Genetically Predicted Glucose-Dependent Insulinotropic Polypeptide (GIP) Levels and Cardiovascular Disease Risk Are Driven by Distinct Causal Variants in the GIPR Region.
Genetically Predicted Glucose-Dependent Insulinotropic Polypeptide (GIP) Levels and Cardiovascular Disease Risk Are Driven by Distinct Causal Variants in the GIPR Region.
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DOI：
10.2337/db21-0103
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发表时间：
2021-11
期刊：
影响因子：
7.7
通讯作者：
Langenberg C
中科院分区：
文献类型：
--
作者：
Bowker N;Hansford R;Burgess S;Foley CN;Auyeung VPW;Erzurumluoglu AM;Stewart ID;Wheeler E;Pietzner M;Gribble F;Reimann F;Bhatnagar P;Coghlan MP;Wareham NJ;Langenberg C
There is considerable interest in GIPR agonism to enhance the insulinotropic and extrapancreatic effects of GIP, thereby improving glycemic and weight control in type 2 diabetes (T2D) and obesity. Recent genetic epidemiological evidence has implicated higher GIPR-mediated GIP levels in raising coronary artery disease (CAD) risk, a potential safety concern for GIPR agonism. We therefore aimed to quantitatively assess whether the association between higher GIPR-mediated fasting GIP levels and CAD risk is mediated via GIPR or is instead the result of linkage disequilibrium (LD) confounding between variants at the GIPR locus. Using Bayesian multitrait colocalization, we identified a GIPR missense variant, rs1800437 (G allele; E354), as the putatively causal variant shared among fasting GIP levels, glycemic traits, and adiposity-related traits (posterior probability for colocalization [PPcoloc] > 0.97; PP explained by the candidate variant [PPexplained] = 1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in APOE (rs7412; distance to E354 ∼770 Kb; R2 with E354 = 0.004; PPcoloc > 0.99; PPexplained = 1). Further, conditioning the association between E354 and CAD on the residual LD with rs7412, we observed slight attenuation in association, but it remained significant (odds ratio [OR] per copy of E354 after adjustment 1.03; 95% CI 1.02, 1.04; P = 0.003). Instead, E354’s association with CAD was completely attenuated when conditioning on an additional established CAD signal, rs1964272 (R2 with E354 = 0.27), an intronic variant in SNRPD2 (OR for E354 after adjustment for rs1964272: 1.01; 95% CI 0.99, 1.03; P = 0.06). We demonstrate that associations with GIP and anthropometric and glycemic traits are driven by genetic signals distinct from those driving CAD and lipid traits in the GIPR region and that higher E354-mediated fasting GIP levels are not associated with CAD risk. These findings provide evidence that the inclusion of GIPR agonism in dual GIPR/GLP1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect that has yet to be assessed in clinical trials.
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影响因子：
16.2
作者：
Jujić A;Nilsson PM;Atabaki-Pasdar N;Dieden A;Tuomi T;Franks PW;Holst JJ;Torekov SS;Ravassa S;Díez J;Persson M;Ahlqvist E;Melander O;Gomez MF;Groop L;Magnusson M
通讯作者：
Magnusson M
综合基因组分析暗示有限的外周脂肪储存能力在人类胰岛素抵抗的发病机理中。
影响因子：
30.8
作者：
Lotta LA;Gulati P;Day FR;Payne F;Ongen H;van de Bunt M;Gaulton KJ;Eicher JD;Sharp SJ;Luan J;De Lucia Rolfe E;Stewart ID;Wheeler E;Willems SM;Adams C;Yaghootkar H;EPIC-InterAct Consortium;Cambridge FPLD1 Consortium;Forouhi NG;Khaw KT;Johnson AD;Semple RK;Frayling T;Perry JR;Dermitzakis E;McCarthy MI;Barroso I;Wareham NJ;Savage DB;Langenberg C;O'Rahilly S;Scott RA
通讯作者：
Scott RA
影响因子：
7.7
作者：
Berglund, Lisa M.;Lyssenko, Valeriya;Gomez, Maria F.
通讯作者：
Gomez, Maria F.
DOI：
10.1056/nejmoa1603827
发表时间：
2016-07-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Marso SP;Daniels GH;Brown-Frandsen K;Kristensen P;Mann JF;Nauck MA;Nissen SE;Pocock S;Poulter NR;Ravn LS;Steinberg WM;Stockner M;Zinman B;Bergenstal RM;Buse JB;LEADER Steering Committee;LEADER Trial Investigators
通讯作者：
LEADER Trial Investigators
影响因子：
8.2
作者：
Jujic, Amra;Atabaki-Pasdar, Naeimeh;Magnusson, Martin
通讯作者：
Magnusson, Martin