Dietary Patterns,Genetic Polymorphisms Of Insulin Signaling Pathway Genes And Risk Of Gestational Diabetes Mellitus

ObjectivesThis thesis aims to identify the dietary patterns among pregnant women,evaluate the relationship between dietary patterns and risk of gestational diabetes mellitus(GDM),and examine whether genetic polymorphisms of insulin signaling pathway genes modify the relationship between dietary patterns and risk of GDM in Taiyuan Birth Cohort population.The results of the study will provide important clues to the preventive strategies and the discovery of biological basis for GDM.MethodsThe first project included all participants recruited in the Taiyuan Birth Cohort study between March 2012 and October 2016.A case-control study design was used to evaluate the relationship between dietary patterns and risk of GDM.Subjects diagnosed with GDM in Taiyuan Birth Cohort were treated as cases,and non-GDM subjects were treated as controls.Food Frequency Questionnaire was used to collect the information on dietary for the time periods of one year before pregnancy,the first trimester,and the second trimester.The second project was a nested case-control study to evaluate the relationship between genetic polymorphisms of insulin signaling pathway genes and risk of GDM.The subjects diagnosed with GDM between March 1,2012 and July 30,2014 were included as cases,non GDM subjects were 1:1 frequency matched to cases by maternal age,gestational age and residential address.DNA was extracted,isolated,and purified from whole blood samples according to a standard phenol-chloroform extraction method.Genotyping was conducted using Illumina Golden Gate Platform.The odds ratios(ORs)and 95% confidence interval(95%CI)were estimated by unconditional logistical regression adjusting for maternal age,maternal body mass index(BMI),parity,and family history of diabetes using R software.min P test and Haploview were used for gene-level analysis and haplotype analysis respectively.The third project used the same study population as the second project to investigate the interactions between dietary patterns and genetic polymorphisms in insulin signaling pathway genes and two genes related to GDM susceptibility identified by current literatures.The logistic regression model,crossover analysis and generalized multifactor dimensionality reduction method were used to analysis the multiplicative interaction and the additive interaction.Results 1.Vegetables,Cereal and Meat patterns were identified in our study population through dietary pattern analysis.Vegetables dietary factor loaded heavily on bean products,green leafy vegetables,and other vegetables.Cereal dietary factor loaded heavily on cereal,kelp,pickle,nuts and fruits.Meat dietary factor loaded heavily on meat,dairy,egg,nuts and fruits.Vitamins dietary factor which loaded heavily on vitamin A,carrotene,vitamin C,dietary fiber,vitamin B2,vitamin B6,folate,protein,calcium and potassium.Vegetables dietary pattern during one year before pregnancy,the first and second trimester were associated with reduced risk of GDM,and it was reduced by 6%,6% and 9%(Ptrend = 0.026,0.017,0.001)when the vegetables factor scores increased by a quartile.Vitamins dietary pattern during one year before pregnancy,the first and second trimester were also associated with reduced risk of GDM.The GDM risk was reduced by 10%(Ptrend = 0.0001,0.0001,0.0001)when the vitamins factor scores increased by a quartile during these three periods.2.SOS1 gene rs7598922 A allele was associated with reduced GDM risk.Specifically,women who carried AG or AA genotypes had reduced risk compared to women who carried GG genotype(OR= 0.62,95% CI= 0.43-0.88 for AG genotype and OR=0.28,95% CI= 0.09-0.73 for AA genotype).There was a significant trend(P for trend =xxx).SOS1 gene were associated with GDM risk at gene level after adjusted for multiple comparisons using FDR method.Haplotype AAAA(OR= 0.68,95%CI = 0.48-0.95,P=0.025)and GGGG(OR= 0.62 95%CI = 0.43-0.91,P=0.013)in SOS1 gene were also associated with reduced GDM risk compared to haplotype GAAA.3.CDKAL1 gene rs4712527,rs7748720,and rs6938256 G allele carriers experienced reduced GDM risk.Women who carried the rs4712527,rs7748720,and rs6938256 AG genotype(OR = 0.64,95% CI = 0.44-0.92;OR = 0.57,95% CI = 0.39-0.81;and OR = 0.63,95% CI 0.45-0.89 respectively)or rs4712527,rs7748720,and rs6938256 GG genotype(OR = 0.21,95% CI = 0.05-0.69;OR = 0.15,95% CI = 0.03-0.47;and OR =0.39,95% CI =0.20-0.74 respectively)had reduced risk of GDM with significant dose response(Ptrend = 0.001,0.00003,0.0005 respectively).The CDKAL1 was associated with the risk of GDM at gene level after adjusted for multiple comparisons using FDR(P= 0.007).4.Negative multiplicative interactions(ORI=0.39,95%CI= 0.20-0.77,P= 0.007;ORI= 0.37,95%CI= 0.19-0.74,P=0.004;ORI=0.39,95%CI= 0.20-0.77,P=0.007)and negative additive interactions(S=0.36,95%CI = 0.16-0.83,P= 0.043;S=0.29,95%CI= 0.11-0.76,P=0.033;S=0.33,95%CI= 0.14-0.81,P=0.042)were found in CDKAL1 SNPs rs2819996,rs9366363,rs7753271 and cereal dietary pattern during the second trimester.The A allele in these three SNPs and cereal dietary pattern exposure were associated with increased GDM risk,and it was decreased when the two factors co-exposure compared with each factor exposure alone.The CDKAL1 rs9295478-cereal-meat three factors interaction model was statistically significant by GMDR analysis(P=0.011),the three factors co-exposure would increase GDM risk(OR=3.40,95%CI 2.12-5.44).5.The ACACA gene rs9904250 + cereal + meat three factors interaction model was statistically significant by GMDR analysis(P=0.001),these factors co-exposure would increase GDM risk(OR=3.23,95%CI = 2.03-5.14).Conclusions 1.The vegetables dietary pattern and vitamins dietary pattern during one year before pregnancy,the first and second trimesters were associated with reduced risk of GDM in Taiyuan Birth Cohort.The results suggested that dietary factors may be involved in the development of GDM,indicating possible ways for GDM prevention.2.SOS1 gene was associated with reduced risk of GDM at gene level,suggesting that polymorphisms of insulin signaling pathway genes may be involved in the development of GDM.CDKAL1 rs4712527,rs7748720 and rs6938256 SNPs were associated with reduced GDM risk,and the association was verified statistically significant at gene level.These results suggested a potential role of CDKAL1 in GDM development in Taiyuan Birth Cohort.3.Significant interactions of CDKAL1 rs2819996,rs9366363 and rs7753271 were found with cereal dietary pattern.Significant interactions of CDKAL1 rs9295478 and ACACA rs9904250 were also found with cereal and meat dietary pattern.These results may provide important clues to identify high risk population who are susceptible to GDM and prevent GDM by modify their dietary patterns.In brief,our study evaluated the relationships between diet patterns and genetic variations in including insulin signaling pathway genes and previous published GDM susceptibility genes,and we found that vegetables dietary pattern and vitamins dietary pattern were associated with reduced risk of GDM.The study also found that the interactions between cereal,meat dietary pattern and CDKAL1,ACACA genes in risk of GDM.These results suggested a possible role of dietary factors in prevention of GDM,and they provided clues to identify high risk population who are susceptible to GDM and prevent GDM by modifying their dietary patterns.