Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve

Abstract

Bicuspid aortic valve (BAV) is a heritable congenital heart defect and an important risk factor for valvulopathy and aortopathy. Here we report a genome-wide association scan of 466 BAV cases and 4,660 age, sex and ethnicity-matched controls with replication in up to 1,326 cases and 8,103 controls. We identify association with a noncoding variant 151 kb from the gene encoding the cardiac-specific transcription factor, GATA4, and near-significance for p.Ser377Gly in GATA4. GATA4 was interrupted by CRISPR-Cas9 in induced pluripotent stem cells from healthy donors. The disruption of GATA4 significantly impaired the transition from endothelial cells into mesenchymal cells, a critical step in heart valve development.

Variants in cardiac GATA genes associated with bicuspid aortic valve

“…However, these changes could be taken into account in the analyses of other BAV subjects. In any case, there is also the possibility of linkage disequilibrium with other BAV‐associated loci in nearby regions described in other studies and, thus, it would be necessary to genotype such variants in our population to demonstrate that these other variants are not driving our findings.…”

“…It is interesting to note that p.Ser377Gly in GATA4, presenting similar frequencies in our BAV and TAV groups, was definitely associated with BAV in a European American population. 11 One of the reasons for this discrepancy could be the limited number of cases analysed in our study, which constitutes one of the main limitations. In addition, larger populations allow the discovery of novel additional variants that may be involved in the disease.…”

“…However, these changes could be taken into account in the analyses of other BAV subjects. In any case, there is also the possibility of linkage disequilibrium with other BAV-associated loci in nearby regions described in other studies 11,13,14,27,38 and, thus, it would be necessary to genotype such variants in our population to demonstrate that these other variants are not driving our findings. Apart from these variants, we identified another 11 variants in our population in the three GATA genes, but our results do not provide evidence for a substantial role in BAV for all of them.…”

“…8 These transcription factors work as positive regulators of many cardiac-specific promoters 9 and they are involved in a variety of physiological and pathological cardiac processes, since alterations in these genes lead to various forms of congenital heart defects. 10 A recent publication that analysed a large cohort of BAV cases reported the association between a functional genetic variant in GATA4 and BAV, 11 but several variants in other genes of the GATA family have been associated with this disease. [12][13][14] Despite the known association of mutations in the GATA family of transcription factors and BAV, there are no studies examining the genetic variation of all cardiac GATA members (GATA4, 5, and 6) in a population of patients with BAV.…”

Functionally significant, novelGATA4variants are frequently associated with Tetralogy of Fallot

“…Although, the majority of them are polymorphic except c.1220C>A; p.Pro407Gln in our cohort, which is also reported in Chinese and Japanese population as a known polymorphism (Kodo et al., ; Liu, Li, Xu, & Sun, ; Peng, Wang, Zhou, & Li, ; Qian et al., ; Yoshida et al., ; Zhang et al., ). Variants c.1129A>G; p.Ser377Gly, c.1138G>A; p.Val380Met, c.1180C>A; p.Pro394Thr, and c.1273G>A; p.Asp425Asn have been associated with the disease in other populations (Butler et al., ; Granados‐Riveron et al., ; Mattapally et al., ; Tomita‐Mitchell et al., ; Yang et al., ). However, these are detected in healthy control individuals in Indian population in our study, therefore could not be correlated with the disease.…”