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

Orho-Melander, Marju (author): Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups

Melander, Olle (author): Lund University,Lunds universitet,Kardiovaskulär forskning - hypertoni,Forskargrupper vid Lunds universitet,Cardiovascular Research - Hypertension,Lund University Research Groups

Guiducci, Candace (author)

Perez-Martinez, Pablo (author)

Corella, Dolores (author)

Roos, Charlotta (author): Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups

Tewhey, Ryan (author)

Rieder, Mark J. (author)

Hall, Jennifer (author)

Abecasis, Goncalo (author)

Tai, E. Shyong (author)

Welch, Cullan (author)

Arnett, Donna K. (author)

Lyssenko, Valeriya (author): Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups

Lindholm, Eero (author): Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups

Saxena, Richa (author)

de Bakker, Paul I. W. (author)

Burtt, Noel (author)

Voight, Benjamin F. (author)

Hirschhorn, Joel N. (author)

Tucker, Katherine L. (author)

Hedner, Thomas (author)

Tuomi, Tiinaimaija (author)

Isomaa, Bo (author)

Eriksson, Karl-Fredrik (author): Lund University,Lunds universitet,Vaskulära sjukdomar - kliniska studier,Forskargrupper vid Lunds universitet,Vascular Diseases - Clinical Research,Lund University Research Groups

Taskinen, Marja-Riitta (author)

Wahlstrand, Bjoern (author)

Hughes, Thomas E. (author)

Parnell, Laurence D. (author)

Lai, Chao-Qiang (author)

Berglund, Göran (author): Lund University,Lunds universitet,Internmedicin - epidemiologi,Forskargrupper vid Lunds universitet,Internal Medicine - Epidemiology,Lund University Research Groups

Peltonen, Leena (author)

Vartiainen, Erkki (author)

Jousilahti, Pekka (author)

Havulinna, Aki S. (author)

Salomaa, Veikko (author)

Nilsson, Peter (author): Lund University,Lunds universitet,Internmedicin - epidemiologi,Forskargrupper vid Lunds universitet,Internal Medicine - Epidemiology,Lund University Research Groups

Groop, Leif (author)

Altshuler, David (author)

Ordovas, Jose M. (author)

Kathiresan, Sekar (author)

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(creator_code:org_t)

American Diabetes Association, 2008
2008
English.
In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 57:11, s. 3112-3121

Related links:: http://dx.doi.org/10... (free); show more...; http://diabetes.diab...; https://lup.lub.lu.s...; https://doi.org/10.2...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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

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By the author/editor: Orho-Melander, M ...; Melander, Olle; Guiducci, Candac ...; Perez-Martinez, ...; Corella, Dolores; Roos, Charlotta; show more...; Tewhey, Ryan; Rieder, Mark J.; Hall, Jennifer; Abecasis, Goncal ...; Tai, E. Shyong; Welch, Cullan; Arnett, Donna K.; Lyssenko, Valeri ...; Lindholm, Eero; Saxena, Richa; de Bakker, Paul ...; Burtt, Noel; Voight, Benjamin ...; Hirschhorn, Joel ...; Tucker, Katherin ...; Hedner, Thomas; Tuomi, Tiinaimai ...; Isomaa, Bo; Eriksson, Karl-F ...; Taskinen, Marja- ...; Wahlstrand, Bjoe ...; Hughes, Thomas E ...; Parnell, Laurenc ...; Lai, Chao-Qiang; Berglund, Göran; Peltonen, Leena; Vartiainen, Erkk ...; Jousilahti, Pekk ...; Havulinna, Aki S ...; Salomaa, Veikko; Nilsson, Peter; Groop, Leif; Altshuler, David; Ordovas, Jose M.; Kathiresan, Seka ...; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

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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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