Common Missense Variant in the Glucokinase Regulatory Protein Gene Is Associated With Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations

被引：236

作者：

Orho-Melander, Marju ^{[1
]}

Melander, Olle ^{[1
]}

Guiducci, Candace ^{[2
,3
]}

Perez-Martinez, Pablo ^{[4
,5
]}

Corella, Dolores ^{[6
,7
]}

Roos, Charlotta ^{[1
]}

Tewhey, Ryan ^{[2
,3
]}

Rieder, Mark J. ^{[8
]}

Hall, Jennifer ^{[9
]}

Abecasis, Goncalo ^{[10
]}

Tai, E. Shyong ^{[11
]}

Welch, Cullan ^{[9
]}

Arnett, Donna K. ^{[12
]}

Lyssenko, Valeriya ^{[1
]}

Lindholm, Eero ^{[1
]}

Saxena, Richa ^{[2
,3
]}

de Bakker, Paul I. W. ^{[2
,3
]}

Burtt, Noel ^{[2
,3
]}

Voight, Benjamin F. ^{[2
,3
]}

Hirschhorn, Joel N. ^{[2
,3
]}

Tucker, Katherine L. ^{[13
]}

Hedner, Thomas ^{[14
]}

Tuomi, Tiinaimaija ^{[15
,16
]}

Isomaa, Bo ^{[16
]}

Eriksson, Karl-Fredrik ^{[1
]}

Taskinen, Marja-Riitta ^{[15
]}

Wahlstrand, Bjoern ^{[14
]}

Hughes, Thomas E. ^{[17
]}

Parnell, Laurence D. ^{[5
]}

Lai, Chao-Qiang ^{[5
]}

Berglund, Goran ^{[18
]}

Peltonen, Leena ^{[19
]}

Vartiainen, Erkki ^{[20
]}

Jousilahti, Pekka ^{[20
]}

Havulinna, Aki S. ^{[20
]}

Salomaa, Veikko ^{[20
]}

Nilsson, Peter ^{[1
]}

Groop, Leif ^{[1
,15
]}

Altshuler, David ^{[2
,3
,21
,22
,23
]}

Ordovas, Jose M. ^{[5
]}

Kathiresan, Sekar ^{[2
,3
,24
]}

机构：

[1] Lund Univ, Malmo Gen Hosp, Clin Res Ctr, Dept Clin Sci, S-21401 Malmo, Sweden

[2] Harvard Univ, Cambridge, MA 02138 USA

[3] MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02139 USA

[4] Univ Cordoba, Reina Sofia Univ Hosp, Lipids & Atherosclerosis Res Unit, Cordoba, Spain

[5] Tufts Univ, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, Nutr & Genom Lab, Boston, MA USA

[6] Univ Valencia, Sch Med, Genet & Mol Epidemiol Unit, Valencia, Spain

[7] Univ Valencia, Sch Med, CIBER Fisiopatol Obesidad & Nutr, Valencia, Spain

[8] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[9] Univ Minnesota, Dept Med, Lillehei Heart Inst, Minneapolis, MN 55455 USA

[10] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[11] Singapore Gen Hosp, Dept Endocrinol, Singapore 0316, Singapore

[12] Tufts Univ, Jean Mayer US Dept Agr, Human Nutr Res Ctr, Dietary Assessment & Epidemiol Res Program, Boston, MA 02111 USA

[13] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA

[14] Sahlgrens Acad, Dept Clin Pharmacol, Gothenburg, Sweden

[15] Univ Helsinki, Helsinki Univ Hosp, Dept Med, Helsinki, Finland

[16] Folkhalsan Res Ctr, Helsinki, Finland

[17] Novartis Inst BioMed Res, Cambridge, MA USA

[18] Lund Univ, Dept Clin Sci, Malmo, Sweden

[19] Natl Publ Hlth Inst, Biomedicum, Dept Mol Med, Helsinki, Finland

[20] Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Helsinki, Finland

[21] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[22] Ctr Human Genet Res, Boston, MA USA

[23] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

[24] Harvard Univ, Sch Med, Cardiovasc Dis Prevent Ctr,Cardiol Div, Dept Med,Massachusetts Gen Hosp, Boston, MA USA

来源：

DIABETES | 2008年 / 57卷 / 11期

基金：

瑞典研究理事会; 英国医学研究理事会;

关键词：

D O I：

10.2337/db08-0516

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 GCYR 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 similar to 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 GCYR rs780094 is associated with opposite effects on fasting plasma triglyceride (P-meta = 3 x 10(-56)) and glucose (P-meta = 1 x 10(-13)) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reactive protein (CRP) level (P = 5 x 10(-5)). Both fine-mapping approaches revealed a common missense GCKR variant (rs1260326, Pro446Leu, 34% frequency, r(2) = 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. Diabetes 57:3112-3121, 2008

引用

页码：3112 / 3121

页数：10

共 40 条

[1] DESIGN AND FEASIBILITY
BERGLUND, G
ELMSTAHL, S
JANZON, L
LARSSON, SA
[J]. JOURNAL OF INTERNAL MEDICINE, 1993, 233 (01) : 45 - 51
[2] Long-term outcome of the Malmo Preventive Project:: mortality and cardiovascular morbidity
Berglund, G
Nilsson, P
Eriksson, KF
Nilsson, JÅ
Hedblad, B
Kristenson, H
Lingärde, F
[J]. JOURNAL OF INTERNAL MEDICINE, 2000, 247 (01) : 19 - 29
[3] Risk factor clustering in patients with hypertension and non-insulin-dependent diabetes mellitus.: The Skaraborg Hypertension Project
Bog-Hansen, E
Lindblad, U
Bengtsson, K
Ranstam, J
Melander, A
Råstam, L
[J]. JOURNAL OF INTERNAL MEDICINE, 1998, 243 (03) : 223 - 232
[4] Differences in regulatory properties between human and rat glucokinase regulatory protein
Brocklehurst, KJ
Davies, RA
Agius, L
[J]. BIOCHEMICAL JOURNAL, 2004, 378 (02) : 693 - 697
[5] Environmental factors modulate the effect of the APOE genetic polymorphism on plasma lipid concentrations:: Ecogenetic studies in a mediterranean Spanish population
Corella, D
Guillén, M
Sáiz, C
Portolés, O
Sabater, A
Cortina, S
Folch, J
González, JI
Ordovas, JM
[J]. METABOLISM-CLINICAL AND EXPERIMENTAL, 2001, 50 (08): : 936 - 944
[6] Cutter J, 2001, B WORLD HEALTH ORGAN, V79, P908
[7] Can dietary factors explain differences in serum cholesterol profiles among different ethnic groups (Chinese, Malays and Indians) in Singapore?
Deurenberg-Yap, M
Li, T
Tan, WL
van Staveren, WA
Chew, SK
Deurenberg, P
[J]. ASIA PACIFIC JOURNAL OF CLINICAL NUTRITION, 2001, 10 (01) : 39 - 45
[8] Evidence from transgenic mice that glucokinase is rate limiting for glucose utilization in the liver
Ferre, T
Riu, E
Bosch, F
Valera, A
[J]. FASEB JOURNAL, 1996, 10 (10) : 1213 - 1218
[9] Gavin JR, 1997, DIABETES CARE, V20, P1183
[10] CONTROL OF GLYCEMIA
GERICH, JE
[J]. BAILLIERES CLINICAL ENDOCRINOLOGY AND METABOLISM, 1993, 7 (03): : 551 - 586

← 1 2 3 4 →