title: Association of genetic polymorphisms of de novo nucleotide biosynthesis with increased CHD susceptibility in the northern Chinese population.
abstract: Congenital heart disease (CHD) is one of most prevalent birth defects in the world. However, the underlying molecular mechanism(s) have not been fully understood. Here we report that increased CHD susceptibility is associated with genetic polymorphisms for de novo nucleotide biosynthesis in northern Chinese population, which has been reported with lower plasma folate levels. Nine tagSNPs of four genes (GART, ATIC, MTHFD1 and SHMT1) in de novo nucleotide biosynthesis were sequenced in 802 sporadic CHD patients and 1093 controls from two Han Chinese populations, located in north China (Shandong) and South China (Shanghai), respectively. Six SNPs were found to be significantly associated with CHDs or septation defects only in the Shandong population dataset, but none displayed significant association with any CHDs in the Shanghai population dataset as well as in the combined dataset. We also showed that the minor A allele of rs7279549 in GART reduced transcriptional activity and displayed lower affinity for unknown transcription factor(s), demonstrating the allele is a functional risk factor for CHD in Shandong population. Our study indicates that dysregulation of de novo nucleotide biosynthesis pathway may conditionally contribute to CHD pathogenesis in northern Chinese.
authors.affiliation: State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University.
authors.forename: Y-C
authors.identifier: http://orcid.org/0000-0002-4465-0457
authors.initials: YC
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University.
authors.forename: L-L
authors.initials: LL
authors.lastname: Kuang
authors.affiliation: Children's Hospital of Fudan University, Shanghai, China.
authors.forename: S-N
authors.initials: SN
authors.lastname: Sun
authors.affiliation: Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan, China.
authors.forename: W-Y
authors.initials: WY
authors.lastname: Duan
authors.affiliation: Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan, China.
authors.forename: B
authors.initials: B
authors.lastname: Qiao
authors.affiliation: State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University.|Obstetrics & Gynecology Hospital, Institute of Reproduction & Development, Fudan University, Shanghai, China.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Wang
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics; D019731:Carbon-Nitrogen Ligases / Q000235:genetics*; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000235:genetics*; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics*; D015778:Minor Histocompatibility Antigens / Q000235:genetics*; D009097:Multienzyme Complexes / Q000235:genetics*; D009709:Nucleotide Deaminases / Q000235:genetics*; D009711:Nucleotides / Q000096:biosynthesis / Q000235:genetics; D051026:Phosphoribosylglycinamide Formyltransferase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D015778:Minor Histocompatibility Antigens; D009097:Multienzyme Complexes; D009711:Nucleotides; D014157:Transcription Factors; C113120:inosine monophosphate synthase; C539735:MTHFD1 protein, human; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D019877:Hydroxymethyl and Formyl Transferases; D012696:Glycine Hydroxymethyltransferase; C520541:SHMT protein, human; D051026:Phosphoribosylglycinamide Formyltransferase; D009709:Nucleotide Deaminases; D019731:Carbon-Nitrogen Ligases; C494823:GART protein, human
keywords: congenital heart diseases; de novo nucleotide biosynthesis; genetic polymorphism