Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.
Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.
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2型糖尿病易感性变异对定量血糖特征的影响揭示了机械异质性。
DOI：
10.2337/db13-0949
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发表时间：
2014-06
期刊：
影响因子：
7.7
通讯作者：
MAGIC Investigators
中科院分区：
文献类型：
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作者：
Dimas AS;Lagou V;Barker A;Knowles JW;Mägi R;Hivert MF;Benazzo A;Rybin D;Jackson AU;Stringham HM;Song C;Fischer-Rosinsky A;Boesgaard TW;Grarup N;Abbasi FA;Assimes TL;Hao K;Yang X;Lecoeur C;Barroso I;Bonnycastle LL;Böttcher Y;Bumpstead S;Chines PS;Erdos MR;Graessler J;Kovacs P;Morken MA;Narisu N;Payne F;Stancakova A;Swift AJ;Tönjes A;Bornstein SR;Cauchi S;Froguel P;Meyre D;Schwarz PE;Häring HU;Smith U;Boehnke M;Bergman RN;Collins FS;Mohlke KL;Tuomilehto J;Quertemous T;Lind L;Hansen T;Pedersen O;Walker M;Pfeiffer AF;Spranger J;Stumvoll M;Meigs JB;Wareham NJ;Kuusisto J;Laakso M;Langenberg C;Dupuis J;Watanabe RM;Florez JC;Ingelsson E;McCarthy MI;Prokopenko I;MAGIC Investigators
已确诊的2型糖尿病患者表现出β细胞功能障碍和胰岛素抵抗。为了确定导致糖尿病状态的基本过程，我们研究了37个已建立的易感基因座的2型糖尿病风险变体与胰岛素原加工、胰岛素分泌和胰岛素敏感性指数之间的关系。我们纳入了多达58，614名非糖尿病受试者的基础测量数据和17，327名动态测量数据。我们使用加性遗传模型，调整性别、年龄和BMI，然后进行固定效应、逆方差荟萃分析。聚类分析根据其与这些连续血糖表型的关系将风险位点分为五大类。第一簇（PPARG、KLF 14、IRS 1、GCKR）的特征在于对胰岛素敏感性的主要影响。第二个簇（MTNR 1B，GCK）的特征是与胰岛素分泌减少和空腹高血糖症相关的风险等位基因。ARAP 1构成了第三个簇，其特征在于胰岛素加工缺陷。第四个簇（TCF 7 L2、SLC 30 A8、HHEX/IDE、CDKAL 1、CDKN 2A/2B）由影响胰岛素加工和分泌的基因座定义，而空腹血糖水平没有可检测的变化。最后一组包含20个风险位点，与连续血糖特征没有明确的关联。通过收集关于连续血糖性状的大量数据，我们揭示了2型糖尿病风险变异影响疾病易感性的不同机制。
Patients with established type 2 diabetes display both β-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.
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影响因子：
--
作者：
Banasik K;Hollensted M;Andersson E;Sparsø T;Sandbaek A;Lauritzen T;Jørgensen T;Witte DR;Pedersen O;Hansen T
通讯作者：
Hansen T
影响因子：
8.2
作者：
Langenberg C;Pascoe L;Mari A;Tura A;Laakso M;Frayling TM;Barroso I;Loos RJ;Wareham NJ;Walker M;RISC Consortium
通讯作者：
RISC Consortium
DOI：
10.1006/bbrc.2000.2169
发表时间：
2000-02-16
影响因子：
3.1
作者：
Awata, T;Inoue, K;Katayama, S
通讯作者：
Katayama, S
新的遗传基因座涉及禁食葡萄糖稳态及其对2型糖尿病风险的影响。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
3
作者：
Mägi R;Morris AP
通讯作者：
Morris AP