scholarly journals The Linkage Phase of the Polymorphism KCNH2-K897T Influences the Electrophysiological Phenotype in hiPSC Models of LQT2

2021 ◽  
Vol 12 ◽  
Author(s):  
Lettine van den Brink ◽  
Karina O. Brandão ◽  
Loukia Yiangou ◽  
Albert Blanch-Asensio ◽  
Mervyn P. H. Mol ◽  
...  
Keyword(s):  
Ion Channel ◽  
Cardiac Arrhythmias ◽  
Genetic Variants ◽  
Genetic Diseases ◽  
Field Potential ◽  
Tail Region ◽  
Linkage Phase ◽  
Common Genetic Variants ◽  
The Common ◽  
Induced Pluripotent

While rare mutations in ion channel genes are primarily responsible for inherited cardiac arrhythmias, common genetic variants are also an important contributor to the clinical heterogeneity observed among mutation carriers. The common single nucleotide polymorphism (SNP) KCNH2-K897T is associated with QT interval duration, but its influence on the disease phenotype in patients with long QT syndrome type 2 (LQT2) remains unclear. Human induced pluripotent stem cells (hiPSCs), coupled with advances in gene editing technologies, are proving an invaluable tool for modeling cardiac genetic diseases and identifying variants responsible for variability in disease expressivity. In this study, we have used isogenic hiPSC-derived cardiomyocytes (hiPSC-CMs) to establish the functional consequences of having the KCNH2-K897T SNP in cis- or trans-orientation with LQT2-causing missense variants either within the pore-loop domain (KCNH2A561T/WT) or tail region (KCNH2N996I/WT) of the potassium ion channel, human ether-a-go-go-related gene (hERG). When KCNH2-K897T was on the same allele (cis) as the primary mutation, the hERG channel in hiPSC-CMs exhibited faster activation and deactivation kinetics compared to their trans-oriented counterparts. Consistent with this, hiPSC-CMs with KCNH2-K897T in cis orientation had longer action and field potential durations. Furthermore, there was an increased occurrence of arrhythmic events upon pharmacological blocking of hERG. Collectively, these results indicate that the common polymorphism KCNH2-K897T differs in its influence on LQT2-causing KCNH2 mutations depending on whether it is present in cis or trans. This study corroborates hiPSC-CMs as a powerful platform to investigate the modifying effects of common genetic variants on inherited cardiac arrhythmias and aids in unraveling their contribution to the variable expressivity of these diseases.

A genome-wide association identified the common genetic variants influence disease severity in β0-thalassemia/hemoglobin E

2009 ◽  
Vol 127 (3) ◽  
pp. 303-314 ◽  
Author(s):  
Manit Nuinoon ◽  
Wattanan Makarasara ◽  
Taisei Mushiroda ◽  
Iswari Setianingsih ◽  
Pustika Amalia Wahidiyat ◽  
...  
Keyword(s):  
Disease Severity ◽  
Genetic Variants ◽  
Genome Wide Association ◽  
Hemoglobin E ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome ◽  
The Common

scholarly journals Population-scale single-cell RNA-seq profiling across dopaminergic neuron differentiation

2020 ◽  
Author(s):  
J Jerber ◽  
DD Seaton ◽  
ASE Cuomo ◽  
N Kumasaka ◽  
J Haldane ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Genetic Variants ◽  
Neuronal Development ◽  
Induced Pluripotent Stem Cell ◽  
Great Promise ◽  
Tissue Samples ◽  
Ips Cell ◽  
Common Genetic Variants ◽  
Induced Pluripotent

AbstractCommon genetic variants can have profound effects on cellular function, but studying these effects in primary human tissue samples and during development is challenging. Human induced pluripotent stem cell (iPSC) technology holds great promise for assessing these effects across different differentiation contexts. Here, we use an efficient pooling strategy to differentiate 215 iPS cell lines towards a midbrain neural fate, including dopaminergic neurons, and profile over 1 million cells sampled across three differentiation timepoints using single cell RNA sequencing. We find that the proportion of neuronal cells produced by each cell line is highly reproducible over different experimental batches, and identify robust molecular markers in pluripotent cells that predict line-to-line differences in cell fate. We identify expression quantitative trait loci (eQTL) that manifest at different stages of neuronal development, and in response to oxidative stress, by exposing cells to rotenone. We find over one thousand eQTL that colocalise with a known risk locus for a neurological trait, nearly half of which are not found in GTEx. Our study illustrates how coupling single cell transcriptomics with long-term iPSC differentiation can profile mechanistic effects of human trait-associated genetic variants in otherwise inaccessible cell states.

scholarly journals Are the common genetic variants associated with colorectal cancer risk for DNA mismatch repair gene mutation carriers?

2013 ◽  
Vol 49 (7) ◽  
pp. 1578-1587 ◽  
Author(s):  
Aung Ko Win ◽  
John L. Hopper ◽  
Daniel D. Buchanan ◽  
Joanne P. Young ◽  
Albert Tenesa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Risk ◽  
Mismatch Repair ◽  
Genetic Variants ◽  
Mismatch Repair Gene ◽  
Repair Gene ◽  
Dna Mismatch ◽  
Common Genetic Variants ◽  
The Common ◽  
Dna Mismatch Repair Gene

scholarly journals Common idiopathic pulmonary fibrosis risk variants are associated with hypersensitivity pneumonitis

Thorax ◽  
2022 ◽  
pp. thoraxjnl-2021-217693
Author(s):  
Haruhiko Furusawa ◽  
Anna L Peljto ◽  
Avram D Walts ◽  
Jonathan Cardwell ◽  
Philip L Molyneaux ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Genetic Variants ◽  
Genetic Risk ◽  
Lung Fibrosis ◽  
Hypersensitivity Pneumonitis ◽  
Risk Variants ◽  
Common Genetic Variants ◽  
The Common ◽  
Genetic Risk Variants

A subset of patients with hypersensitivity pneumonitis (HP) develop lung fibrosis that is clinically similar to idiopathic pulmonary fibrosis (IPF). To address the aetiological determinants of fibrotic HP, we investigated whether the common IPF genetic risk variants were also relevant in study subjects with fibrotic HP. Our findings indicate that common genetic variants in TERC, DSP, MUC5B and IVD were significantly associated with fibrotic HP. These findings provide support for a shared etiology and pathogenesis between fibrotic HP and IPF.

scholarly journals Genomic editing of metformin efficacy-associated genetic variants in SLC47A1 does not alter SLC47A1 expression

2021 ◽  
Author(s):  
Sebastian Kalamajski ◽  
Mi Huang ◽  
Jonathan Dalla-Riva ◽  
Maria Keller ◽  
Adem Y Dawed ◽  
...  
Keyword(s):  
Genetic Variants ◽  
In Silico ◽  
Meta Analysis ◽  
Metformin Treatment ◽  
Common Variants ◽  
Common Genetic Variants ◽  
The Common ◽  
Genomic Editing ◽  
In Silico Analyses ◽  
Hba1c Levels

Abstract Several pharmacogenetics studies have identified an association between a greater metformin-dependent reduction in HbA1c levels and the minor A allele at rs2289669 in intron 10 of SLC47A1, encoding multidrug and toxin extrusion 1 (MATE1), a presumed metformin transporter. It is currently unknown if the rs2289669 locus is a cis-eQTL, which would validate its role as predictor of metformin efficacy. We looked at association between common genetic variants in the SLC47A1 gene region and HbA1c reduction after metformin treatment using locus-wise meta-analysis from the MetGen consortium. CRISPR-Cas9 was applied to perform allele editing of, or genomic deletion around, rs2289669 and of the closely linked rs8065082 in HepG2 cells. The genome-edited cells were evaluated for SLC47A1 expression and splicing. None of the common variants including rs2289669 showed significant association with metformin response. Genomic editing of either rs2289669 or rs8065082 did not alter SLC47A1 expression or splicing. Experimental and in silico analyses show that the rs2289669-containing haploblock does not appear to carry genetic variants that could explain its previously reported association with metformin efficacy.

Genetic Variation: Impact on Folate (and Choline) Bioefficacy

2010 ◽  
Vol 80 (45) ◽  
pp. 319-329 ◽  
Author(s):  
Allyson A. West ◽  
Marie A. Caudill
Keyword(s):  
Carbon Metabolism ◽  
Genetic Variants ◽  
Plasma Homocysteine ◽  
Water Soluble ◽  
Gene Interactions ◽  
Dietary Folate ◽  
Methyl Donors ◽  
Common Genetic Variants ◽  
One Carbon Metabolism ◽  
The Impact

Folate and choline are water-soluble micronutrients that serve as methyl donors in the conversion of homocysteine to methionine. Inadequacy of these nutrients can disturb one-carbon metabolism as evidenced by alterations in circulating folate and/or plasma homocysteine. Among common genetic variants that reside in genes regulating folate absorptive and metabolic processes, homozygosity for the MTHFR 677C > T variant has consistently been shown to have robust effects on status markers. This paper will review the impact of genetic variants in folate-metabolizing genes on folate and choline bioefficacy. Nutrient-gene and gene-gene interactions will be considered along with the need to account for these genetic variants when updating dietary folate and choline recommendations.

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