Gene Polymorphisms And Risk Of Congenital Heart Disease In A Chinese Population

Congenital heart disease(CHD)is the leading non-infectious cause of death in children and the incidence appears to be 1%in live births and 5-10%in spontaneously aborted pregnancies.In China,the prevalence of CHD was 73.2 per 10,000 births in high-prevalence areas.Chromosomal defects and environment tetatogens only cause a small portion of the disease.Most CHD is sporadic and considered to be multi-factorial in origin,with various genes interacting with each other or with environmental factors to determine the disease etiology.Therefore, genetic variants contribute to the production and/or biological activity of heart modifier genes may determine susceptibility of CHD.The heart is the first organ to form and function during development. Numerous signaling pathways contributed to the development of the heart, such as vascular endothelial growth factor(VEGF),NFATc1,Notch, Wnt/β-catenin,BMP/TGF-β,ErbB,and NF1/Ras.Spatiotemporal expression pattern of VEGF was the first indication of a specific role for VEGF in CHD cases.It is reported that VEGF was required for proper heart morphogenesis at stages where the heart is still avascular. VEGF-expressing endothelial cells in the cushion-forming region may be a unique subpopulation of endothelial cells predetermined to undergo endocardium transform to mesenchyme(EMT).Furthermore,the importance of appropriate timing and dosage of VEGF during heart development was highlighted by shared cardiovascular developmental defects in animal models,including mice heterozygous for VEGF allele and transgenic mice,which have a 2-to 3-fold increased VEGF.Evidence also showed that increased VEGF levels during right ventricular outflow tract development can lead to abnormal development of both cushion and myocardial structures.VEGF gene polymorphisms may play a role in susceptibility of congenital valvuoseptal heart defects.However,it is reported that VEGF gene polymorphisms may also be related with congenital heart disease,such as tetralogy of Fallot(TOF)and pulmonary stenosis.The single nucleotide polymorphisms(SNPs)variants in VEGF gene may contribute to the production and/or biological activity and determine susceptibility of congenital heart disease.To test this hypothesis,we conducted a case-control study to evaluate the association between VEGF polymorphisms and congenital heart diseases.Furthermore,we evaluate the association between NFATc1,ET1,MTHFR and related genes in a case-control studies in Chinese population. 1:Association study of VEGF polymorphisms and congenital heart diseaseA hospital-based case-control study was conducted,including 476 CHD patients and 557 age and sex frequency-matched non-CHD controls. VEGF-2578C＞A,-1498T＞C,-634G＞C,and+936C＞T polymorphisms were measured by PCR-RFLP method.In the single locus analyses,none of the four polymorphisms achieved significant difference in the genotype distributions between the cases and the controls.Multivariate logistic regression analyses revealed that none of the four SNPs were significantly associated with the risk of CHD,In the stratified analyses, no associations were observed between -2578C＞A,-1498T＞C,-634G＞C, and+936C＞T genotypes and CHD risk for individuals categorized by CHD types. 2:A Tandem Repeat Polymorphism in NFATc1 is associated with an increased risk of perimembranous ventricular septal defect in a Chinese populationNFATc1 plays a critical role during the valve and septal development.Genetic variants in NFATc1 may contribute to its biological function,and therefore,were hypothesized to be associated with perimembranous ventricular septal defect(PmVSD)heart defect susceptibility.We genotyped a tandem repeat polymorphism and a common non-synonymous polymorphism Cys751Gly of NFATc1 in a hospital based case-control study of 217 perimembranous ventricular septal defect cases and 557 non-CHD controls in a Chinese population. This study included 217 perimembranous ventricular heart defect patients and 557 non-CHD controls.The patients were consecutively recruited from the First Affiliated Hospital of Nanjing Medical University and the Nanjing Children's Hospital,Nanjing,China,between March 2006 and October 2007.All patients were non-syndromic cases,Ultrasonic diagnosed and confirmed in surgical operations.The controls were non-CHD out-patients,matched to the cases on age(±3 years)and sex, recruited from the above referred hospitals during the same time period and most of them with trauma,hernia or infectious diseases.All subjects were genetically unrelated ethnic Han Chinese.We found LL genotype may be a risk genotype against PmVSD(adjusted OR=1.68,95%CI =1.02-2.78).We also evaluated the tandem repeat polymorphism among complete atrioventricular canal(CAVC)cases.Although CAVC was suffered with a limited sample size,a non-significant increased CAVC risk associated with the LL genotype was observed(adjusted OR=2.44, 95%CI=0.43-13.76 for homozygote comparison and adjusted OR=1.83, 95%CI=0.39-8.50 in recessive model).However,we didn't find any association between Cys751Gly and PmVSD heart defect risk.These findings suggest that the NFATc1 tandem repeat polymorphism may serve as a biomarker of PmVSD susceptibility.Further studies are warranted to verify these results. 3:ET1 Taq1 Polymorphism is associated with a decreased risk of perimembranous ventricular septal defect in a Chinese populationET1 plays an important role during heart development.Genetic variants in ET1 may contribute to its biological function,and therefore, were hypothesized to be associated with perimembranous ventricular septal defect(PmVSD)heart defect susceptibility.We genotyped ET1 Taq1 polymorphism in a hospital based case-control study of 217 perimembranous ventricular septal defect cases and 557 non-CHD controls in a Chinese population.This study included 217 perimembranous ventricular heart defect patients and 557 non-CHD controls.The patients were consecutively recruited from the First Affiliated Hospital of Nanjing Medical University and the Nanjing Children's Hospital,Nanjing,China,between March 2006 and October 2007.All patients were non-syndromic cases,Ultrasonic diagnosed and confirmed in surgical operations.The controls were non-CHD out-patients,matched to the cases on age(±3 years)and sex,recruited from the above referred hospitals during the same time period and most of them with trauma,hernia or infectious diseases.All subjects were genetically unrelated ethnic Han Chinese.We found CC genotype may be a protective genotype against PmVSD(adjusted OR=0.43,95%CI =0.20-0.94).These findings suggest that the ET1 Taq1 polymorphism may serve as a protective biomarker of PmVSD susceptibility.Further studies are warranted to verify these results. 4:No association was found between children's MTHFR and MTHFD polymorphisms and risk of congenital heart diseases in a Chinese populationMaternal high plasma homocysteine concentration is a risk factor of CHD.It has been reliably shown that plasma homocysteine concentrations can be reduced by folic acid.Also accumulative evidence suggests that maternal folate supplement has a protective effect on CHD. The methylenetetrahydrofolate reductase(MTHFR)and methylenetetrahydrofolate dehydrogenase(MTHFD)both play important roles in folate and homocysteine(Hcy)metabolisms and polymorphisms of MTHFR and MTHFD may result in disturbance of the folate-mediated homocysteine pathway.However,evidences also show MTHFR and MTHFD polymorphisms of the fetus may be related with risk factors of CHD.The purpose of this study is to test the hypothesis that genetic variants of MTHFR and MTHFD of CHD patients are associated with risk of CHD.We genotyped C677T and A1298C and G1793A in MTHFR,G1958A and T401C in MTHFD in a case-control study of 502 CHD cases and 527 non-CHD controls in a Chinese population.We did not find any associated between different variant genotypes of MTHFR C677T and A1298C and G1793A and for MTHFD 1958AA and 401CC there were no significantly increased or decreased risk between CHD cases and controls,(adjusted OR=0.78,95%CI=0.55-1.11 for MTHFR 667TT;adjusted OR=1.17,95%CI=0.59-2.33 for 1298CC;adjusted OR=0.26,95%CI=0.05-1.17 for 1793AA),compared with 667CC and 1298 AA and 1793GG genotypes.For MTHFD(adjusted OR=0.85, 95%CI=0.53-1.36 for MTHFD 401CC;adjusted OR=0.56, 95%CI=0.30-1.06 for 1958AA),compared with 401TT and 1958 GG genotypes,respectively.Further studies are warranted to verify these results.Especially for the MTHFR and MTHFD genotypes of mothers and maternal plasma homocysteine levels and the risk factor of CHD. Lung cancer is the leading cause of cancer-related deaths.World wide,it is estimated that there are 900 000 new cases of lung cancer in men and 330 000 new cases in women every year.In China,the incidence and mortality rates have been increasing rapidly in the last two decades and accumulating tobacco use was considered as the most important cause for lung cancer.Tobacco smoke is a well-established etiological factor for lung cancer.However,only about 20%of the smokers develop lung cancer in their lifetime,indicating the genetic susceptibility of lung cancer.Genes involved in cell cycle checkpoint control,DNA damage repair and DNA-damage-induced apoptosis are related with lung cancer susceptibility.Recent molecular biological studies have clearly indicated that lung cancer is a disease caused by the accumulation of multiple genetic defects in both tumor suppressor genes and dominant oncogenes.The genesis of lung cancer is the result of multiple acquired genetic events including mutations in oncogenes and tumor suppressor genes. Factors related to cell cycle or apoptosis have been studied in recent publications and may be related with lung cancer susceptibility.Aberrant cell cycle control is a hallmark of cancer,the eukaryotic cell cycle is driven by cyclins,regulated by cyclin-dependent kinases(CDKs)and negatively regulated by CDK inhibitors(CKIs).Abnormal function of CDKs and CKIs can cause the deregulated proliferative activity frequently seen in tumor cells.Single Nucleotide Polymorphisms(SNPs) are most common form of DNA sequence variation.Cyclins,CDKs and CKIs polymorphisms may be related with gene expression and might have an effect on human tumorigenesis.We therefore hypothesized:(1). Cyclins,CDKs and CKIs polymorphisms may contribute to individual's susceptibility to lung cancer;(2).The interaction between associated gene polymorphisms and environment factors(tobacco smoke et al.)may be related with individual's susceptibility to lung cancer.To test this hypothesis,we conducted a case-control study to evaluate the association of Cyclins,CDKs and CKIs polymorphisms and environment factors with lung cancer risk in Chinese people by molecular epidemiology study methods,to clarify the risk genotypes of lung cancer, and to be considered as a biomarker for screen the high risks and susceptible people.