Effects Of Behavioral Factors During Pregnancy And Obesity-related Gene Polymorphisms In Offspring And Their Interaction On Fetal Growth And Birth Weight

Objective:Overweight and obesity are very remarkable public health problem in the21st century.Childhood overweight obesity children can not only induce hypertension,hyperglycemia,hyperlipidemia,high uric acid metabolic abnormalities,such as the increase in the risk,and continue into adulthood,leading to a variety of adult chronic diseases（such as hypertension,type 2 diabetes,fatty liver disease,metabolic syndrome,etc.）.Birth weight is an important index to evaluate fetal development in utero and newborn health status.Previous studies have shown that abnormal birth weight is closely related to the risk of progeny lifetime obesity and related chronic diseases.There is a U-shaped relationship between birth weight and the incidence of overweight and obesity in childhood and adulthood.Birth macrosomia is a clear etiological risk factor for the occurrence of progeny obesity,while low birth weight infants can also lead to an increase in the incidence of childhood abdominal obesity through catch-up growth.It is of great practical significance to predict the birth weight of the fetus in the middle and late pregnancy through ultrasound detection during pregnancy,and to conduct early intervention during pregnancy,which is of great practical significance to guide the delivery of the newborn with normal birth weight.In addition,both genetic factors and behavioral factors during pregnancy affect the intrauterine growth and development of the fetus.Genetic factors play a decisive role in the susceptibility to diseases,while environmental and behavioral factors can promote the occurrence of diseases.In recent years,scholars at home and abroad began to pay attention to the influence of the interaction between genes and environment on metabolic diseases,but there is a lack of research on the interaction between environmental behavioral factors and genes during pregnancy and intrauterine development of children.Based on this,the objective of this study is divided into the following three aspects:First,based on the prospective birth cohort project to conduct a study on the correlation between maternal behavioral factors during pregnancy and fetal growth deviation and abnormal birth weight,to identify the specific influencing factors;The second is to explore the effects of obesity-related gene polymorphisms on fetal intrauterine growth and birth weight by collecting DNA from umbilical cord blood.Third,to explore the interaction between different gene polymorphisms and environmental behavioral factors on fetal growth and birth weight,so as to provide a theoretical basis for exploring the potential mechanism of fetal growth deviation and abnormal birth weight,and lay a foundation for the precise prevention and control of adverse birth weight.Methods:In the early stage of this study,pregnant women who met the inclusion criteria were included and screened based on prospective birth cohort,baseline survey was conducted in the early trimester,and on-site follow-up was conducted in the second trimester,third trimester and postpartum respectively.Maternal pre-pregnancy weight and height were obtained at baseline during early pregnancy.Ultrasound in the second and third trimesters was performed by a specialist ultrasound physician.Neonatal length,birth weight and other indicators were measured by the obstetrician,and recorded by the follow-up investigator after the obstetrician filled in the health handbook at the time of delivery.The methods of investigation at each stage include physical examination,questionnaire survey,clinical data collection and biological sample collection.Questionnaire content including during pregnancy during pregnancy（including pregnancy early and mid pregnancy and late pregnancy）basic information,history of disease,family history of disease,maternal history,history of childbirth,the pregnancies,medical history,physical examination and interrogation,clinical examination index,auxiliary examination project,lifestyle,psychological factors,environmental behavior exposure factors（diet,physical activity and sleep）.Dietary during pregnancy was measured using the dietary Frequency questionnaire（FFQ）,physical activity during pregnancy was measured using the physical activity Questionnaire during pregnancy（PPAQ）,and sleep quality during pregnancy was measured using the Pittsburgh Sleep Index Scale（PSQI）.The main ultrasound measurements in the second and third trimesters were double parietal diameter（BPD）,head circumference（HC）,abdominal circumference（AC）and femur length（FL）.Neonatal survey mainly includes basic information,delivery,birth weight and length,etc.Neonatal genetic information was standardized and stored in neonatal umbilical cord blood samples,and DNA was extracted.SNP loci were selected through NCBI-db SNP database and combined with literature reports to identify 10 children’s BMI-related SNP loci,and genotyping was conducted by gene chip.Epi Data3.1 software was used for double data entry,and Stata16.0 software was used for data analysis.Dietary pattern,physical activity level,sleep quality and other factors during pregnancy were associated with birth weight,estimated intrauterine weight and other outcomes.The principal component analysis method was used to analyze 21 food components,calculate the dietary pattern score,and classify the dietary pattern according to the score.The T-test was used to compare the pattern scores of different demographic statistical variables.The correlation between dietary pattern scores and anthropometric values of newborn and fetus was analyzed by linear regression.The main indicators of neonatal birth weight were birth weight and birth length,and the main indicators of fetal measurement were estimated fetal weight after adjusting for gestational age.Multiple Logistic regression model was used to evaluate the relationship between dietary patterns,physical activity,sleep and other factors and intrauterine growth abnormalities of macrosomia,low birth weight（LBW）,above gestational age（LGA）,and below gestational age（SGA）babies（>90th percentile or<10th percentile）of risk.Genotyping data can be analyzed using Taq Man Genotyper software to obtain genotyping results and amplified scatter plots.The goodness-of-fitχ²test was used to calculate whether the genotype distribution of each point was consistent with Hardy-Weinberg equilibrium.Logistic regression was used to analyze the association between gene polymorphism and the risk of fetal growth deviation and abnormal birth weight.Multiple Logistic regression model was used to analyze the interaction between environmental factors and gene polymorphism.All statistical analyses were performed using STATA16.0 statistical software,and the test level was P<0.05.Results:1.A total of 2,017 mother and child pairs were included in this project.56.88%of pregnant women had normal weight before pregnancy,the rate of overweight and obesity before pregnancy reached 29.99%,and the rate of low weight before pregnancy was 13.13%.The mean gestational age of delivery was 38.24±2.53weeks,and 83.81%of the newborns were of normal birth weight.The gestational age was 24.56±1.15 weeks,and the estimated weight of 56.27%fetus was in the appropriate range.The gestational age was 32.15±1.28 weeks,and 61.49%of the estimated fetal weight was in the appropriate range.2.In terms of behavioral factors during pregnancy,four dietary patterns were extracted according to dietary survey data during pregnancy:fish-seafood pattern,high protein pattern,meat staple pattern and fruit and vegetable pattern.In early pregnancy,fish-seafood pattern scores were significantly positively correlated with the risk of low birth weight infants（T3 vs.T1:OR=1.90;95%CI:1.03 1.48）.During the second trimester,fish-seafood pattern scores were significantly associated with LGA（T3 vs T1:OR=2.00,95%CI:1.32-3.04）,and meat-staple pattern scores were negatively associated with LGA risk（T3 vs T1:OR=0.61,95%CI:0.40-0.94）.Higher fish-seafood pattern scores were associated with a risk reduction of EFW>P₉₀（T3 vs T1:OR=0.59,95%CI:0.37-0.93）.Higher high-protein pattern scores were associated with an increased risk of EFW>P₉₀（T3 vs T1:OR=2.02,95%CI:1.28-3.17）.In terms of the relationship between physical activity during pregnancy and fetal growth and birth weight,the multivariate Logistic regression analysis showed that physical activity during pregnancy was strongly correlated with fetal growth deviation and abnormal birth weight.Increased physical activity in the third trimester（PA≥200Met-hour/week）was associated with a reduced risk of macrosomia（OR=0.35,95%CI:0.12-0.99）.Increased physical activity during the first,second and third trimesters was associated with a reduced risk of low birth weight babies.Moderate physical activity in the first trimester and higher physical activity in the second trimester were associated with a reduced risk of SGA and a reduced risk of low fetal abdominal circumference.Studies of sleep during pregnancy have found that poor sleep quality during the second trimester is associated with lower estimated fetal weight during the second trimester.3.According to the Hardy-Weinberg balance test,8 loci were selected to study the relationship between obesity related gene polymorphism in offspring and fetal growth and birth weight.Both heterozygous C/T genotypes and homozygous T/T genotypes at rs6567160 of MC4R gene were associated with a reduced risk of low estimated fetal body weight(EFW<P₁₀)（OR=0.21,95%CI:0.05-0.83;OR=0.19,95%CI:0.05-0.71）.The G/G homozygous genotype at rs10938397 of GNPDA2 gene was associated with a reduced risk of fetal abdominal circumference(>P₉₀)（OR=0.19,95%CI:0.04-0.82）,and the G allele was protective against fetal abdominal circumference in the second trimester.GNPDA2 gene rs13130484 T/T homozygous genotype was associated with a reduced risk of fetal abdominal circumference(>P₉₀)（OR=0.21,95%CI:0.05-0.91）,and C/T heterozygous genotype was significantly associated with the risk of fetal macrosomia（OR=2.07,95%CI:1.05-4.07）.In the third trimester of pregnancy,A/T heterozygous genotype at rs9939609 of the FTO gene was significantly associated with the risk of large fetal biparietal diameter(>P₉₀)（OR=2.16,95%CI:1.07-4.34）and with a reduced risk of small fetal abdominal circumference(<P₁₀)（OR=0.14,95%CI:0.03 to 0.75）;Homozygous T/T genotypes were associated with a reduced risk of fetal abdominal circumference(<P₁₀)（OR=0.11,95%CI:0.02-0.52）.The G/G homozygous genotype at rs6235 of PCSK1 gene was significantly associated with the risk of larger than gestational age（OR=1.98,95%CI:1.08-3.64）,and the G/G homozygous genotype was significantly associated with estimated fetal underweight(<P₁₀)（OR=3.87,95%CI:1.30-11.49）.4.In a study of the interaction between behavioral factors during pregnancy and progenitor obesity-related gene polymorphisms on fetal growth and birth weight,an increased intake of high-protein diets during the second trimester was protective against second-trimester estimated underweight in fetuses with the MC4R rs6567160C/T genotype（T2 vs.T1,OR:0.04,95%CI:0.002-0.63）.In fetus with MC4R rs6567160 C/T and T/T genotypes,increased high-protein pattern intake was positively associated with an increased risk of estimated fetal weight in the second trimester（C/T:T3 vs.T1,OR:4.58,95%CI:1.12-18.58,T/T:T3 vs.T1,OR:4.09,95%CI:1.48-11.33）.In individuals with C/T genotypes,increased intake of fish-seafood and meat staples during the second trimester was negatively associated with the risk of estimated fetal weight in the second trimester（T3 vs.T1,OR:0.25,95%CI:0.07-0.96;T3 vs.T1,OR:0.29,95%CI:0.10-0.88）.For T/T genotype progeny,an increase in high-protein pattern intake during the second trimester was negatively associated with the risk of larger than gestational age（T2 vs.T1,OR:0.39,95%CI:0.20-0.77）.During the second trimester,the meat-staple dietary pattern was a protective factor for estimated weight gain during the second trimester in the offspring of the FTO rs9939609 T/T genotype（T3 vs.T1,OR:0.31,95%CI:0.12-0.79）,high protein pattern was a risk factor for estimated weight gain in the second trimester（T3 vs.T1,OR:4.63,95%CI:1.89-11.37）.For T/T genotype progeny,high protein pattern in the first trimester was a risk factor for larger than gestational age（T3 vs.T1,OR:2.28,95%CI:1.05-4.96）,and high protein pattern in the second trimester was a protective factor for larger than gestational age（T2 vs.T1,OR:0.48,95%CI:0.26-0.89）.For offspring of FTO rs9939609 C/T/genotype,moderately increased physical activity during pregnancy（100≤PA<200 Met-hour/week）was protective against LGA risk（OR:0.27,95%CI:0.08-0.87）.Conclusion:In this large cohort study based on a population in northern China,dietary patterns,physical activity and sleep during pregnancy are associated with fetal growth deviation and abnormal birth weight.Fish-seafood pattern and high protein pattern were risk factors for growth deviation and abnormal birth weight,while meat-staple food pattern was protective factor.Moderate and more physical activity during pregnancy has a protective effect on the growth of head circumference and the appropriate birth weight during fetal development.Good sleep quality during pregnancy is beneficial for achieving an appropriate estimated body weight for the fetus.SNP polymorphisms in different genes are associated with fetal growth deviation and abnormal birth weight:The C/T genotype of the MC4R gene rs6567160,the A/T and T/T genotype of the FTO gene rs9939609,the G/G genotype of the GNPDA2 gene rs10938397,and the T/T genotype of the rs3130484 played a certain protective role against fetal growth deviation and abnormal birth weight.T/T genotype of GNPDA2gene rs13130484,G/G genotype of PCSK1 gene rs6235,C/T genotype of BDNF gene rs6265,T/T genotype of rs10938397,The A/G and G/G genotypes of BDNF gene rs7138803 and FTO gene rs9939609A/T genotype were risk factors.Found in the study of the interaction,for some the same SNP genotypes,different dietary patterns may produce different interactions,which affect fetal growth deviation and abnormal birth weight,and to explore the interaction of the two,as early in life provide theoretical basis for accurate control and prevention of childhood obesity.It plays an important guiding role in disease prevention.