| BackgroundWomen with a history of gestational diabetes(GDM)face a significantly higher risk of postpartum type 2 diabetes(T2DM).Therefore,women with prior GDM have become an important group of T2DM prevention and control.In recent years,more than 40 T2DM incidence prediction models have been developed worldwidely,but most of these risk prediction models were constructed in the general population.So far,there has been no prediction of the incidence of postpartum T2DM among women who have a history of GDM.In addition to environmental factors,genetic factors are also important reasons for the onset of T2DM.At present,nearly 20 Genome-Wide Association Studies(GWAS)have found more than 70 T2DM-related Single Nucleotide Polymorphisms(SNPs).However,for better health economic value,not all T2DM-related SNPs found by GWAS are necessary to construct genetic risk scores(GRS).Therefore,how to select the valuable target SNPs that can be used for T2DM risk stratification,GRS construction,and high-risk population definition,has become one of the important research contents in the post-GWAS erea.Lifestyle intervention has been confirmed as one most important and effective T2DM prevention method.However,the evidence for lifestyle interventions for GDM women is limited due to the current small number of trials,small sample sizes,and large variations in methodological quality.More randomized controlled trials are needed to evaluate the effect of lifestyle interventions on GDM women,especially the long-term effect.Genetic factors not only play a significant role in the pathogenesis of T2DM,but an important role in the intervention of T2DM.The effects for people with different genetic risks may be different when they receive the same interventions.To our knowledge,there are seldom studies to evaluate wether different genetic risks have different effects on lifestyle interventions in already high-risk populations,such as women who have had GDM.Preliminary project introduction:"Tianjin lifestyle intervention on preventing postpartum T2DM among GDM women" is an ongoing randomized controlled trial.Totally 1263 women who had GDM after delivery(average 2.24 years)were recalled and underwent the baseline 75g oral glucose tolerance test(OGTT).Of them,83 people were diagnosed as T2DM.The 1180 women who were not diagnosed as T2DM were randomly assigned to the lifestyle intervention group and the routine management group(586 and 594,respectively),to evaluate whether postpartum lifestyle interventions could reduce the incidence of postpartum T2DM in women who had prior GDM.Objectives1.To develop a traditional predict model for incident risk of postpartum T2DM;2.To select the target SNPs that can be used for T2DM risk stratification;3.To develop a comprehensive predict model for incident risk of postpartum T2DM;4.To report the effect after the first year of a lifestyle intervention trial in women with a history of GDM.5.To compare the effects of a lifestyle intervention trial among GDM women stratified according to the GRS.Methods1.Based on the baseline survey,a retrospective cohort study in 1263 Chinese women with GDM,of whom 83 were diagnosed as T2D at 2.3 years postpartum,was conducted.Multivariate Cox proportional hazards models were used to investigate the independent predictors for post-partum T2D.The results of multivariate analyses were used to formulate nomograms for predicting incident risk of post-partum T2D.The predictive accuracy was evaluated using the area under the receiver operating characteristic curve(ROC).2.Forty SNPs based on the baseline blood samples(80 T2DM and 1160 non-T2DM women)were tested.The targeted SNPs suitable for risk stratification of T2DM were selected using the area under the curve(AUC)of ROC,the integrated discrimination improvement(IDI)and the net reclassification improvement(NRI).GRS was calculated using a simple additive genetic risk score method,and the population was divided into low and high genetic risk groups according to GRS based on the 11 SNPs.3.Based on the traditional risk factors and the genetic risks constructed by the 11 SNPs,a comprehensive prediction model was constructed.A multi-factor Cox proportional hazard regression model was used to evaluate the association between each risk factor and postpartum T2DM[risk ratios(HRs)and 95%confidence intervals(95%Cl)].4.After the baseline survey,the 1180 GDM women who were not diagnosed as T2D were randomly assigned to receive a 4-year lifestyle intervention(intervention group,n=586)or standard care(control group,n=594).After the first year of intervention,the changes in body size between the intervention group and the control group were compared using Per-Protocol(PP)and Intention to Treat(ITT)analyses.We also compared the changes in lifestyle compliance rate and blood index between the intervention group and the control group.5.Based on the genetic risks constructed by the 11 SNPs,the population was divided into high and low genetic risk groups.The results of the randomized controlled trial were re-analyzed,and x2 test and T test were used to compare the effects of the intervention in the high and low genetic risk groups.Results1.On multivariate analyses,independent predictors of postpartum T2DM in GDM women included family history of diabetes[hazard ratio(HR)and 95%confidential interval:1.93(1.24-3.01)],history of pregnancy-induced hypertension[3.11(1.86-5.21)]pre-pregnancy body mass index(BMI)[1.00,1.91(1.15-3.18)and 3.36(1.87-6.01)for BMI<24,24-,and?28 kg/m2],and 2-hour glucose at 26-30 gestational weeks[1.00,2.72(1.36-5.43)and 8.32(3.98-17.38)for 2 hour glucose at 7.8?,8.5?,and?11.1 mmol/L).The overall AUC of nomogram was 82.8%(95%CI:78.1%-87.5%),with AUCs of 85.9%(95%CI:79.7%-92.1%)and 83.2%(95%CI:77.9%-88.6%)for postpartum 2-year and 3-year risk of T2D,respectively.2.Totally 39 models were developed by adding the SNPs loci one by one according to their genetically explained proportion of postpartum T2DM risk(PVi),and all the models included the SNP locus(rs10906115)with the highest estimated PVi.Analyses of the models revealed one SNP locus could significantly improve the AUC(P=0.019),eight SNP loci could significantly improve the IDI,and eight SNP loci could significantly improve the NRI(All P<0.05).Totally 11 SNP loci(rs10906115,rs2779116,rs7034200,rs7041847,rs780094,rs5015480,rs11212617,rs831571,rs7944584,rs6815464,and rs35767)were identified with potential application in predicting postpartum T2DM among the women with GDM history,which together could explained 5.5%of cumulative genetic risk of postpartum T2DM among the women with GDM history.3.After incorporating genetic risk stratification into the traditional factor prediction model,the association of each traditional risk factor and postpartum T2DM was similar to the main result,while genetic risk stratification was not significantly associated with postpartum T2DM risk.However,compared with the low genetic risk stratification,women in the high genetic risk stratification have an increased T2DM risk at 3 years postpartum(HR:1.28,95%CI:0.66-2.50).4.After the first year of lifestyle intervention,the lifestyle compliance rate in the intervention group tended to be higher than that of the control group.The body size change was more obvious in the intervention group as compared with the control group,including weight change(-0.82 kg vs.-0.09 kg,P=0.001),weight change percentage(-1.12%vs.-0.03%,P=0.002),Changes in BMI(-0.32 kg/m2 vs.0.04kg/m2,P=0.001),changes in waist circumference(-1.76 cm vs.-0.73 cm,P=0.003),changes in body fat percentage(-0.50%vs.0.05%,P=0.001),and these differences were more pronoulced in women with baseline BMI?24 kg/m2.For blood indicators,there were significant differences in fasting insulin change(-0.10 mmol/L vs.0.66 mmol/L,P=0.011)and HOMA_IR change(-0.02 vs.0.14,P=0.035)betweent the intervention and the control groups.5.After the first year of lifestyle intervention,the dietary fiber intake in the low genetic risk group significantly increased,while ercises in leisure time in the high genetic risk group significantly increased.By changing lifestyles,in the low genetic risk group,there were no significant differences in the body size changes of the GDM women in the intervention and the control groups;but the 2-hour blood glucose change(-0.2±1.4 mmol/L vs.0.3 ± 1.8mmol/L,P=0.014),cholesterol changes(0.0±0.6 mmol/L vs.0.2±0.6 mmol/L,P=0.016)and the abnormal blood glucose rate(23.2%vs.36.7%,P=0.012)were significantly improved in the intervention group as compared with control group.In the high genetic risk group,the body size changes of the GDM women in the intervention group were significantly different from those in the control group,including weight change(-0.9±3.5 kg vs.0.0±3.2 kg,P=0.008),and weight change percentage(-1.3±5.4%vs.0.3±4.9%,P=0.004),change in BMI(-0.3±1.4 kg/m2 vs.0.0 ± 1.2 kg/m2,P=0.009),change in waist circumference(-1.9 ± 5.1 cm vs.-0.6± 5.2 cm,P=0.020),changes in body fat rate(-0.6± 2.6%vs.0.1±2.2%,P=0.005),and fasting insulin changes were significantly better than that in the control group(-0.2±4.5mmol/L vs.0.8±5.0mmol/L,P=0.038)Conclusions1.This study developed an easy-to-use nomogram,with non-invasive clinical characteristics,which can accurately predict the risk of postpartum T2D in women with a history of GDM.It may facilitate risk communication between patients and clinicians.2.Among the 40 GWAS-identified SNP loci associated with postpartum T2DM among women with a history of GDM,11 SNP loci with significant improvement in risk prediction or risk reclassification could be used to predict potential risk of postpartum T2DM after GDM.3.The genetic risk stratification was not significantly associated with overall postpartum T2DM risk,2-year risk,and 3-year risk,but the results might suggest that with the increase of postpartum time,the effect of genetic risk on postpartum T2DM might be more strongly in women with GDM.4.The 1-year lifestyle intervention led to significant weight losses after delivery in women who had GDM,and the effect was more pronounced in women who were overweight at baseline.5.The one-year lifestyle intervention postpartum was effective both in the low and high genetic risk groups,including lifestyle changes and blood indicators changes.The effect of lifestyle intervention is more effective in women with high genetic risk for weight loss. |
PDF Full Text Request