The Associations Between OSAHS And Dyslipidemia

Part 1 Interrelationships among common predictors of cardiovascular diseases in patients of OSAHSBackground: The apolipoprotein B/apolipoprotein A-I(APOB/APOA-I)and insulin resistance(IR)had been recognized as common cardiovascular diseases(CVD)risk factors.However,whether they were risk factors for CVD in obstructive sleep apnea hypopnea syndrome(OSAHS)had been rarely studied.Besides,interrelationships between the APOB/APOA-I,IR and OSAHS remain unclear.This study was designed to investigate the relationships between OSAHS,APOB/APOA-I and IR,analyze their relationships with 10-year high Framingham CVD risk.Methods: 6433 participants with suspected OSA from the Sleep Center of Shanghai Jiao Tong University Affiliated Sixth Hospital were screened from July 2009 to July 2017,and 4010 participants were finally included in this study.Anthropometric indictors,fasting biochemical and polysomnographic parameters were collected.FRS was calculated for each subjects.10-year CVD risk >20% was defined as high risk category.The interrelationships between IR,OSAHS,and the APOB/APOA-I was evaluated through logistic regressions analysis and restricted cubic spline(RCS)analysis.Mediation analyses were qualified to assess the mediation effects.Logistic regressions analysis was used to evaluate the relationships between APOB/APOA-I,HOMA-IR,OSAHS and 10-year high CVD risk.Results: The RCS mapped a nonlinear dose-effect relationship between IR,AHI and APOB/APOA-I.Mediation analyses showed IR explain 9.7%,4.7% and 10.8% of the association between apnea-hypopnea index(AHI),oxygen desaturation index(ODI),micro-arousal index(MAI)and APOB/APOA-I,respectively.AHI,HOMA-IR,APOB/APOA-I,IR and OSAHS were all risk factors for 10-year high CVD risk as assessed by FRS(OR=1.010,1.094 and 5.365,respectively,all P<0.001).Conclusions: Our study revealed that nonlinear interrelationships among APOB/APOA-I,IR and OSAHS.IR may serve as a potential mediator between APOB/APOA-I and OSAHS.APOB/APOA-I,IR,OSAHS were all risk factors for 10-year high CVD risk.Part 2 Influence of apolipoprotein A-I and B genetic variation on insulin resistance,metabolic syndrome in obstructive sleep apneaBackground: Both apolipoprotein A-I(APOA-I)and apolipoprotein B(APOB)are associated with insulin resistance(IR),metabolic syndrome(Met S)and obstructive sleep apnea hyponea syndrome(OSAHS).Serum APOA-I and APOB levels are influenced by multiple single nucleotide polymorphism(SNP)variants.However,whether the genetic variants of APOA-I and APOB exert a collaborative effect on IR and Met S in OSAHS remains uncertain.The study was designed to use genetic risk score(GRS)to explore the cumulative effects of APOA-I,APOB genetic variants on IR and Met S in OSAHS.Methods: Initially,5259 subjects with 12 APOA-I SNPs and 30 APOB SNPs from genomic database of the Sleep Center of Shanghai Jiao Tong University Affiliated Sixth Hospital were screened from Janury 2007 to Janury 2018,and 4 APOA-I SNPs and 5 APOB SNPs in 4007 participants were finally included in this study.For each participant,GRS was calculated based on the cumulative effect of multiple genetic variants of APOA-I and APOB.Logistic regression analyses were used to evaluate the relationships between APOA-I,APOB genetic polymorphisms and Met S,IR.Logistic regression analyses were also used to evaluate the risk of IR and Met S in the top quintile of APOA-I and APOB GRS.Linear regression analyses were used to evaluate correlations between APOA-I GRS,APOB GRS and clinical indictors.Results: APOA-I SNP rs9804646 variants had a lower risk of IR(OR=0.856,P=0.013),while rs888246 variants increased the risk of IR(OR=1.340,P=0.011).APOB SNP had no associations with IR(P>0.05).APOA-I SNP rs964184 and rs 888246 variants increased the risk of Met S(OR=1.353,P<0.001;OR=1.271,P=0.03).APOA-I SNP rs9804646 and APOB SNP rs2854725 variants had a lower risk of Met S(OR=0.777,P<0.001;OR=0.829,P=0.01).Multivariate logistic regression analyses found higher APOB/APOA-I and APOB increased the risk of IR(OR = 2.285,3.168,both P < 0.001)after adjustments,while APOA-I GRS decreased the risk of IR(OR== 0.917,P < 0.001).APOB/APOA-I and APOB increased the risk of Met S(OR=14.488,6.098,both P < 0.001)while APOA-I GRS and APOA-I decreased the risk of Met S after adjustments(OR = 0.870,0.09,both P < 0.001).In addition,individuals in the top quintile of the APOA-I genetic score distribution had a lower risk of insulin resistance and Met S after adjustments(OR = 0.761,P = 0.007;OR = 0.637,P < 0.001,respectively).APOA-I GRS correlated with HOMA-IR,TG,LDL-C,APOA-I,APOB/APOA-I(P<0.05).APOB GRS had correlations with TC,LDL-C,APOB,APOB/APOA-I(P<0.05)Conclusion: In patients with OSAHS,the cumulative effects of APOA-I genetic variants contributed to insulin resistance and Met S.APOA-I GRS and APOB GRS associated with multiple metabolic components.Part 3 The role of Angiopoietin-like protein4,8 in men of OSAHS with dyslipidemiaBackground: Dyslipidemia commonly found in men with obstructive sleep apnea hypopnea syndrome(OSAHS),but the mechanism remains unclear.Angiopoietin-like protein 4(ANGPTL4)and ANGPTL8 are known as important regulators in lipid metabolism by inhibiting lipoprotein lipase.However,the roles of ANGPTL4 and ANGPTL8 in dyslipidemia in OSAHS have not studied yet.This study was designed to investigate the serum ANGPTL4,8 levels in male patients with OSAHS and the effects of ANGPTL4 and ANGPTL8 functional single nucleotide polymorphism(SNP)variants on blood lipids in patients with OSAHS to evaluate the role of ANGPTL4,8 on dyslipidemia of OSAHS patients.Method: 4455 male OSAHS patients containing ANGPTL4 T266 M,ANGPTL8 R59 W and clinical indictors in the genomic database of the Sleep Center of Shanghai Jiao Tong University Affiliated Sixth Hospital from January 2007 to January 2018 were included in this study.The serum ANGPTL4,8 levels of 158 non-OSAHS,145 moderate OSAHS and 164 severe OSAHS matching for age and BMI selected from the database were evaluated via ELIISA method.ANOVA was used to analyze the serum ANGPTL4,8 levels among groups.Correlation analysis were used to analyze the relationship between serum ANGPTL4,ANGPTL8 R59 W levels with clinical indictors including blood lipids.Correlation analysis were used to analyze the relationship between ANGPTL4 T266 M and ANGPTL8 R59 W genetic variations with clinical parameters.Chi-squared test was used to predict the risk between T266 M,R59W and dyslipidemia of OSAHS.Molecular dynamics simulations were performed using Gromacs v5.0.2 software and the surface charge distributions of the wild-type and R59 W variant proteins were analyzed.Results: The serum ANGPTL4 levesl were not significantly different among the groups and serum ANGPTL8 levels were significantly different among the groups(P=0.006).Serum ANGPTL4 level had no associations with blood lipids.Serum ANGPTL8 levels were associated with TG,APOB,apnea-hyponea index(AHI),oxygen desaturation index(ODI),and micro-arousal index(MAI)(?=0.103,P=0.026;?=0.109,P=0.018;?=0.14,P=0.003;?=0.132,P=0.005;?=0.111,P=0.017).Studies in the genomic database found that R59 W had negative correlations with total cholesterol(TC),triglycerides(TG),high-density lipoprotein cholesterol(HDL-C),APOA-I,and apolipoprotein E(?=-0.044,P=0.003;?=-0.032,P=0.034;?=-0.074,P<0.001;?=0.089,P<0.001;?=-0.047,P=0.002).T266 M had no associations with any clinical indictors(P>0.05).R59 W variants increased the risk of lower HDL-C and lower APOA-I(OR=1.221,P=0.001;OR=1.369,P<0.001),decreased the risk of hyper TC(OR=0.808,P=0.001).Through molecular dynamics simulation analysis,we found that the potential energy of wild-type ANGPTL4 was higher than the variants of T266 M,and T266 M variant protein was more stable than wild-type ANGPTL4.The energy of variant R59 W is slightly higher than that of wild type.ANGPTL8 variant protein were unstable.The surface charge distribution of the ANGPTL4 and its variant protein did not differ much.The surface charge distribution was obviously different between wild-type and R59 W variant.Conclusion: Serum ANGPTL8 levels had associations with OSAHS severity.ANGPTL8 genetic variant were associated with blood lipids because of the instability of protein variant structure and the changes of charge distribution caused by the variant of ANGPTL8 R59 W.It was not observed in ANGPLT4.We suspected that R59 W not T266 M accounted for dyslipidemia in OSAHS.