp） JAZF1 rs864745、CDC123/CAMK1D rs12779790、TSPAN8/LGR5 rs7961581、THADA rs7578597、ADAMTS9 rs4607103、NOTCH2 rs10923931、DCD rs1153188、VEGFA rs9472138和BCL11A rs10490072进行基因分型。胰岛素敏感性来源于空腹血糖和胰岛素浓度、口服葡萄糖耐量试验（OGTT）和高胰岛素-血糖钳夹。根据OGTT数据估计胰岛素分泌。在对混杂变量进行适当调整并对多个比较进行Bonferroni校正（校正α-水平：p = 0.0014）后，没有一个snp与肥胖、胰岛素敏感性或胰岛素分泌可靠相关（均p≥0.0117，显性遗传模型）。ADAMTS9 SNP rs4607103和VEGFA SNP rs9472138的风险等位基因分别倾向于与胰岛素敏感性和胰岛素分泌的多个指标相关，但没有达到正式的统计学意义。该研究有足够的效力（1-β = 0.8），可以检测到0.19≤d≤0.25 （α = 0.0014）和0.13≤d≤0.16 （α = 0.05）的效应量。与第一组gwa衍生的2型糖尿病候选snp相比，我们无法检测到新的风险位点与糖尿病前期表型的可靠关联。ADAMTS9 SNP rs4607103和VEGFA SNP rs9472138可能分别对胰岛素敏感性和胰岛素分泌产生微弱影响，有待于更大规模的研究进一步证实。
Genome-wide association (GWA) studies identified a series of novel type 2 diabetes risk loci. Most of them were subsequently demonstrated to affect insulin secretion of pancreatic β-cells. Very recently, a meta-analysis of GWA data revealed nine additional risk loci with still undefined roles in the pathogenesis of type 2 diabetes. Using our thoroughly phenotyped cohort of subjects at an increased risk for type 2 diabetes, we assessed the association of the nine latest genetic variants with the predominant prediabetes traits, i.e., obesity, impaired insulin secretion, and insulin resistance. One thousand five hundred and seventy-eight metabolically characterized non-diabetic German subjects were genotyped for the reported candidate single nucleotide polymorphisms (SNPs) JAZF1 rs864745, CDC123/CAMK1D rs12779790, TSPAN8/LGR5 rs7961581, THADA rs7578597, ADAMTS9 rs4607103, NOTCH2 rs10923931, DCD rs1153188, VEGFA rs9472138, and BCL11A rs10490072. Insulin sensitivity was derived from fasting glucose and insulin concentrations, oral glucose tolerance test (OGTT), and hyperinsulinemic-euglycemic clamp. Insulin secretion was estimated from OGTT data. After appropriate adjustment for confounding variables and Bonferroni correction for multiple comparisons (corrected α-level: p = 0.0014), none of the SNPs was reliably associated with adiposity, insulin sensitivity, or insulin secretion (all p≥0.0117, dominant inheritance model). The risk alleles of ADAMTS9 SNP rs4607103 and VEGFA SNP rs9472138 tended to associate with more than one measure of insulin sensitivity and insulin secretion, respectively, but did not reach formal statistical significance. The study was sufficiently powered (1-β = 0.8) to detect effect sizes of 0.19≤d≤0.25 (α = 0.0014) and 0.13≤d≤0.16 (α = 0.05). In contrast to the first series of GWA-derived type 2 diabetes candidate SNPs, we could not detect reliable associations of the novel risk loci with prediabetic phenotypes. Possible weak effects of ADAMTS9 SNP rs4607103 and VEGFA SNP rs9472138 on insulin sensitivity and insulin secretion, respectively, await further confirmation by larger studies.
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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：
16.2
作者：
Stumvoll, M;Mitrakou, A;Gerich, J
通讯作者：
Gerich, J
影响因子：
7.7
作者：
Palmer, Nicholette D.;Goodarzi, Mark O.;Bowden, Donald W.
通讯作者：
Bowden, Donald W.
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：
5.8
作者：
Furukawa, Yasushi;Shimada, Takeshi;Nanjo, Kishio
通讯作者：
Nanjo, Kishio