| Objective:To reveal the associations between the cholesterol metabolism and the risk of gestational diabetes mellitus(GDM)from three aspects(diet,gene and metabolic status),the objectives of this study are as follows:1.To investigate the associations between dietary cholesterol intakes,cholesterol metabolism-related gene polymorphisms and the risk of GDM,and examine the genenutrition interactions with GDM.2.To explore the associations between serum cholesterol metabolism marker levels in the first trimester and GDM,and further examine the relationship between dietary cholesterol intakes,cholesterol metabolism-related gene polymorphisms and cholesterol metabolism marker levels.Method:This study selected pregnant women who were enrolled in the Tongji Birth Cohort(TJBC)from March 2018 to June 2021.GDM cases and controls were matched in a 1:2ratio according to a nested case-control design,matched for maternal age,pre-pregnancy BMI,ethnicity and primiparity.GDM was diagnosed according to the 75-g 2-h oral glucose tolerance test(OGTT)at 24-28 gestational weeks.A validated food frequency questionnaire was used to investigate the dietary cholesterol intakes during pregnancy.Loci of cholesterol metabolism-related gene were determined by the time-of-flight mass spectrometry.The mutation information of multiple loci of different pathways of cholesterol metabolismrelated gene was combined by calculating genetic risk score(GRS)and weighted genetic risk score(w GRS).Nine cholesterol metabolism markers were detected using gas chromatography-mass spectrometry.Conditional logistic regression models were used to estimate odd ratios(ORs)and 95% confidence intervals(95% CIs)of GDM according to dietary cholesterol intakes,cholesterol metabolism-related gene polymorphisms and cholesterol metabolism marker levels,respectively.The interactions of dietary cholesterol intakes with mutations in different cholesterol metabolism-related pathways were further evaluated on the risk of GDM and the levels of cholesterol metabolism markers.Results:1.A total of 1116 pregnant women were matched in a 1:2 ratio according to a nested case-control design,including 372 GDM subjects and 744 control subjects,to investigate the associations between dietary cholesterol intakes,cholesterol metabolism-related gene polymorphisms and the risk of GDM,and examine the gene-nutrition interactions with GDM.(1)In terms of dietary cholesterol intake,each 100 mg/d increased in energy-adjusted cholesterol intake was associated with a 14% increased in the risk of GDM in pregnant women(OR: 1.14,95% CI: 1.04,1.26).After adjusted confounding factors,this association remained significant(OR: 1.14,95% CI: 1.02,1.28).(2)In terms of polymorphisms at single loci of cholesterol metabolism-related gene,polymorphisms in three loci of the cholesterol 7-alpha-hydroxylase gene(CYP7A1)in the cholesterol synthesis pathway were significantly associated with the risk of GDM after adjusted confounding factors.The ORs for the risk of GDM were 1.28(1.06,1.54),1.27(1.06,1.53)and 1.26(1.04,1.51)for each additional mutant base at the rs3808607,rs8192871,and rs7833904 of CYP7A1.Haplotype analysis of the four loci of CYP7A1 showed a significantly increased risk of GDM in the all-mutant TTGA haplotype at the three key loci(OR: 1.27,95% CI: 1.06,1.53).(3)In terms of GRS and w GRS of cholesterol metabolism-related gene,according to the cholesterol metabolism pathways GRS and w GRS of control group,the subjects were grouped into tertile 1(T1),tertile 2(T2)and tertile 3(T3).The risks of GDM were higher in T3 groups of GRS and w GRS of cholesterol synthesis pathway compared to T1 groups,with the adjusted ORs for GDM of 1.40(1.02,1.92)and 1.48(1.08,2.03),respectively.The risk of GDM was higher in T3 group of w GRS of cholesterol absorption pathway compared to T1 group,with the adjusted OR for GDM of 1.55(1.11,2.16).(4)The results of the combined effect analysis of dietary cholesterol intake and polymorphisms related to cholesterol metabolism showed that the risks of GDM were increased by 256% and 261% in the highest quartiles of dietary cholesterol intake and the highest quartiles of both pathways of cholesterol synthesis and absorption w GRS,respectively,compared with the lowest quartile of the two factors.After stratification of different pathways of cholesterol metabolism-related w GRS,the positive association between dietary cholesterol and GDM was strengthened with increasing cholesterol absorption w GRS,and there was a significant positive interaction between dietary cholesterol intake and cholesterol absorption pathway w GRS and risk of GDM(P = 0.041).2.A total of 462 pregnant women were matched in a 1:2 ratio according to a nested case-control design,including 154 GDM subjects and 308 control subjects,to explore the associations between serum cholesterol metabolism marker levels in the first trimester and GDM,and further examine the relationship between dietary cholesterol intakes,cholesterol metabolism-related gene polymorphisms and cholesterol metabolism marker levels.(1)Compared to the control group,the ratios of cholesterol absorption markers(cholestanol and β-sitosterol)to TC were significantly lower and the ratios of cholesterol synthesis markers(lathosterol and desmosterol)to TC were significantly higher in the GDM group.After adjusted confounding factors,per 1 standard deviation increased in the logtransformed ratios of cholesterol absorption markers(cholestanol and β-sitosterol)to TC,the risks of GDM were reduced by 22% and 22% with the adjusted ORs of 0.78(0.62,0.97)and 0.78(0.63,0.98),respectively.The associations between per 1 standard deviation increased in the log-transformed ratios of cholesterol synthesis markers(lathosterol and desmosterol)to TC and the risks of GDM with the ORs of 1.26(1.02,1.56)and 1.26(1.00,1.57)in the original model,respectively,which disappeared after adjustment for insulin levels and other factors.(2)There were significant positive correlations between cholesterol synthesis markers and synthesis markers,and between cholesterol absorption markers and absorption markers,and there were significant negative correlations between cholesterol synthetic markers and absorption markers.Insulin levels and HOMA-IR were significantly positively correlated with markers of cholesterol synthesis and significantly negatively correlated with markers of cholesterol absorption.Fasting blood glucoses were positively correlated with markers of cholesterol synthesis,but not significantly related to absorption markers.(3)In the relationships between dietary cholesterol intake,cholesterol metabolismrelated gene polymorphisms and cholesterol metabolism markers,the ratios of cholesterol synthesis markers(lathosterol and lanosterol)to TC(log-transformed)changed by-0.03(-0.06,-0.001)and-0.04(-0.07,-0.01)with each increase of dietary cholesterol intake by 100mg/d,respectively.However,this effect of dietary cholesterol intakes on lathosterol existed only in the T3 group of cholesterol synthesis pathway GRS,and the effect of dietary cholesterol on lanosterol was only present in the T3 group of cholesterol absorption pathway GRS and the T1 group of cholesterol synthesis pathway GRS.Conclusion:High dietary cholesterol intakes during pregnancy significantly increased the risk of GDM.Cholesterol metabolism-related gene polymorphisms were significantly associated with the risk of GDM.Metabolic states of high synthesis and low absorption of cholesterol metabolism markers in the first trimester increased the risk of GDM.Mutations in cholesterol absorption pathway genes interacted with dietary cholesterol and had an impact on the risk of GDM.Cholesterol synthesis marker levels decreased with increased dietary cholesterol intakes,and dietary cholesterol intakes had different effects on cholesterol synthesis markers in different cholesterol metabolism genetic backgrounds. |
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