Lower Circulating Folate Induced by a Fidgetin Intronic Variant Is Associated With Reduced Congenital Heart Disease Susceptibility

作者：Dan Wang, Feng Wang, Kai-hu Shi, Hui Tao, Li Yang, Rui Zhao, Han Lu, Wenyuan Duan, Bin Qiao, Shi‐Min Zhao, Hongyan Wang, Jian‐Yuan Zhao · 发表于：Circulation · 年份：2017 · DOI：10.1161/circulationaha.116.025164 · 被引用次数：73 · 研究领域：Folate and B Vitamins Research、Growth Hormone and Insulin-like Growth Factors、Connective tissue disorders research

Background: Folate deficiency is an independent risk factor for congenital heart disease (CHD); however, the maternal plasma folate level is paradoxically not a good diagnostic marker. Genome-wide surveys have identified variants of nonfolate metabolic genes associated with the plasma folate level, suggesting that these genetic polymorphisms are potential risk factors for CHD. Methods: To examine the effects of folate concentration-related variations on CHD risk in the Han Chinese population, we performed 3 independent case-control studies including a total of 1489 patients with CHD and 1745 control subjects. The expression of the Fidgetin (FIGN) was detected in human cardiovascular and decidua tissue specimens with quantitative real-time polymerase chain reaction and Western blotting. The molecular mechanisms were investigated by luciferase reporter assays, surface plasmon resonance, and chromatin immunoprecipitation. FIGN-interacting proteins were confirmed by tandem affinity purification and coimmunoprecipitation. Proteasome activity and metabolite concentrations in the folate pathway were quantified with a commercial proteasome activity assay and immunoassays, respectively. Results: The +94762G>C (rs2119289) variant in intron 4 of the FIGN gene was associated with significant reduction in CHD susceptibility ( P =5.1×10 −14 for the allele, P =8.5×10 –−13 for the genotype). Analysis of combined samples indicated that CHD risks in individuals carrying heterozygous (GC) or...