High Blood Pressure and Intraocular Pressure: A Mendelian Randomization Study

Plotnikov, Denis; Huang, Yu; Khawaja, Anthony P; Foster, Paul J.; Zhu, Zhuoting; Guggenheim, Jeremy A.; He, Mingguang

doi:10.1167/iovs.63.6.29

Cited by 22 publications

(19 citation statements)

References 54 publications

(51 reference statements)

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“…A GWAS for autorefraction-measured refractive error was carried out in 95 619 UK Biobank participants of European ancestry aged 40 to 69 years who underwent noncycloplegic autorefraction. Details of the sample and the GWAS parameters have been reported previously …”

Section: Methodsmentioning

confidence: 99%

Association Between Polygenic Risk Score and Risk of Myopia

et al. 2020

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; for the UK Biobank Eye and Vision Consortium IMPORTANCE Myopia is a leading cause of untreatable visual impairment and is increasing in prevalence worldwide. Interventions for slowing childhood myopia progression have shown success in randomized clinical trials; hence, there is a need to identify which children would benefit most from treatment intervention. OBJECTIVES To examine whether genetic information alone can identify children at risk of myopia development and whether including a child's genetic predisposition to educational attainment is associated with improved genetic prediction of the risk of myopia. DESIGN, SETTING, AND PARTICIPANTS Meta-analysis of 3 genome-wide association studies (GWAS) including a total of 711 984 individuals. These were a published GWAS for educational attainment and 2 GWAS for refractive error in the UK Biobank, which is a multisite cohort study that recruited participants between January 2006 and October 2010. A polygenic risk score was applied in a population-based validation sample examined between September 1998 and September 2000 (Avon Longitudinal Study of Parents and Children [ALSPAC] mothers). Data analysis was performed from February 2018 to May 2019. MAIN OUTCOMES AND MEASURES The primary outcome was the area under the receiver operating characteristic curve (AUROC) in analyses for predicting myopia, using noncycloplegic autorefraction measurements for myopia severity levels of less than or equal to −0.75 diopter (D) (any), less than or equal to −3.00 D (moderate), or less than or equal to −5.00 D (high). The predictor variable was a polygenic risk score (PRS) derived from genome-wide association study data for refractive error (n = 95 619), age of onset of spectacle wear (n = 287 448), and educational attainment (n = 328 917). RESULTS A total of 383 067 adults aged 40 to 69 years from the UK Biobank were included in the new GWAS analyses. The PRS was evaluated in 1516 adults aged 24 to 51 years from the ALSPAC mothers cohort. The PRS had an AUROC of 0.67 (95% CI, 0.65-0.70) for myopia, 0.75 (95% CI, 0.70-0.79) for moderate myopia, and 0.73 (95% CI, 0.66-0.80) for high myopia. Inclusion in the PRS of information associated with genetic predisposition to educational attainment marginally improved the AUROC for myopia (AUROC, 0.674 vs 0.668; P = .02), but not those for moderate and high myopia. Individuals with a PRS in the top 10% were at 6.1-fold higher risk (95% CI, 3.4-10.9) of high myopia. CONCLUSIONS AND RELEVANCE A personalized medicine approach may be feasible for detecting very young children at risk of myopia. However, accuracy must improve further to merit uptake in clinical practice; currently, cycloplegic autorefraction remains a better indicator of myopia risk (AUROC, 0.87).

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Section: Methodsmentioning

confidence: 99%

Association Between Polygenic Risk Score and Risk of Myopia

et al. 2020

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“…Cluster 2 GWAS highlighted some brain-specific genes such as C1QL1 (complement C1q like 1), MAPT (microtubule associated protein tau), and GFAP (glial fibrillary acidic protein). C1QL1, MAPT, and GFAP are known genotypes associated with blood pressure traits [76][77][78].…”

Section: Discussionmentioning

confidence: 99%

Cluster Analysis Identified Clinically Relevant Metabolic Syndrome Endophenotypes

Lim

Chen

et al. 2022

Preprint

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Aims/hypothesis Metabolic syndrome (MetS) is a collection of cardiovascular risk factors; however, the high prevalence and heterogeneity impede proper and effective clinical management of MetS. In order for precision medicine to work for MetS, we aimed to identify clinically relevant MetS sub-phenotypes. Methods We conducted cluster analysis on individuals from UK Biobank based on MetS criteria to reveal endophenotypes, identified the corresponding cardiometabolic traits and established the association across 21 clinical outcomes. Genome-wide association studies were conducted to identify associated genotypic traits. We further compared the genotypic traits to reveal endophenotypes-specific genotypic traits. Lastly, potential drug targets were identified for the different endophenotypes. Results Five MetS subgroups were identified which were Cluster 1 (C1): non-descriptive, Cluster 2 (C2): hypertensive, Cluster 3 (C3): obese, Cluster 4 (C4): lipodystrophy-like, and Cluster 5 (C5): hyperglycaemic. Some MetS clusters had higher CVD risks such as C1 (OR=6.765) and C5 (OR=9.486). Despite being non-descriptive across all cardiometabolic traits, C1 had higher risks for most clinical outcomes. MetS clusters also had different risks to various types of cancers. GWAS of each MetS clusters revealed different genotypic traits. LPCAT2 was associated with all clusters except C2 and expression is specific to immune cells. C1 GWAS revealed novel findings of TRIM63, MYBPC3, MYLPF, and RAPSN. Intriguingly, C1, C3, and C4 were associated with genes highly expressed in brain tissues: CN1H2, TMEM151A, MT3, and C1QTNF4. The cluster-specific genotypic traits also revealed potential drug repurposing targets specific to the endophenotypes. Conclusion/interpretation MetS is highly heterogeneous with endophenotypes that are different in terms of phenotypic and genotypic traits. GWAS of subgroups revealed novel cardiometabolic genotypes which were masked by heterogeneity of MetS.

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“…Most of all, ED involves decreased activity of the endothelial nitric oxide synthase (eNOS encoded by NOS3) and thus reduced bioavailability of vasodilatory nitric oxide (NO). Importantly, large-scale GWASs identified polymorphisms in the NOS3 gene as significantly correlated with BP traits [27,38]. Although well explored, the therapeutic potential of targeting the NO pathway is unexploited, as no drugs targeting eNOS are currently in clinical use for systemic HT (reviewed elsewhere [43]).…”

Section: The Nitric Oxide Pathwaymentioning

confidence: 99%

Novel biomarkers and emerging tools to identify causal molecular pathways in hypertension and associated cardiovascular diseases

2023

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Hypertension (HT) is a modifiable risk factor for life-threatening cardiovascular diseases (CVDs) including coronary artery disease, heart failure, or stroke. Despite significant progress in understanding the pathophysiological mechanisms of the disease, the molecular pathways targeted by HT treatment remain largely unchanged. This warrants the need for finding novel biomarkers, which are causally related to persistent high blood pressure (BP) and may be pharmacologically targeted. Analytical output derived from large-scale biobanks, containing high-throughput genetic and biochemical data, such as OLINK and SomaScan-based proteomics or Nuclear Magnetic Resonance-based metabolomics, as well as novel analytical tools including the Mendelian randomization (MR) approach, enabling genetic causal inference, may create new treatment opportunities for HT and related CVDs. MR analysis may constitute additional evidence for observational studies and facilitate selection of drug targets for clinical testing and has been already used to nominate potentially causal biomarkers for HT and CVDs such as circulating glycine, branched-chain amino acids, lipoprotein(a), insulin-like growth factor 1, or fibronectin 1. Using the MR framework, genetic proxies for targets of already known drugs, such as statins, PCSK9, and ACE inhibitors, may additionally be informative about potential side effects and eventually contribute to more personalized medicine. Finally, genetic causal inference may disentangle independent direct effects of correlated traits such as lipid classes or markers of inflammation on cardiovascular clinical outcomes such as atherosclerosis and HT. While several novel HT-targeting drugs are currently under clinical investigation (e.g. brain renin-angiotensin-aldosterone system inhibitors or endothelin-1 receptor antagonists), analysis of high-throughput proteomic and metabolomic data from well-powered studies may deliver novel druggable molecular targets for HT and associated CVDs.

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High Blood Pressure and Intraocular Pressure: A Mendelian Randomization Study

Cited by 22 publications

References 54 publications

Association Between Polygenic Risk Score and Risk of Myopia

Association Between Polygenic Risk Score and Risk of Myopia

Cluster Analysis Identified Clinically Relevant Metabolic Syndrome Endophenotypes

Novel biomarkers and emerging tools to identify causal molecular pathways in hypertension and associated cardiovascular diseases

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