The Association Of 5-HTR2A Gene Polymorphism With The Pathogenesis And Outcomes Of Patients With Obstructive Sleep Apnea-hypopnea Syndrome

Objective(s):This study enrolled a prospective cohort of patient with obstructive sleep apnea hypopnea syndrome(OSAHS),to explore the association between 5-hydr oxytryptamine receptor 2A(5-HTR2A)gene polymorphism and serum 5-hydrox ytryptamine(5-HT)levels,the severity of disease and clinical outcomes.We also analyzed the impact of continuous positive airway pressure(CPAP)treatment ef ficacy on cardiovascular and cerebrovascular adverse events in this cohort.Methods:1.A total of 300 consecutive cases with OSAHS were enrolled,and baseline data including demographic characteristics,previous history,comorbidities,physical examinations,laboratory indicators,and polysomnography(PSG)data were collected in database.2.Use the Generalized Anxiety Disorder Scale,Patient Health Questionnaire Depression Scale,Somatization Symptom Self Assessment Scale,and Psychosomatic Symptom Scale to assess the psychosomatic status of this cohort.3.Collect 3ml of peripheral blood of each patient after informed consent,to measure serum 5-HT level using enzyme linked immunosorbent assay,and then extract DNA from blood sample.4.Detect six candidate single nucleotide polymorphisms(SNPs)in the 5-HTR2A gene.5.Follow up for 1 year,and record the occurrence of major adverse cardio vascular and cerebrovascular events(MACCEs)in the database.6.Establish dominant,recessive,and co-dominant allele models to compare the carrier frequency differences of each SNP between the MACCE group and the non-MACCE group.Establish multivariate COX regression models to analyze the independent risk predictors of MACCE in patients with OSAHS.Results:1.Baseline data showed that:compared to the mild group,the moderate and severe groups presented with more male gender,higher body mass index,more presentation of snoring,lethargy,fatigue,also had higher level of uric acid and triglycerides,and lower night blood oxygen saturation(P﹤0.05).2.K-M survival curves found that CPAP did not improve the risk of MACCE in moderate and severe groups(P﹥0.05).3.The ROCs showed that when the age was≥53 years old,the sensitivity and specificity of predicting the occurrence of MACCE in this cohort were 58.1%and61%,respectively.BMI≥529.76kg/m~2,the sensitivity and specificity of predicting cardiovascular and cerebrovascular events in OSAHS patients were 26.7%and 80.3%,respectively.4.There was no significant difference in serum 5-HT levels among the mild,moderate and severe OSAHS groups(P﹥0.05).The level of serum 5-HT in the OSAHS with depression group was significantly higher than that in the OSAHS without depression group(1620.59±345.04ng/ml,1456.38±282.61ng/ml,P﹦0.002).And the level of serum 5-HT in the OSAHS with somatization disorder group was significantly higher than that in the OSAHS without somatization disorder group(1582.47±321.13ng/ml,1462.12±306.19ng/ml,P﹦0.024).5.141 patients with OSAHS completed the psychological scale evaluation.Compared with the control group,there were no significant differences in the allele frequencies and genotype distributions of rs1885884,rs9316235,rs6311,rs9526240,rs1923888,and rs1928040 between the depression and anxiety groups with OSAHS(P﹥0.05).The six SNP loci were not significantly associated with the severity of OSAHS.6.The dominant,recessive,and co-dominant models showed that there was no significant difference in the frequency of the variant alleles of rs1885884,rs9316235,rs6311,rs9526240,rs1923888,and rs1928040 in the 5-HTR 2A gene between the MACCE group and the non-MACCE group(P﹥0.05).7.Multivariate Cox regression analysis showed that comorbidities of coronary artery disease or hypertension was independent risk factors of MACCE in patients with OSAHS,and the risk of MACCE in patients with rs1885884 G mutation was significantly increased(HR﹦1.639,95%CI 1.014-2.651,P﹦0.044)than cases without the mutation.No association has been found between rs9316235,rs6311,rs9526240,rs1923888,and rs1928040 and the occurrence of MACCE in this cohort.Conclusion(s):1.OSAHS coexisted with coronary artery disease or hypertension was independently associated with MACCE.Serum 5-HT level,AHI,and CPAP treatment did not show a correlation with the risk of MACCE in this study.2.CPAP treatment could improve the AHI of patients with OSAHS.But we found the number of patients who were prescribed with CPAP could not persist in CPAP treatment well.Their poor compliance might cause bias to some extent.3.5-HTR 2A gene rs9316235 was associated with clinical indicators of OSAHS including serum 5-HT level,BMI,AHI,coexisted with hypertension or coronary heart disease,and snoring symptom.Rs1885884 was correlated with serum 5-HT level,AHI,and nighttime minimum blood oxygen saturation.4.Serum 5-HT level was associated with emotional disorders(depressive state,somatization disorder)in patients with OSAHS.Rs9316235,rs6311,rs9526240,rs1923888,rs1928040,and rs1885884 did not show a correlation with emotional disorders(anxiety,depression,somatization disorder).5.The SNP rs1885884 G mutation carrier on 5-HTR2A gene might be involved in the pathogenesis of OSAHS,and the risk of MACCE in patients with the mutation carrier genotype(GG+CG)was 1.6 times higher than that in patients with the wild type(CC).