ArticleFrontiers in genetics2012
Whole-exome sequencing and an iPSC-derived cardiomyocyte model provides a powerful platform for gene discovery in left ventricular hypertrophy.
Article in Frontiers in genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 23 citations in OpenAlex.
- Vascular Smooth Muscle Cells From Hypertensive Patient-Derived Induced Pluripotent Stem Cells to Advance Hypertension Pharmacogenomics.Stem cells translational medicine · 2015Trial
- Targeted next-generation sequencing for genetic variants of left ventricular mass status among community-based adults in Taiwan.Frontiers in genetics · 2022Article
- Sympathetic Neurons Regulate Cardiomyocyte Maturation in Culture.Frontiers in cell and developmental biology · 2022Article
- Whole-Exome Sequencing and hiPSC Cardiomyocyte Models IdentifyFrontiers in genetics · 2021Article
- Salt-inducible kinase 1 maintains HDAC7 stability to promote pathologic cardiac remodeling.The Journal of clinical investigation · 2020Article
- Differential interactions of missing in metastasis and insulin receptor tyrosine kinase substrate with RAB proteins in the endocytosis of CXCR4.The Journal of biological chemistry · 2019Article
- Clinical correlates and heritability of cardiac mechanics: The HyperGEN study.International journal of cardiology · 2019Article
- A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy.BMC medical genomics · 2018Article
- The Histone Demethylase JMJD2A Modulates the Induction of Hypertrophy Markers in iPSC-Derived Cardiomyocytes.Frontiers in genetics · 2018Article
- Molecular Approaches in HFpEF: MicroRNAs and iPSC-Derived Cardiomyocytes.Journal of cardiovascular translational research · 2017Review
- Human Induced Pluripotent Stem Cells as a Platform for Personalized and Precision Cardiovascular Medicine.Physiological reviews · 2016Review
- G-protein Coupled Receptor Signaling in Pluripotent Stem Cell-derived Cardiovascular Cells: Implications for Disease Modeling.Frontiers in cell and developmental biology · 2015Review
- A methodology to identify and prioritize gene candidates for human disease.Frontiers in genetics · 2012Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
rationaleLeft ventricular hypertrophy (LVH) is a heritable predictor of cardiovascular disease, particularly in blacks.
objectiveDetermine the feasibility of combining evidence from two distinct but complementary experimental approaches to identify novel genetic predictors of increased LV mass.
methodsWhole-exome sequencing (WES) was conducted in seven African-American sibling trios ascertained on high average familial LV mass indexed to height (LVMHT) using Illumina HiSeq technology. Identified missense or nonsense (MS/NS) mutations were examined for association with LVMHT using linear mixed models adjusted for age, sex, body weight, and familial relationship. To functionally assess WES findings, human induced pluripotent stem cell-derived cardiomyocytes (induced pluripotent stem cell-CM) were stimulated to induce hypertrophy; mRNA sequencing (RNA-seq) was used to determine gene expression differences associated with hypertrophy onset. Statistically significant findings under both experimental approaches identified LVH candidate genes. Candidate genes were further prioritized by seven supportive criteria that included additional association tests (two criteria), regional linkage evidence in the larger HyperGEN cohort (one criterion), and publically available gene and variant based annotations (four criteria).
resultsWES reads covered 91% of the target capture region (of size 37.2 MB) with an average coverage of 65×. WES identified 31,426 MS/NS mutations among the 21 individuals. A total of 295 MS/NS variants in 265 genes were associated with LVMHT with q-value <0.25. Of the 265 WES genes, 44 were differentially expressed (P < 0.05) in hypertrophied cells. Among the 44 candidate genes identified, 5, including HLA-B, HTT, MTSS1, SLC5A12, and THBS1, met 3 of 7 supporting criteria. THBS1 encodes an adhesive glycoprotein that promotes matrix preservation in pressure-overload LVH. THBS1 gene expression was 34% higher in hypertrophied cells (P = 0.0003) and a predicted conserved and damaging NS variant in exon 13 (A2099G) was significantly associated with LVHMT (P = 4 × 10(-6)).
conclusionCombining evidence from cutting-edge genetic and cellular experiments can enable identification of novel LVH risk loci.
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