背景:室间隔缺损(VSD)是生命最初几个月因心脏异常而死亡的主要原因之一。据报道,新生儿VSD的患病率高达4%。尽管在药物方面取得了显著进展,VSD的治疗和外科手术,由于复杂的遗传和环境相互作用,VSD的遗传病因仍处于起步阶段。
方法:从不同的儿科心脏单位招募了350名受试者(200名VSD儿童和150名健康对照)。收集儿科临床和人口统计学数据。总共六个变体,rs1017(ISL1),rs7240256(NFATc1),rs36208048(VEGF),HEY2,rs11067075(TBX5)和rs1801133(MTHFR)基因的变体通过四ARMSPCR和PCR-RFLP方法进行基因分型。
结果:结果表明,在病例中,ISL1基因中的rs1017(g.16138A>T)变异体的T和A等位基因的等位基因频率分别为0.42和0.58,对照组分别为0.75和0.25。AA的频率,TA和TT基因型为,52%,11%和37%的病例与21%的病例相比,对照组分别为8%和71%。对于NFATc1变体rs7240256,病例中的次要等位基因频率(MAF)为0.43,而对照组为0.23。对于VEGF基因的变异,基因型频率为0%(A),32%(CA)和68%(CC)的病例和0.0%的病例,对照组分别为33%和67%。病例中C和A的等位基因频率分别为0.84和0.16,对照组为0.83和0.17。TBX5多态性rs11067075(g.51682G>T)在病例中T和G等位基因的等位基因频率分别为0.44和0.56,对照组为0.26和0.74。在我们的儿科队列中,我们没有检测到HEY2基因变异的存在(g.126117350A>C)。对于MTHFR基因中的rs1801133(g.14783C>T)变体,基因型频率为25%(CC),62%(CT)和13%(TT)的病例,与88%相比,10%和2%的对照组。在巴基斯坦儿科队列中发现ISL1,NFATc1,TBX5和MTHFR变体与VSD相关,而VEGF和HEY2变体在我们的队列中完全不存在。
结论:我们建议对巴基斯坦人群的心脏发育基因标记进行更广泛的遗传筛查,这将有助于降低VSD的风险。
BACKGROUND: Ventricular septal defects (VSDs) are one of the leading causes of death due to cardiac anomalies during the first months of life. The prevalence of VSD in neonates is reported up to 4%. Despite the remarkable progress in medication, treatment and surgical procedure for VSDs, the genetic etiology of VSDs is still in infancy because of the complex genetic and environmental interactions.
METHODS: Three hundred fifty subjects (200 VSD children and 150 healthy controls) were recruited from different pediatric cardiac units. Pediatric clinical and demographic data were collected. A total of six variants, rs1017 (ISL1), rs7240256 (NFATc1), rs36208048 (VEGF), variant of HEY2, rs11067075 (TBX5) and rs1801133 (MTHFR) genes were genotyped by tetra-ARMS PCR and PCR-RFLP methods.
RESULTS: The results showed that in cases, the rs1017 (g.16138A > T) variant in the ISL1 gene has an allele frequency of 0.42 and 0.58 respectively for the T and A alleles, and 0.75 and 0.25 respectively in the controls. The frequencies of the AA, TA and TT genotypes were, 52%, 11% and 37% in cases versus 21%, 8% and 71% respectively in the controls. For the NFATc1 variant rs7240256, minor allele frequency (MAF) was 0.43 in cases while 0.23 in controls. For the variant in the VEGF gene, genotype frequencies were 0% (A), 32% (CA) and 68% (CC) in cases and 0.0%, 33% and 67% respectively in controls. The allele frequency of C and A were 0.84 and 0.16 in cases and 0.83 and 0.17 respectively in controls. The TBX5 polymorphism rs11067075 (g.51682G > T) had an allelic frequency of 0.44 and 0.56 respectively for T and G alleles in cases, versus 0.26 and 0.74 in the controls. We did not detect the presence of the HEY2 gene variant (g.126117350A > C) in our pediatric cohort. For the rs1801133 (g.14783C > T) variant in the MTHFR gene, the genotype frequencies were 25% (CC), 62% (CT) and 13% (TT) in cases, versus 88%, 10% and 2% in controls. The ISL1, NFATc1, TBX5 and MTHFR variants were found to be in association with VSD in the Pakistani pediatric cohort whilst the VEGF and HEY2 variants were completely absent in our cohort.
CONCLUSIONS: We propose that a wider programme of genetic screening of the Pakistani population for genetic markers in heart development genes would be helpful in reducing the risk of VSDs.