scholarly journals Genetically predicted glucose-dependent insulinotropic polypeptide (GIP) levels and cardiovascular disease risk are driven by distinct causal variants in the GIPR region

2021 ◽  
Author(s):  
Nicholas Bowker ◽  
Robert Hansford ◽  
Stephen Burgess ◽  
Christopher N. Foley ◽  
Victoria P.W. Auyeung ◽  
...  
Keyword(s):  
Weight Control ◽  
Disease Risk ◽  
Safety Concern ◽  
Cardiovascular Disease Risk ◽  
Missense Variant ◽  
Causal Variant ◽  
Potential Safety ◽  
Artery Disease ◽  
Glycaemic Traits ◽  
Cad Risk

<p><a></a><a>There is considerable interest in GIPR agonism to enhance the insulinotropic and extra-pancreatic effects of GIP, thereby improving glycaemic 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 <i>GIPR</i> locus. Using Bayesian multi-trait colocalisation, we identified a <i>GIPR</i> missense variant rs1800437 (G allele; E354) as the putatively causal variant shared between fasting GIP levels, glycaemic traits and adiposity-related traits (posterior probability for colocalisation, PP<sub>coloc</sub>>0.97; PP explained by the candidate variant; PP<sub>explained</sub>=1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in <i>APOE</i> (rs7412; distance to E354 ~770Kb; R<sup>2</sup> with E354 = 0.004; PP<sub>coloc</sub>>0.99; PP<sub>explained</sub>=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 (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, (R<sup>2</sup> with E354=0.27), an intronic variant in <i>SNRPD2</i> (OR for E354 after adjustment for rs1964272: 1.01; 95% CI, 0.99, 1.03; P=0.06). We demonstrate that associations with GIP, anthropometric and glycaemic traits are driven by distinct genetic signals from those driving CAD and lipid traits in the <i>GIPR</i> region, and 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/GLP-1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect which has yet to be assessed in clinical trials.</a></p>

scholarly journals Genetically predicted glucose-dependent insulinotropic polypeptide (GIP) levels and cardiovascular disease risk are driven by distinct causal variants in the GIPR region

2021 ◽  
Author(s):  
Nicholas Bowker ◽  
Robert Hansford ◽  
Stephen Burgess ◽  
Christopher N. Foley ◽  
Victoria P.W. Auyeung ◽  
...  
Keyword(s):  
Weight Control ◽  
Disease Risk ◽  
Safety Concern ◽  
Cardiovascular Disease Risk ◽  
Missense Variant ◽  
Causal Variant ◽  
Potential Safety ◽  
Artery Disease ◽  
Glycaemic Traits ◽  
Cad Risk

<p><a></a><a>There is considerable interest in GIPR agonism to enhance the insulinotropic and extra-pancreatic effects of GIP, thereby improving glycaemic 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 <i>GIPR</i> locus. Using Bayesian multi-trait colocalisation, we identified a <i>GIPR</i> missense variant rs1800437 (G allele; E354) as the putatively causal variant shared between fasting GIP levels, glycaemic traits and adiposity-related traits (posterior probability for colocalisation, PP<sub>coloc</sub>>0.97; PP explained by the candidate variant; PP<sub>explained</sub>=1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in <i>APOE</i> (rs7412; distance to E354 ~770Kb; R<sup>2</sup> with E354 = 0.004; PP<sub>coloc</sub>>0.99; PP<sub>explained</sub>=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 (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, (R<sup>2</sup> with E354=0.27), an intronic variant in <i>SNRPD2</i> (OR for E354 after adjustment for rs1964272: 1.01; 95% CI, 0.99, 1.03; P=0.06). We demonstrate that associations with GIP, anthropometric and glycaemic traits are driven by distinct genetic signals from those driving CAD and lipid traits in the <i>GIPR</i> region, and 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/GLP-1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect which has yet to be assessed in clinical trials.</a></p>

scholarly journals Genetically predicted glucose-dependent insulinotropic polypeptide (GIP) levels and cardiovascular disease risk are driven by distinct causal variants in the GIPR region

2021 ◽  
Author(s):  
Nicholas Bowker ◽  
Robert Hansford ◽  
Stephen Burgess ◽  
Christopher N. Foley ◽  
Victoria P.W. Auyeung ◽  
...  
Keyword(s):  
Weight Control ◽  
Disease Risk ◽  
Safety Concern ◽  
Cardiovascular Disease Risk ◽  
Missense Variant ◽  
Causal Variant ◽  
Potential Safety ◽  
Artery Disease ◽  
Glycaemic Traits ◽  
Cad Risk

<p><a></a><a>There is considerable interest in GIPR agonism to enhance the insulinotropic and extra-pancreatic effects of GIP, thereby improving glycaemic 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 <i>GIPR</i> locus. Using Bayesian multi-trait colocalisation, we identified a <i>GIPR</i> missense variant rs1800437 (G allele; E354) as the putatively causal variant shared between fasting GIP levels, glycaemic traits and adiposity-related traits (posterior probability for colocalisation, PP<sub>coloc</sub>>0.97; PP explained by the candidate variant; PP<sub>explained</sub>=1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in <i>APOE</i> (rs7412; distance to E354 ~770Kb; R<sup>2</sup> with E354 = 0.004; PP<sub>coloc</sub>>0.99; PP<sub>explained</sub>=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 (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, (R<sup>2</sup> with E354=0.27), an intronic variant in <i>SNRPD2</i> (OR for E354 after adjustment for rs1964272: 1.01; 95% CI, 0.99, 1.03; P=0.06). We demonstrate that associations with GIP, anthropometric and glycaemic traits are driven by distinct genetic signals from those driving CAD and lipid traits in the <i>GIPR</i> region, and 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/GLP-1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect which has yet to be assessed in clinical trials.</a></p>

scholarly journals Physical activity, sedentary behavior and risk of coronary artery disease, myocardial infarction and ischemic stroke: a two-sample Mendelian randomization study

2021 ◽  
Author(s):  
Martin Bahls ◽  
Michael F. Leitzmann ◽  
André Karch ◽  
Alexander Teumer ◽  
Marcus Dörr ◽  
...  
Keyword(s):  
Physical Activity ◽  
Myocardial Infarction ◽  
Coronary Artery Disease ◽  
Ischemic Stroke ◽  
Coronary Artery ◽  
Sedentary Behavior ◽  
Mendelian Randomization ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Artery Disease

Abstract Aims Observational evidence suggests that physical activity (PA) is inversely and sedentarism positively related with cardiovascular disease risk. We performed a two-sample Mendelian randomization (MR) analysis to examine whether genetically predicted PA and sedentary behavior are related to coronary artery disease, myocardial infarction, and ischemic stroke. Methods and results We used single nucleotide polymorphisms (SNPs) associated with self-reported moderate to vigorous PA (n = 17), accelerometer based PA (n = 7) and accelerometer fraction of accelerations > 425 milli-gravities (n = 7) as well as sedentary behavior (n = 6) in the UK Biobank as instrumental variables in a two sample MR approach to assess whether these exposures are related to coronary artery disease and myocardial infarction in the CARDIoGRAMplusC4D genome-wide association study (GWAS) or ischemic stroke in the MEGASTROKE GWAS. The study population included 42,096 cases of coronary artery disease (99,121 controls), 27,509 cases of myocardial infarction (99,121 controls), and 34,217 cases of ischemic stroke (404,630 controls). We found no associations between genetically predicted self-reported moderate to vigorous PA, accelerometer-based PA or accelerometer fraction of accelerations > 425 milli-gravities as well as sedentary behavior with coronary artery disease, myocardial infarction, and ischemic stroke. Conclusions These results do not support a causal relationship between PA and sedentary behavior with risk of coronary artery disease, myocardial infarction, and ischemic stroke. Hence, previous observational studies may have been biased. Graphic abstract

scholarly journals Polygenic Hyperlipidemias and Coronary Artery Disease Risk

2019 ◽  
Author(s):  
Pietari Ripatti ◽  
Joel T Rämö ◽  
Nina J Mars ◽  
Sanni Söderlund ◽  
Christian Benner ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Cumulative Exposure ◽  
Risk Scores ◽  
Lipid Levels ◽  
Artery Disease ◽  
The Impact ◽  
Cad Risk

AbstractBackgroundHyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). Monogenic familial hypercholesterolemia associates with higher increase in CAD risk than expected from a single LDL-C measurement, likely due to lifelong cumulative exposure to high LDL-C. It remains unclear to what extent a high polygenic load of LDL-C or TG-increasing variants associates with increased CAD risk.Methods and ResultsWe derived polygenic risk scores (PRS) with ∼6M variants for LDL-C and TG with weights from a UK biobank-based genome-wide association study with ∼500K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the FINRISK cohort, and to CAD risk in 135 300 individuals (13 695 CAD cases) from the FinnGen project.In FINRISK, LDL-C ranged from 2.83 (95% CI 2.79-2.89) to 3.80 (3.72-3.88) and TG from 0.99 (0.95-1.01) to 1.52 (1.48-1.58) mmol/l between the lowest and highest 5% of the respective PRS distributions. The corresponding CAD prevalences ranged from 8.2% to 12.7% for the LDL-C PRS and from 8.2% to 12.1% for the TG PRS in FinnGen. Furthermore, CAD risk was 1.36-fold higher (OR, 95% CI 1.24-1.49) for the LDL-C PRS and 1.31-fold higher (1.20-1.44) for the TG PRS for those with the PRS >95th percentile vs those without. These estimates were only slightly attenuated when adjusting for a CAD PRS (OR 1.26 [95% CI 1.15-1.39] for LDL-C and 1.21 [1.10-1.32] for TG PRS).ConclusionsThe CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and mostly independent of a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing more direct guidance for clinical translation.

Measurement of Toe-Brachial Indices in People with Subnormal Toe Pressures

2018 ◽  
Vol 108 (2) ◽  
pp. 115-125 ◽  
Author(s):  
Sylvia McAra ◽  
Robert Trevethan
Keyword(s):  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Careful Consideration ◽  
Descriptive Statistics ◽  
Insufficient Information ◽  
Peripheral Artery ◽  
Sequential Position ◽  
Lower Baseline ◽  
Single Reading ◽  
Artery Disease

Background: Insufficient information exists about the nature of toe-brachial indices (TBIs) and how best to obtain them, yet their validity may be particularly important for the identification and management of peripheral artery disease and cardiovascular disease risk. We explore ways in which valid TBI measurements might be obtained. Methods: The TBI data were recorded from 97 people with subnormal toe pressures. Most people provided three TBI readings from each foot on six different occasions over a 6-month period. The foot with the lower baseline TBI was noted. Results: For most people, only small inconsistencies existed among the three readings taken from each foot on a single occasion, and there were no consistent differences based on sequence. However, for some people there were noticeable and unsystematic differences among the measures. Selecting any specific one of the three readings based on its sequential position, or averaging specific readings, did not yield TBIs that were unequivocally typical for a person, and taking the lowest reading of each set seemed to offer the most expedient solution in this context. That permitted baseline descriptive statistics to be produced for both the higher and lower pressure feet, between which there was a statistically significant TBI difference. Conclusions: Accurate and consistent TBI readings cannot be assumed for people with subnormal toe pressures, and taking only a single reading or indiscriminately averaging readings seems inadvisable. Two readings and, if they are discrepant, additional readings, are recommended for each foot, ideally on several occasions, and careful consideration should be given to determine the most representative reading for each foot. Cuff sizes and other sources of inaccuracy or distortion should not be ignored, and standardized protocols for obtaining TBIs are recommended.

An Overview of Genetic Factors Influencing Plasma Lipid Levels and Coronary Artery Disease Risk

1999 ◽  
Vol 123 (12) ◽  
pp. 1219-1222 ◽  
Author(s):  
I. Cetin Ozturk ◽  
Anthony A. Killeen
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Disease Risk ◽  
Plasma Lipid ◽  
Density Lipoprotein ◽  
Major Effect ◽  
Genetic Component ◽  
Cholesterol Acyl Transferase ◽  
Artery Disease ◽  
Cad Risk

Abstract Background.—Coronary artery disease (CAD) is a major cause of morbidity and mortality in most Western countries and its origin involves a significant genetic component. Methods.—Genetic and epidemiologic studies have been performed to identify factors that influence the CAD risk in the population. Results.—The primary loci that have been demonstrated to be associated with increased CAD risk owing to genetic mutations include the low-density lipoprotein receptor, apolipoprotein B-100, and lipoprotein(a). Additional implicated loci include lipoprotein lipase, apolipoprotein CII, cholesteryl ester transfer protein, apolipoprotein AI, and lecithin–cholesterol acyl transferase. Conclusions.—Numerous mutations in known genes exert a major effect on CAD risk in some patients. However, in most patients with CAD, the genetic component is believed to be attributable to the aggregate effect of loci that, individually, exert only a minor influence on lipoprotein levels.

scholarly journals Polygenic Hyperlipidemias and Coronary Artery Disease Risk

2020 ◽  
Vol 13 (2) ◽  
Author(s):  
Pietari Ripatti ◽  
Joel T. Rämö ◽  
Nina J. Mars ◽  
Yu Fu ◽  
Jake Lin ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Odds Ratio ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Risk Scores ◽  
Lipid Levels ◽  
Artery Disease ◽  
The Impact ◽  
Cad Risk

Background: Hyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). While monogenic familial hypercholesterolemia associates with severely increased CAD risk, it remains less clear to what extent a high polygenic load of a large number of LDL (low-density lipoprotein) cholesterol (LDL-C) or triglyceride (TG)-increasing variants associates with increased CAD risk. Methods: We derived polygenic risk scores (PRSs) with ≈6M variants separately for LDL-C and TG with weights from a UK Biobank–based genome-wide association study with ≈324K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the National FINRISK Study (FINRISK) cohort and to CAD risk in 135 638 individuals (13 753 CAD cases) from the FinnGen project (FinnGen). Results: In FINRISK, median LDL-C was 3.39 (95% CI, 3.38–3.40) mmol/L, and it ranged from 2.87 (95% CI, 2.82–2.94) to 3.78 (95% CI, 3.71–3.83) mmol/L between the lowest and highest 5% of the LDL-C PRS distribution. Median TG was 1.19 (95% CI, 1.18–1.20) mmol/L, ranging from 0.97 (95% CI, 0.94–1.00) to 1.55 (95% CI, 1.48–1.61) mmol/L with the TG PRS. In FinnGen, comparing the highest 5% of the PRS to the lowest 95%, CAD odds ratio was 1.36 (95% CI, 1.24–1.49) for the LDL-C PRS and 1.31 (95% CI, 1.19–1.43) for the TG PRS. These estimates were only slightly attenuated when adjusting for a CAD PRS (odds ratio, 1.26 [95% CI, 1.16–1.38] for LDL-C and 1.24 [95% CI, 1.13–1.36] for TG PRS). Conclusions: The CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and partially overlapping with a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing additional guidance for clinical translation.

scholarly journals Genetically modulated educational attainment and coronary disease risk

2019 ◽  
Vol 40 (29) ◽  
pp. 2413-2420 ◽  
Author(s):  
Lingyao Zeng ◽  
Ioanna Ntalla ◽  
Thorsten Kessler ◽  
Adnan Kastrati ◽  
Jeanette Erdmann ◽  
...  
Keyword(s):  
Risk Factors ◽  
Educational Attainment ◽  
Genetic Variants ◽  
Disease Risk ◽  
Inverse Correlation ◽  
Genetic Education ◽  
Genome Wide ◽  
Artery Disease ◽  
Meta Analyses ◽  
Cad Risk

Abstract Aims Genetic disposition and lifestyle factors are understood as independent components underlying the risk of multiple diseases. In this study, we aim to investigate the interplay between genetics, educational attainment—an important denominator of lifestyle—and coronary artery disease (CAD) risk. Methods and results Based on the effect sizes of 74 genetic variants associated with educational attainment, we calculated a ‘genetic education score’ in 13 080 cases and 14 471 controls and observed an inverse correlation between the score and risk of CAD [P = 1.52 × 10−8; odds ratio (OR) 0.79, 95% confidence interval (CI) 0.73–0.85 for the higher compared with the lowest score quintile]. We replicated in 146 514 individuals from UK Biobank (P = 1.85 × 10−6) and also found strong associations between the ‘genetic education score’ with ‘modifiable’ risk factors including smoking (P = 5.36 × 10−23), body mass index (BMI) (P = 1.66 × 10−30), and hypertension (P = 3.86 × 10−8). Interestingly, these associations were only modestly attenuated by adjustment for years spent in school. In contrast, a model adjusting for BMI and smoking abolished the association signal between the ‘genetic education score’ and CAD risk suggesting an intermediary role of these two risk factors. Mendelian randomization analyses performed with summary statistics from large genome-wide meta-analyses and sensitivity analysis using 1271 variants affecting educational attainment (OR 0.68 for the higher compared with the lowest score quintile; 95% CI 0.63–0.74; P = 3.99 × 10−21) further strengthened these findings. Conclusion Genetic variants known to affect educational attainment may have implications for a health-conscious lifestyle later in life and subsequently affect the risk of CAD.

MirSNPs in clopidogrel metabolism genes predict cardiovascular disease risk: a case–control study and meta-analysis

2020 ◽  
Author(s):  
Anu Radha Sharma ◽  
Sourav Patagi ◽  
Abdul Razak UK ◽  
Ranjan Shetty ◽  
Shashikiran Umakanth ◽  
...  
Keyword(s):  
Case Control Study ◽  
Disease Risk ◽  
Meta Analysis ◽  
Cardiovascular Disease Risk ◽  
Case Control ◽  
Amplification Refractory Mutation System ◽  
Mutation System ◽  
Artery Disease ◽  
Relationship Of ◽  
Control Study

Aim: The present study was conducted to decipher the inter-relationship of SNPs and miRNAs involved in pharmacogenomics of clopidogrel on predisposition to cardiovascular diseases (CVDs). Materials & methods: A case–control study was conducted on 410 cases and 386 controls to analyze the association of 13 mirSNPs on CVDs risk. Genotyping was performed by tetra-primer amplification refractory mutation system PCR and validated using Sanger DNA sequencing. miRNA expression analysis was performed using TaqMan assays. A meta-analysis was performed for PON1 rs662 with coronary artery disease. Results & conclusion: PON1 rs662, PON1 rs3917577, CYP3A5 rs15524, COL4A1 rs874204 and PTGIR rs1126510 polymorphisms showed association with CVDs. The miRNA hsa-miR-224-5p showed differential expression in the PON1 rs3917577 GG genotype. The meta-analysis showed the population-specific impact of PON1 rs662 on South Asian and Middle East populations.

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