| Telomeres are tandem repeats of TTAGGG nucleotides and specific binding-protein complexes capped the ends of eukaryotic chromosomes that are crucial in maintaining chromosomal integrity and genomic stability.During somatic cell divisions,telomeres progressively shorten.Therefore,telomere length can reflect the senescence of cells.Currently telomere length was confirmed as a biomarker that can indicate the risk of age-related disease.Although the telomere length of tissue derived cells can providing more direct evidence for the relationship between telomere length and disease risk,as telomere length are strongly correlated between different tissues and with its high accessibility and high DNA quality,peripheral blood leucocyte cells is now being widely analyzed in telomere length studies.Epidemiology studies have found that telomere lengths of the adults are mainly determined by environmental factors and genetic factors and telomere length depends on telomere length at birth and oxidative stress after birth.Individual telomere length at birth is most variable and it is found that telomere length in early life can better predict life than that in later life.Telomere length at birth will cause a lifelong impact on individuals,with its influence exceeding other risk exposure in later life.Thus research on newborn telomere length is of great significance.Currently results of newborn telomere length were inconsistent and just come from studies with small sample sizes.Other studies confirmed newborn telomere length was largely related to genetics but evidence for the relationship between genetic variants and telomere length in and abroad were mainly focus on adults and the genetic variation of telomere length at birth has not been reported.Therefore,we firstly investigated the influence ofenvironmental exposures on newborn telomere length.Furthermore,we evaluated the effect of genetic factors on neonatal telomere length.Part I:Effect of environmental factors on newborn telomere lengthEpidemiology studies have investigated social demographic factors and environmental factors that influence newborn telomere length.A study from Friedrich et al on 15 newborns found that gestational age and birth weight etc affected the umbilical cord telomere length;another study from Entringer et al on 27 newborns found that there was a significant effect of pregnancy specific stress on cord blood telomere length;but there still another study from Cross JA et al on 81 newborns found that there were no relationship between cord blood telomere length and maternal age,gestational age,smoking and birth weight etc.These studies were small sample sized and the results were inconsistent.Therefore,we conducted a cross-sectional study to investigate the environmental factors influencing telomere length at birth.444 cases were recruited from Nanjing Drum Tower hospital.Questionnaire surveys,physical examinations and clinical testing were conducted in pregnant women and the maternal peripheral bloods as well as their matching umbilical venous blood samples were collected.We use quantitative PCR method to measure the telomere length.In brief,relative telomere length(RTL)were determined by the ratio of telomere repeat copy number(T)to single copy gene copy number(S)and expressed as T/S ratio.All samples were run in duplicate and the mean of two measurements was used in the statistical analyses.Paired T test were used to compare maternal and neonatal telomere length.Variance analysis and T test were used to compare relative telomere length between different subgroups.Using the general linear model to analyze the correlations between maternal and neonatal telomere length and the correlations between telomere length and other continuous variables.As a result,the overall RTL of maternal blood was significantly shorter(mean:0.309)than of cord blood(mean:0.358,P<0.001)but there was no relationship between maternal blood telomere length and cord blood telomere length.We observed a significant positive correlation between maternal education level and the RTL of cord blood(P = 0.022).There was no obvious correlations between telomere length(both maternal and cord telomere length)and gestational age,delivery mode,newborn sex and birth weight(P>0.05).More dairy intake during pregnancy,maternal telomere length were shorter(P = 0.048).Maternal and neonatal telomere length did not differ in subgroups of different levels food intake,as follows fruits and vegetables,meat,animal offal,fish and shrimp,bean products,baked and preserved food,folic acid and vitamins(P>0.05).Coffee drinking during pregnancy was associated with shorter neonatal telomere length(P = 0.011).Second hand smoke exposure,alcohol consumption and drinking tea during pregnancy were not associated with maternal and neonatal telomere length(P>0.05).Physical exercise during pregnancy was correlated with longer maternal telomere length(P = 0.01)but not associated with neonatal telomere length(P = 0.187).Our study was the first to assess the effect of various environment exposures during pregnancy on maternal and newborn telomere length comprehensively.We provided valuable clues to reveal the role of telomeres in disease.Part Ⅱ:Effect of genetic factors on newborn telomere lengthStudies have shown that telomere length was heritable and the heritability estimates range from 36 to 90%.Therefore investigating the heritable variations and genes is of great significance in clarifying the internal mechanism of telomere length regulation.In recent years,genome-wide association study(GWAS)have been widely used in association studies between genes and disease and it was based on large group of DNA samples to look for genetic factors associated with complex diseases so as to reveal the genes with respect to disease occurrence,development and treatment.So far multiple genetic variants were reported in Europeans,including 3q26(TERC),4q32.2(NAF1),5p15.33(TERT),10q24.33(OBFC1)and 20q13.3(RTEL1)etc.which have been confirmed directly involved in telomere functional regulation,as well as 2p16.2(ACYP2)and 19p12(ZNF208)etc.which have not been confirmed in telomere functional regulation.These studies provided valuable clues for illustrating the genetic mechanism of telomere length.However,there was no evidence for telomere length related genetic variants in newborns.In present study,TaqMan 7900 genotyping platforms were used to compare the associations between the established telomere length affecting genetic variants and telomere length in both the maternal peripheral blood and cord blood of newborns.In order to analyze the correlation between related genetic variants and maternal as well as newborn telomere length more comprehensively,we calculated Weighted Genetic Scores(WGS)of the eight genetic variants and analyzed the correlation between WGS and maternal peripheral blood as well as umbilical venous blood telomere length to evaluate the comprehensive effect of the eight genetic variations on maternal and neonatal telomere length.General linear model analysis was used to estimate the correlations between telomere length and genetic variants or WGS.In maternal samples,we found that rs10936599 and rs2736100 exhibited significant associations with longer RTL(β=0.0119,P=0.041 and β=0.011,P=0.046),which was in accordance with that reported in Caucasians.We observed significant correlation between maternal WGS and RTL(R2=0.012,P=0.025),which was more predominant than any of the variants alone.Regression analysis did not reveal any obvious association between the eight reported TL SNPs alone or in combination and cord blood RTL(P=0.716).We primarily addressed that genetic variants may influencing telomere length by affecting its resistant capacity for the external environmental exposures during the growth and development stage of offspring,rather than predetermined before birth.Our study comprehensively analyzed the correlation between reported genetic variants and telomere length among mothers and newborns and helps to further clarify the molecular mechanisms of inheritance pattern of telomere length. |
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