Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
Major facilitator superfamily domain containing 2A (MFSD2A) was recently characterized as a sodium-dependent lysophosphatidylcholine transporter expressed at the blood-brain barrier endothelium. It is the primary route for importation of docosohexaenoic acid and other long-chain fatty acids into fetal and adult brain and is essential for mouse and human brain growth and function. Remarkably, MFSD2A is the first identified major facilitator superfamily member that uniquely transports lipids, implying that MFSD2A harbors unique structural features and transport mechanism. Here, we present three three-dimensional structural models of human MFSD2A derived by homology modeling using MelB- and LacY-based crystal structures and refined by biochemical analysis. All models revealed 12 transmembrane helices and connecting loops and represented the partially outward-open, outward-partially occluded, and inward-open states of the transport cycle. In addition to a conserved sodium-binding site, three unique structural features were identified as follows: a phosphate headgroup binding site, a hydrophobic cleft to accommodate a hydrophobic hydrocarbon tail, and three sets of ionic locks that stabilize the outward-open conformation. Ligand docking studies and biochemical assays identified Lys-436 as a key residue for transport. It is seen forming a salt bridge with the negative charge on the phosphate headgroup. Importantly, MFSD2A transported structurally related acylcarnitines but not a lysolipid without a negative charge, demonstrating the necessity of a negatively charged headgroup interaction with Lys-436 for transport. These findings support a novel transport mechanism by which lysophosphatidylcholines are "flipped" within the transporter cavity by pivoting about Lys-436 leading to net transport from the outer to the inner leaflet of the plasma membrane. Major facilitator superfamily domain containing 2A (MFSD2A) was recently characterized as a sodium-dependent lysophosphatidylcholine transporter expressed at the blood-brain barrier endothelium. It is the primary route for importation of docosohexaenoic acid and other long-chain fatty acids into fetal and adult brain and is essential for mouse and human brain growth and function. Remarkably, MFSD2A is the first identified major facilitator superfamily member that uniquely transports lipids, implying that MFSD2A harbors unique structural features and transport mechanism. Here, we present three three-dimensional structural models of human MFSD2A derived by homology modeling using MelB- and LacY-based crystal structures and refined by biochemical analysis. All models revealed 12 transmembrane helices and connecting loops and represented the partially outward-open, outward-partially occluded, and inward-open states of the transport cycle. In addition to a conserved sodium-binding site, three unique structural features were identified as follows: a phosphate headgroup binding site, a hydrophobic cleft to accommodate a hydrophobic hydrocarbon tail, and three sets of ionic locks that stabilize the outward-open conformation. Ligand docking studies and biochemical assays identified Lys-436 as a key residue for transport. It is seen forming a salt bridge with the negative charge on the phosphate headgroup. Importantly, MFSD2A transported structurally related acylcarnitines but not a lysolipid without a negative charge, demonstrating the necessity of a negatively charged headgroup interaction with Lys-436 for transport. These findings support a novel transport mechanism by which lysophosphatidylcholines are "flipped" within the transporter cavity by pivoting about Lys-436 leading to net transport from the outer to the inner leaflet of the plasma membrane.
Aims To examine the relationship between vision impairment (VI) and employment outcomes in a multiethnic Asian population. Methods We included 7608 Asian individuals aged ≥40 years (mean (SD) age: 58.4 (10.3) years; 64.8% male) from the Singapore Epidemiology Eye Disease Study (response rate: 78.8%), a population-based cohort study (mean follow-up period: 6.2 years). Presenting visual acuity (VA) was assessed using a logarithm of the minimum angle of resolution (logMAR) chart, with VI defined as mild (VA >0.3 to <0.6 logMAR) and moderate to severe (VA ≥0.6 logMAR). Self-reported employment statuses at both baseline and follow-up were used as outcomes. Underemployment was defined as a decline in occupational skill level, categorised by International Standard Classification of Occupations, at follow-up compared with baseline. Multinomial logistic regression models were used to determine independent associations between VI and various employment outcomes, adjusted for variables that were found to significantly differ across employment statuses. Results Presenting VI was prevalent in 20.2% (N=1536) of participants. Compared with those without VI, participants with mild and moderate to severe VI were more likely to be unemployed at baseline (OR 1.47, 95% CI 1.15 to 1.87, p=0.002 and 2.74, 95% CI 1.94 to 3.89, p<0.001, respectively). At follow-up, participants with any VI at baseline were more likely to be underemployed (OR 1.46, 95% CI 1.03 to 2.05, p=0.033). Conclusion VI, even when mild, is associated with unemployment and underemployment. Future studies should investigate whether visual interventions could be used as part of a multipronged strategy to improve employment outcomes for the population.
Our study aimed to examine the relationship between cardiovascular diseases (CVD) with peripapillary retinal fiber layer (RNFL) and macular ganglion cell-inner plexiform layer (GCIPL) thickness profiles in a large multi-ethnic Asian population study.6,024 Asian subjects were analyzed in this study. All participants underwent standardized examinations, including spectral domain OCT imaging (Cirrus HD-OCT; Carl Zeiss Meditec). In total, 9,188 eyes were included for peripapillary RNFL analysis (2,417 Malays; 3,240 Indians; 3,531 Chinese), and 9,270 eyes (2,449 Malays, 3,271 Indians, 3,550 Chinese) for GCIPL analysis. History of CVD was defined as a self-reported clinical history of stroke, myocardial infarction, or angina. Multivariable linear regression models with generalized estimating equations were performed, adjusting for age, gender, ethnicity, diabetes, hypertension, hyperlipidaemia, chronic kidney disease, body mass index, current smoking status, and intraocular pressure.We observed a significant association between CVD history and thinner average RNFL (β = -1.63; 95% CI, -2.70 to -0.56; p = 0.003). This association was consistent for superior (β = -1.79, 95% CI, -3.48 to -0.10; p = 0.038) and inferior RNFL quadrant (β = -2.14, 95% CI, -3.96 to -0.32; p = 0.021). Of the CVD types, myocardial infarction particularly showed significant association with average (β = -1.75, 95% CI, -3.08 to -0.42; p = 0.010), superior (β = -2.22, 95% CI, -4.36 to -0.09; p = 0.041) and inferior (β = -2.42, 95% CI, -4.64 to -0.20; p = 0.033) RNFL thinning. Among ethnic groups, the association between CVD and average RNFL was particularly prominent in Indian eyes (β = -1.92, 95% CI, -3.52 to -0.33; p = 0.018). CVD was not significantly associated with average GCIPL thickness, albeit a consistent negative direction of association was observed (β = -0.22, 95% CI, -1.15 to 0.71; p = 0.641).In this large multi-ethnic Asian population study, we observed significant association between CVD history and RNFL thinning. This finding further validates the impact of impaired systemic circulation on RNFL thickness.
Abstract Background The relationship between baseline cognitive impairment (CI) and incident visual impairment (VI) in Asians is unclear. Objective To determine the associations between baseline CI with incident VI and visual acuity (VA) at 6-year follow-up in multiethnic Asians. Design Cohort. Setting Population-based. Subjects Two thousand three hundred and twenty-four adults aged ≥60 years from the Singapore Epidemiology of Eye Diseases Study (response rate 64%). Methods CI was defined using the validated Abbreviated Mental Test (AMT). VA was objectively measured using a LogMAR chart. Any incident VI was defined as having no VI (Snellen’s VA better than or equal to 20/40) at baseline but present (VA worse than 20/40) at 6-year follow-up. VI severity was defined according to the International Classification of Diseases, 11th Revision. Associations were assessed using logistic and linear regression models. Results Of the 2,324 participants, 248 had CI at baseline. Presence of baseline CI was associated with more than twice the odds of any incident VI, incident mild and moderate–severe VI (OR [95% confidence interval]: 2.48 [1.55–3.90], 2.07 [1.17–3.55], and 2.61 [1.36–4.93], respectively) and worse VA (β [95% confidence interval]: 0.026 [0.006–0.046]) at 6-year follow-up. The leading causes of incident VI were cataract and under-corrected refractive error. Conclusions Older adults with CI had more than double the odds of VI development and poorer VA than their cognitively intact counterparts, and most causes of incident VI were correctable. Strategies such as targeted vision screening and early intervention for early detection and management of vision loss in patients with cognitive decline are warranted.
Aims To characterise the association between visual field (VF) defects and myopic macular degeneration (MMD) in highly myopic adults without glaucoma. Methods Participants (n=106; 181 eyes) with high myopia (HM; spherical equivalent ≤−5.0 D or axial length (AL) ≥26 mm), after excluding glaucoma and glaucoma suspects, from the Singapore Epidemiology of Eye Diseases-HM study were included in this cross-sectional study. Humphrey VF (central 24–2 threshold), cup-disc ratio (CDR) and intraocular pressure (IOP) measurements were performed. Mean deviation (MD) and pattern SD (PSD), VF defects (normal or abnormal; p<0.05 in ≥3 non-edge contiguous locations) and pattern (eg, generalised sensitivity loss) were analysed. MMD presence was diagnosed from fundus photographs. Generalised estimating equations were used for analysing factors (MD, PSD, VF defects, CDR and IOP) associated with MMD. Results Mean age was 55.4±9.9 years and 51.9% were women (AL=26.7±1.1 mm). MMD eyes had lower MD (−3.8±2.9 dB vs −1.1±1.4 dB) and higher PSD (2.8±1.7 dB vs 1.7±0.6 dB). A higher percentage of MMD eyes (n=48) had abnormal VF (62.5% vs 28.6%; p<0.001) compared with no MMD (n=133 eyes). VF pattern in MMD eyes was significantly different from eyes without MMD (p=0.001) with greater generalised sensitivity loss (53.3% vs 10.5%) and arcuate defects (16.7% vs 10.5%). In multivariate analyses, MD (OR=1.52) and PSD (OR=1.67) were significantly (p=0.003) associated with MMD, but VF defects were not associated with MMD. Conclusion Highly myopic adults with MMD may have VF loss when compared with highly myopic patients without MMD even in adults without glaucoma.
Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus, a metabolic disorder, but understanding of its pathophysiology remains incomplete. Meta-analysis of three population-based cross-sectional studies (2004–11) representing three major Asian ethnic groups (aged 40–80 years: Chinese, 592; Malays, 1052; Indians, 1320) was performed. A panel of 228 serum/plasma metabolites and 54 urinary metabolites were quantified using nuclear magnetic resonance (NMR) spectroscopy. Main outcomes were defined as any DR, moderate/above DR, and vision-threatening DR assessed from retinal photographs. The relationship between metabolites and DR outcomes was assessed using multivariate logistic regression models, and metabolites significant after Bonferroni correction were meta-analyzed. Among serum/plasma metabolites, lower levels of tyrosine and cholesterol esters to total lipids ratio in IDL and higher levels of creatinine were positively associated with all three outcomes of DR (all p < 0.005). Among urinary metabolites, lower levels of citrate, ethanolamine, formate, and hypoxanthine were positively associated with all three DR outcomes (all p < 0.005). Higher levels of serum/plasma 3-hydroxybutyrate and lower levels of urinary 3-hydroxyisobutyrate were associated with VTDR. Comprehensive metabolic profiling in three large Asian cohorts with DR demonstrated alterations in serum/plasma and urinary metabolites mostly related to amino acids, lipoprotein subclasses, kidney function, and glycolysis.
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