Heritability of glaucoma and glaucoma-related endophenotypes:Systematic review and meta-analysis

We have systematically extracted all available heritability (h2) estimates of glaucoma and related endophenotypes from the literature and summarized the evidence by meta-analysis. Glaucoma endophenotypes were classified into 10 clusters: intraocular pressure, anterior chamber size, central corneal thickness, cup-to-disc ratio, disc size, cup size, corneal hysteresis, retinal nerve fiber layer thickness, cup shape, and peripapillary atrophy. Random-effects meta-analyses were performed for each cluster. For clusters with n ≥ 10 h2 estimates, we also performed subgroup and meta-regression analyses. The literature search yielded 53 studies. The h2 of primary open-angle glaucoma ranged from 0.17 to 0.81, and was 0.65 for primary angle-closure glaucoma in a single study. The pooled endophenotype h2 estimates were intraocular pressure, 0.43 (0.38-0.48); anterior chamber size, 0.67 (0.60-0.74); central corneal thickness, 0.81 (0.73-0.87); cup-to-disc ratio, 0.56 (0.44-0.68); disc size, 0.61 (0.37-0.81); cup size, 0.58 (0.35-0.78); corneal hysteresis, 0.40 (0.29-0.51); retinal nerve fiber layer thickness, 0.73 (0.42-0.91); cup shape, 0.62 (0.22-0.90); and peripapillary atrophy, 0.73 (0.70-0.75). We identified mean age, ethnicity, and study design as major sources of heterogeneity. Our results confirm the strong influence of genetic factors on glaucoma and its endophenotypes. These pooled h2 estimates provide the most accurate assessment to date of the total genetic variation that can ultimately be explained by gene-finding studies

Development and validation of a questionnaire-based myopia proxy in adults:the LifeLines Cohort Study

Aims To build a questionnaire-based myopia proxy and to validate the proxy by confirming its association with educational attainment and a Polygenic Risk Score (PRS) for myopia. Methods Data were collected between 2014 and 2017 from 88 646 Dutch adults from the LifeLines Cohort. First, we performed principal component analysis (PCA) to responses of five refraction-status questions. Second, we measured the refractive state in a subset of LifeLines participants (n=326) and performed logistic regression using myopia (mean spherical equivalent</p

Development and validation of a questionnaire-based myopia proxy in adults:the LifeLines Cohort Study

Aims To build a questionnaire-based myopia proxy and to validate the proxy by confirming its association with educational attainment and a Polygenic Risk Score (PRS) for myopia. Methods Data were collected between 2014 and 2017 from 88 646 Dutch adults from the LifeLines Cohort. First, we performed principal component analysis (PCA) to responses of five refraction-status questions. Second, we measured the refractive state in a subset of LifeLines participants (n=326) and performed logistic regression using myopia (mean spherical equivalent</p

Heritability and the Genetic Correlation of Heart Rate Variability and Blood Pressure in &gt;29 000 Families The Lifelines Cohort Study:The Lifelines Cohort Study

Dysregulation of the cardiac autonomic nervous system, as indexed by reduced heart rate variability (HRV), has been associated with the development of high blood pressure (BP). However, the underlying pathological mechanisms are not yet fully understood. This study aimed to estimate heritability of HRV and BP and to determine their genetic overlap. We used baseline data of the 3-generation Lifelines population-based cohort study (n=149 067; mean age, 44.5). In-house software was used to calculate root mean square of successive differences and SD of normal-to-normal intervals as indices of HRV based on 10-second resting ECGs. BP was recorded with an automatic BP monitor. We estimated heritabilities and genetic correlations with variance components methods in ASReml software. We additionally estimated genetic correlations with bivariate linkage disequilibrium score regression using publicly available genome-wide association study data. The heritability (SE) estimates were 15.6% (0.90%) for SD of normal-to-normal intervals and 17.9% (0.90%) for root mean square of successive differences. For BP measures, they ranged from 24.4% (0.90%) for pulse pressure to 30.3% (0.90%) for diastolic BP. Significant negative genetic correlations (all P<0.0001) of root mean square of successive differences/SD of normal-to-normal intervals with systolic BP (-0.20/-0.16) and with diastolic BP (-0.15/-0.13) were observed. LD score regression showed largely consistent genetic correlation estimates of root mean square of successive differences/SD of normal-to-normal intervals with systolic BP (range, -0.08 to -0.23) and diastolic BP (range, -0.20 to -0.27). Our study shows a substantial contribution of genetic factors in explaining the variance of HRV and BP measures in the general population. The significant negative genetic correlations between HRV and BP indicate that genetic pathways for HRV and BP partially overlap

Heritability of glaucoma and glaucoma-related endophenotypes:Systematic review and meta-analysis protocol

Introduction Glaucoma is the second leading cause of age-related vision loss worldwide; it is an umbrella term that is used to describe a set of complex ocular disorders with a multifactorial aetiology. Both genetic and lifestyle risk factors for glaucoma are well established. Thus far, however, systematic reviews on the heritability of glaucoma have focused on the heritability of primary open-angle glaucoma only. No systematic review has comprehensively reviewed or meta-analysed the heritability of other types of glaucoma, including glaucoma-related endophenotypes. The aim of this study will be to identify relevant scientific literature regarding the heritability of both glaucoma and related endophenotypes and summarise the evidence by performing a systematic review and meta-analysis. Methods and analysis This systematic review will follow the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols 2015 checklist, which provides a standardised approach for carrying out systematic reviews. To capture as much literature as possible, a comprehensive step-by-step systematic search will be undertaken in MEDLINE (PubMed), EMBASE, Web of Science and ScienceDirect, and studies published until 31 December 2017 will be included. Two reviewers will independently search the articles for eligibility according to predefined selection criteria. A database will be used for screening of eligible articles. The quality of the included studies will be rated independently by two reviewers, using the National Health Institute Quality Assessment tool for Observational Cohort and Cross-Sectional Studies. A random-effects model will be used for the meta-analysis. This systematic review is registered with the International Prospective Register of Systematic Reviews with a registration number: CRD42017064504. Ethics and dissemination We will use secondary data from peer-reviewed published articles, and hence there is no requirement for ethics approval. The results of this systematic review will be disseminated through publication in a peer-reviewed scientific journal

Elliptic flow of charged particles in Pb-Pb collisions at 2.76 TeV

We report the first measurement of charged particle elliptic flow in Pb-Pb collisions at 2.76 TeV with the ALICE detector at the CERN Large Hadron Collider. The measurement is performed in the central pseudorapidity region (|$\eta$|<0.8) and transverse momentum range 0.2< $p_{\rm T}$< 5.0 GeV/$c$. The elliptic flow signal v$_2$, measured using the 4-particle correlation method, averaged over transverse momentum and pseudorapidity is 0.087 $\pm$ 0.002 (stat) $\pm$ 0.004 (syst) in the 40-50% centrality class. The differential elliptic flow v$_2(p_{\rm T})$ reaches a maximum of 0.2 near $p_{\rm T}$ = 3 GeV/$c$. Compared to RHIC Au-Au collisions at 200 GeV, the elliptic flow increases by about 30%. Some hydrodynamic model predictions which include viscous corrections are in agreement with the observed increase.Comment: 10 pages, 4 captioned figures, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/389

Association of Systemic Medication Use with Glaucoma and Intraocular Pressure:The European Eye Epidemiology Consortium

Purpose: To investigate the association of commonly used systemic medications with glaucoma and intraocular pressure (IOP) in the European population. Design: Meta-analysis of 11 population-based cohort studies of the European Eye Epidemiology Consortium. Participants: The glaucoma analyses included 143 240 participants and the IOP analyses included 47 177 participants. Methods: We examined associations of 4 categories of systemic medications—antihypertensive medications (β-blockers, diuretics, calcium channel blockers [CCBs], α-agonists, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers), lipid-lowering medications, antidepressants, and antidiabetic medications—with glaucoma prevalence and IOP. Glaucoma ascertainment and IOP measurement method were according to individual study protocols. Results of multivariable regression analyses of each study were pooled using random effects meta-analyses. Associations with antidiabetic medications were examined in participants with diabetes only. Main Outcome Measures: Glaucoma prevalence and IOP. Results: In the meta-analyses of our maximally adjusted multivariable models, use of CCBs was associated with a higher prevalence of glaucoma (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.08 to 1.39). This association was stronger for monotherapy of CCBs with direct cardiac effects (OR, 1.96; 95% CI, 1.23 to 3.12). No other antihypertensive medications, lipid-lowering medications, antidepressants, or antidiabetic medications were associated with glaucoma. Use of systemic β-blockers was associated with a lower IOP (β coefficient, −0.33 mmHg; 95% CI, −0.57 to −0.08 mmHg). Monotherapy of both selective systemic β-blockers (β coefficient, −0.45 mmHg; 95% CI −0.74 to −0.16 mmHg) and nonselective systemic β-blockers (β coefficient, −0.54 mmHg; 95% CI, −0.94 to −0.15 mmHg) was associated with lower IOP. A suggestive association was found between use of high-ceiling diuretics and lower IOP (β coefficient, −0.30 mmHg; 95% CI, −0.47 to −0.14 mmHg) but not when used as monotherapy. No other antihypertensive medications, lipid-lowering medications, antidepressants, or antidiabetic medications were associated with IOP. Conclusions: We identified a potentially harmful association between use of CCBs and glaucoma prevalence. Additionally, we observed and quantified the association of lower IOP with systemic β-blocker use. Both findings potentially are important, given that patients with glaucoma frequently use systemic antihypertensive medications. Determining causality of the CCB association should be a research priority. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.</p

Association of systemic medication use with glaucoma and intraocular pressure: the E3 Consortium

PURPOSE: To investigate the association of commonly used systemic medications with glaucoma and intraocular pressure (IOP) in the European population. DESIGN: Meta-analysis of eleven population-based cohort studies of the European Eye Epidemiology (E3) consortium. PARTICIPANTS: A total of 143240 participants were included in the glaucoma analyses and 47177 participants in the IOP analyses. METHODS: We examined associations of four categories of systemic medications (antihypertensive medications: beta-blockers, diuretics, calcium channel blockers [CCBs], alpha-agonists, angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers; lipid-lowering medications; antidepressants; antidiabetic medications) with glaucoma prevalence and IOP. Glaucoma ascertainment and IOP measurement method were according to individual study protocols. Multivariable regression analyses were carried out in each study and results were pooled using random effects meta-analyses. Associations with antidiabetic medications were examined in diabetic participants only. MAIN OUTCOME MEASURES: Glaucoma prevalence and IOP. RESULTS: In the meta-analyses of our maximally-adjusted multivariable models, use of CCBs was associated with a higher prevalence of glaucoma (odds ratio [OR] with corresponding 95% confidence interval [95% CI]: 1.23 [1.08 to 1.39]). This association was stronger for monotherapy of CCBs with direct cardiac effects (OR [95% CI]: 1.96 [1.23 to 3.12]). The use of other antihypertensive medications, lipid-lowering medications, antidepressants or antidiabetic medications were not clearly associated with glaucoma. Use of systemic beta-blockers was associated with a lower IOP (Beta [95% CI]: -0.33 [-0.57 to -0.08] mmHg). Monotherapy of both selective (Beta [95% CI]: -0.45 [-0.74 to -0.16] mmHg) and non-selective (Beta [95% CI]: -0.54 [-0.94 to -0.15] mmHg) systemic beta-blockers was associated with lower IOP. There was a suggestive association between use of high-ceiling diuretics and lower IOP (Beta [95% CI]: -0.30 [-0.47; -0.14] mmHg), but not when used as monotherapy. Use of other antihypertensive medications, lipid-lowering medications, antidepressants, or antidiabetic medications were not associated with IOP. CONCLUSIONS: We identified a potentially harmful association between use of CCBs and glaucoma prevalence. Additionally, we observed and quantified the association of lower IOP with systemic beta-blocker use. Both findings are potentially important given that glaucoma patients frequently use systemic antihypertensive medications. Determining whether the CCB association is causal should be a research priority

K0S and Λ production in Pb-Pb collisions at sNN−−−−√=2.76 TeV

The ALICE measurement of K0S and Λ production at midrapidity in Pb-Pb collisions at sNN−−−√=2.76  TeV is presented. The transverse momentum (pT) spectra are shown for several collision centrality intervals and in the pT range from 0.4  GeV/c (0.6  GeV/c for Λ) to 12  GeV/c. The pT dependence of the Λ/K0S ratios exhibits maxima in the vicinity of 3  GeV/c, and the positions of the maxima shift towards higher pT with increasing collision centrality. The magnitude of these maxima increases by almost a factor of three between most peripheral and most central Pb-Pb collisions. This baryon excess at intermediate pT is not observed in pp interactions at s√=0.9  TeV and at s√=7  TeV. Qualitatively, the baryon enhancement in heavy-ion collisions is expected from radial flow. However, the measured pT spectra above 2  GeV/c progressively decouple from hydrodynamical-model calculations. For higher values of pT, models that incorporate the influence of the medium on the fragmentation and hadronization processes describe qualitatively the pT dependence of the Λ/K0S ratio