| Part ⅠIdentification of serum metabolic markers associated with intraocular pressure in ChineseObjective:Identification of serum metabolic markers associated with intraocular pressure(IOP).Methods:This was a cross-sectional,population-based study.Subjects were enrolled from the Singapore Chinese Eye Study.A total of 3,353 Chinese participants aged 40-80 year were enrolled.Study subjects underwent standardized systemic and ocular examinations,and bio-samples were collected from them.The serum samples were analyzed using Nuclear Magnetic Resonance(NMR)spectroscopy to measure 228 metabolites.IOP measurements were obtained using Goldmann tonometer.Eyes with IOP lowering treatment were excluded from the analysis.Multivariable linear regression analysis was used to evaluate the association between serum metabolites and IOP,adjusting for potential confounders,such as age,gender,body mass index(BMI),blood pressure,smoking status,central corneal thickness(CCT),blood pressure-lowering,blood glucose-lowing and lipid-lowering medication.Random Forest(RF)analysis was used to assess the importance of metabolites to IOP and further account for the relationship between metabolites and IOP.The regression coefficient(β)represented the change in IOP(mmHg)for every one standard deviation(SD)increase in the metabolite levels.Results:A total of 2,867 subjects were included for the metabolomic analysis in the study.The mean(SD)age of the study subjects was 58.8(9.5)years,and the mean IOP was 14.3(3.1)mmHg.Regression analysis showed that 14 serum metabolites were significantly associated with IOP.Higher levels of albumin(β=0.29,P=9.42E-08),lactate(β=0.22,P=5.14E-05),pyruvate(β=0.21,P=1.42E-04)and ten lipoprotein subclasses(β per SD ranged from 0.22 to 0.27,all P<1.28E-04)were associated with higher IOP.A higher level of glutamine(β=-0.21,P=1.85E-04)was associated with lower IOP.Random forest analysis confirmed the association of five metabolites(albumin,concentration of medium HDL particles,total lipids in medium HDL,phospholipids in medium HDL and Phospholipids in small HDL).In addition,glycoprotein acetylation was the most significant metabolite associated with IOP identified using random forest analysis.Conclusion:We identified several serum metabolites associated with IOP,in particular albumin and lipoprotein subclasses,and cell energy-generating pathway related metabolites.These findings may provide insight into the complex interplay between metabolic blood constituents and IOP,and the novel way to control IOP.Part ⅡIdentification metabolic markers associated with intraocular pressure in an Asian multiethnic populationObjective:Identification of peripheral blood metabolic markers associated with intraocular pressure(IOP)in an Asian multiethnic population.Methods:This was a cross-sectional,multiethnic population-based study.Subjects were enrolled from the Singapore Epidemiology of Eye Disease study.Including three major ethnics:Chinese,n=3,353;Indians,n=3,400 and Malays,n=3,280 aged 40-80 year.All subjects underwent standardized systemic and ocular examinations,and bio-samples(serum:Chinese and Indians;plasma:Malays)were collected from the subjects.Metabolites(n=228)in either serum or plasma were analyzed and quantified using Nuclear Magnetic Resonance spectroscopy(NMR).IOP measurements were obtained using Goldmann tonometer.Eyes with IOP lowering treatment were excluded from the analysis.After adjusting for potential confounders,such as age,gender,body mass index(BMI),blood pressure,smoking status,central corneal thickness,blood pressure-lowering,blood glucose-lowing and lipid-lowering medication,least absolute shrinkage and selection operator(LASSO)regression was used for metabolites selection.Multivariable linear regression was used to evaluate the relationship between metabolites and IOP in each of the three ethnic groups,followed by a random effect meta-analysis combining the three cohorts.The regression coefficient(β)represented the change in IOP(mmHg)for every one standard deviation(SD)increase in the metabolite levels.Results:A total of 8,891 subjects were included for the metabolomic analysis in the study,including 2,805 Chinese,3,045 Indians and 3,041 Malays.The mean(SD)age of the study subjects was 58.3(10.2)years,and the mean IOP was 15.1(3.1)mmHg.Eleven metabolites were identified to be significantly associated with IOP in at least one ethnic cohort.Among them,six metabolites,including albumin,glucose,lactate,glutamine,ratio of saturated fatty acids to total fatty acids(SFAFA),and cholesterol esters in very large high-density lipoprotein(XLHDLCE),were significantly associated with IOP in all three cohorts.Higher levels of albumin(β=0.24,P=0.002),lactate(β=0.27,P=0.008),glucose(β=0.11,P=0.010),and XLHDLCE(β=0.47,P=0.006),along with lower levels of glutamine(β=0.17,P<0.001)and SFAFA(β=0.21,P=0.008)were associated with higher IOP levels.Conclusion:We identified several novel blood metabolites associated with IOP in an Asian multiethnic population.The results validated the reliability of our first part of the study.Metabolic markers associate with IOP derived from three ethnic groups and two blood samples made our results to be more conservative,reliable and generalizable.Our findings may provide insight into the physiological and pathological processes underlying IOP control,and new targets for managing IOP.Part ⅢMetabolomic analysis of lipid associated with primary open-angle glaucomaObjective:To investigate the associations of blood levels of lipid-related metabolites and primary open-angle glaucoma(POAG).Methods:This was a cross-sectional,multiethnic population-based study.Subjects were enrolled from the Singapore Epidemiology of Eye Disease study.Including three major ethnics:Chinese,n=3,353;Indians,n=3,400;Malays,n=3,280 aged 40-80 year.All subjects underwent standardized systemic and ocular examinations,and bio-samples(serum:Chinese and Indians;plasma:Malays)were collected from the subjects.130 lipoprotein related metabolites(n=130)in either serum or plasma were analyzed and quantified using Nuclear Magnetic Resonance spectroscopy(NMR).Intraocular pressure(IOP)measurements were obtained using Goldmann tonometer.Participants without lipid samples and other potential risk factors(such as age,gender,IOP,BMI,education,systolic blood pressure,axial length and statin treatment)were excluded from the analysis.After adjusting age,gender and ethnicity,least absolute shrinkage and selection operator(LASSO)regression was used for metabolites selection.Logistic regression was used to evaluate the relationship between metabolites and POAG.Bayesian network model was built using metabolites previously identified along with other known risk factors for POAG.Results:A total of 8503 subjects were included for the metabolomic analysis in the study,including 8328 non-POAG participants and 175(2.1%)POAG participants.The mean(SD)age of the study subjects was 57.7(9.9)years.Compared with non-POAG participants,subjects with POAG were older,more likely to be male,had higher IOP and systolic blood pressure,and longer axial length.Using logistic regression,we found lower levels of total HDL3 cholesterol(HDL3-C,OR=0.57 per 1 SD increase in HDL3-C,P=0.007)and higher levels of phospholipids in very large HDL(XLHDLPL,OR=1.46 per 1 SD increase in XLHDLPL,P=0.03)were associated with increased risk of POAG.By Bayesian network,HDL3-C,age and IOP had direct linear relationships with the risk of POAG,XLHDLPL indirectly affected the risk of POAG through the mediation of HDL3-C,age and BMI.Routine blood lipids measurements,such as high-density lipoprotein cholesterol,low-density lipoprotein cholesterol and total cholesterol,were not associated with POAG.Conclusion:We identified two lipoprotein related metabolites(HDL3-C and XLHDLPL)significantly associated with the risk of POAG in a large-scale multiethnic population.However,routine blood lipids(high-density lipoprotein cholesterol,low-density lipoprotein cholesterol and total cholesterol)were not associated with POAG.These findings highlighted the importance of heterogeneity of lipoprotein particles.The dysregulation of cholesterol transport,especially HDL3-C,played an important role in the development of POAG. |
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