Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations.
Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations.
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DOI：
10.2337/db08-0516
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发表时间：
2008-11
期刊：
影响因子：
7.7
通讯作者：
Kathiresan, Sekar
中科院分区：
文献类型：
--
作者：
Orho-Melander, Marju;Melander, Olle;Guiducci, Candace;Perez-Martinez, Pablo;Corella, Dolores;Roos, Charlotta;Tewhey, Ryan;Rieder, Mark J.;Hall, Jennifer;Abecasis, Goncalo;Tai, E. Shyong;Welch, Cullan;Arnett, Donna K.;Lyssenko, Valeriya;Lindholm, Eero;Saxena, Richa;de Bakker, Paul I. W.;Burtt, Noel;Voight, Benjamin F.;Hirschhorn, Joel N.;Tucker, Katherine L.;Hedner, Thomas;Tuomi, Tiinaimaija;Isomaa, Bo;Eriksson, Karl-Fredrik;Taskinen, Marja-Riitta;Wahlstrand, Bjoern;Hughes, Thomas E.;Parnell, Laurence D.;Lai, Chao-Qiang;Berglund, Goran;Peltonen, Leena;Vartiainen, Erkki;Jousilahti, Pekka;Havulinna, Aki S.;Salomaa, Veikko;Nilsson, Peter;Groop, Leif;Altshuler, David;Ordovas, Jose M.;Kathiresan, Sekar
使用全基因组关联方法，我们最近确定了葡萄糖激酶调节蛋白基因（GCKR，rs780094）区域作为欧洲人血浆甘油三酯浓度的一个新的数量性状位点。在这里，我们试图研究GCKR变体与代谢表型的相关性，包括葡萄糖稳态的测量，以评估非欧洲血统样本中的GCKR基因座，并在相关基因组区间进行精细映射。研究设计和方法-我们在12个独立的队列中进行了关联研究，这些队列包括代表几个祖先群体的> 45，000个个体（来自北方和南欧的白人，来自美国的白人，来自美国的非洲裔美国人，来自加勒比海的西班牙裔，以及来自新加坡的华人、马来人和亚洲印第安人）。我们通过估算未分型的HapMap单核苷酸多态性（SNP）和相关基因组间隔中的104个SNP，在染色体2 p23上跨越GCKR和其他16个基因的连锁不平衡的10417 kb区域进行遗传精细定位。我们提供了全面的证据，证明GCKR rs780094对空腹血浆甘油三酯（Pmeta = 3 × 10−56）和葡萄糖（Pmeta = 1 × 10−13）浓度具有相反的影响。此外，我们证实了最近的报道，即相同的SNP与C反应蛋白（CRP）水平相关（P = 5 × 10−5）。两种精细定位方法都揭示了一种常见的错义GCKR变体（rs 1260326，Pro446 Leu，34%频率，r2 = 0.93与rs780094）作为该区域最强的关联信号。结论：这些发现指出了一种人类的分子机制，通过这种机制，较高的甘油三酯和CRP可以与较低的血糖浓度相结合，并将GCKR定位在调节肝脏甘油三酯和葡萄糖代谢的中枢通路中。
OBJECTIVE—Using the genome-wide association approach, we recently identified the glucokinase regulatory protein gene (GCKR, rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metabolic phenotypes, including measures of glucose homeostasis, to evaluate the GCKR locus in samples of non-European ancestry and to fine- map across the associated genomic interval. RESEARCH DESIGN AND METHODS—We performed association studies in 12 independent cohorts comprising >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the U.S., African Americans from the U.S., Hispanics of Caribbean origin, and Chinese, Malays, and Asian Indians from Singapore). We conducted genetic fine-mapping across the ∼417-kb region of linkage disequilibrium spanning GCKR and 16 other genes on chromosome 2p23 by imputing untyped HapMap single nucleotide polymorphisms (SNPs) and genotyping 104 SNPs across the associated genomic interval. RESULTS—We provide comprehensive evidence that GCKR rs780094 is associated with opposite effects on fasting plasma triglyceride (Pmeta = 3 × 10−56) and glucose (Pmeta = 1 × 10−13) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reactive protein (CRP) level (P = 5 × 10−5). Both fine-mapping approaches revealed a common missense GCKR variant (rs1260326, Pro446Leu, 34% frequency, r2 = 0.93 with rs780094) as the strongest association signal in the region. CONCLUSIONS—These findings point to a molecular mechanism in humans by which higher triglycerides and CRP can be coupled with lower plasma glucose concentrations and position GCKR in central pathways regulating both hepatic triglyceride and glucose metabolism.
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影响因子：
11.1
作者：
Berglund, G;Nilsson, P;Lingärde, F
通讯作者：
Lingärde, F
影响因子：
168.9
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5
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5.3
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4.1
作者：
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通讯作者：
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