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

• DOI: 10.1161/circulationaha.116.025164
• Publication Date: 2017-03-17T01:00:23Z
• Authors: Dan Wang; Feng Wang; Kai-Hu Shi; Hui Tao; Yang Li; Rui Zhao; Han Lu; Wenyuan Duan; Bin Qiao; Shi-Min Zhao; Hongyan Wang; Jian-Yuan Zhao
• Keywords: Minor allele frequency; Chromatin immunoprecipitation

Folate deficiency is an independent risk factor for congenital heart disease (CHD); however, the maternal plasma folate level paradoxically not a good diagnostic marker. Genome-wide surveys have identified variants of nonfolate metabolic genes associated with level, suggesting that these genetic polymorphisms are potential factors CHD.To examine effects concentration-related variations on CHD in Han Chinese population, we performed 3 case-control studies including total 1489 patients and 1745 control subjects. The expression Fidgetin (FIGN) was detected human cardiovascular decidua tissue specimens quantitative real-time polymerase chain reaction Western blotting. molecular mechanisms were investigated by luciferase reporter assays, surface plasmon resonance, chromatin immunoprecipitation. FIGN-interacting proteins confirmed tandem affinity purification coimmunoprecipitation. Proteasome activity metabolite concentrations pathway quantified commercial proteasome assay immunoassays, respectively.The +94762G>C (rs2119289) variant intron 4 FIGN gene significant reduction susceptibility (P=5.1×10-14 allele, P=8.5×10--13 genotype). Analysis combined samples indicated risks individuals carrying heterozygous (GC) or homozygous (CC) genotypes reduced 44% (odds ratio [OR]=0.56; 95% confidence interval [CI]=0.47-0.67) 66% (OR=0.34; CI=0.23-0.50), respectively, compared those major GG genotype. Minor C allele carriers who had decreased levels exhibited significantly increased because transcription suppressor CREB1 did bind alternative promoter isoform X3. Mechanistically, led to accumulation both carrier 1 dihydrofolate reductase via inhibition their proteasomal degradation, which promoted absorption metabolism.We report previously undocumented finding circulating induced transmembrane transport utilization, as determined intronic variant, serves protective mechanism against CHD. Our results may explain why do value.