scholarly journals Consistent Assignment of Risk and Benign Allele at rs2303153 in the CF Modifier Gene SCNN1B in Three Independent F508del-CFTR Homozygous Patient Populations

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1554
Author(s):  
Frauke Stanke ◽  
Tim Becker ◽  
Haide Susanne Ismer ◽  
Inga Dunsche ◽  
Silke Hedtfeld ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Risk Allele ◽  
Association Studies ◽  
Regulatory Element ◽  
Genetic Modifier ◽  
Modifier Gene ◽  
Intestinal Epithelia ◽  
Transepithelial Sodium Transport ◽  
Homozygous Patient

CFTR encodes for a chloride and bicarbonate channel expressed at the apical membrane of polarized epithelial cells. Transepithelial sodium transport mediated by the amiloride-sensitive sodium channel ENaC is thought to contribute to the manifestation of CF disease. Thus, ENaC is a therapeutic target in CF and a valid cystic fibrosis modifier gene. We have characterized SCNN1B as a genetic modifier in the three independent patient cohorts of F508del-CFTR homozygotes. We could identify a regulatory element at SCNN1B to the genomic segment rs168748-rs2303153-rs4968000 by fine-mapping (Pbest = 0.0177), consistently observing the risk allele rs2303153-C and the contrasting benign allele rs2303153-G in all three patient cohorts. Furthermore, our results show that expression levels of SCNN1B are associated with rs2303153 genotype in intestinal epithelia (P = 0.003). Our data confirm that the well-established biological role of SCNN1B can be recognized by an association study on informative endophenotypes in the rare disease cystic fibrosis and calls attention to reproducible results in association studies obtained from small, albeit carefully characterized patient populations.

scholarly journals 2045 The role of TGFβ in driving early cystic fibrosis lung disease

2018 ◽  
Vol 2 (S1) ◽  
pp. 33-33
Author(s):  
Elizabeth L. Kramer ◽  
William Hardie ◽  
Kristin Hudock ◽  
Cynthia Davidson ◽  
Alicia Ostmann ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Bronchoalveolar Lavage ◽  
Lung Disease ◽  
Bronchoalveolar Lavage Fluid ◽  
Transforming Growth Factor ◽  
Genetic Modifier ◽  
Lavage Fluid ◽  
Lung Mechanics ◽  
Patient Specific

OBJECTIVES/SPECIFIC AIMS: Transforming growth factor-beta (TGFβ) is a genetic modifier of cystic fibrosis (CF) lung disease. TGFβ’s pulmonary levels in young CF patients and its mechanism of action in CF are unknown. We examined TGFβ levels in children with CF and investigated responses of human airway epithelial cells (AECs) and mice to TGFβ. METHODS/STUDY POPULATION: TGFβ levels in bronchoalveolar lavage fluid from CF patients (n=15) and non-CF control patients (n=21)<6 years old were determined by ELISA. CF mice and non-CF mice were intratracheally treated with an adenoviral TGFβ1 vector or PBS; lungs were collected for analysis at day 7. Human CF and non-CF AECs were treated with TGFβ or PBS for 24 hours then collected for analysis. RESULTS/ANTICIPATED RESULTS: Young CF patients had higher bronchoalveolar lavage fluid TGFβ than non-CF controls (p=0.03). Mouse lungs exposed to TGFβ demonstrated inflammation, goblet cell hyperplasia, and decreased CFTR expression. CF mice had greater TGFβ-induced lung mechanics abnormalities than controls; both CF human AECs and CF mice showed higher TGFβ induced MAPK and PI3K signaling compared with controls. DISCUSSION/SIGNIFICANCE OF IMPACT: For the first time, we show increased TGFβ levels very early in CF. TGFβ drives CF lung abnormalities in mouse and human models; CF models are more sensitive to TGFβ’s effects. Understanding the role of TGFβ in promoting CF lung disease is critical to developing patient specific treatments.

scholarly journals Scarless genome editing reveals risk SNP rs6983267-G and lncRNA CCAT2 dictate targetable PI3K signaling dependence in WNT-dysregulated CRC

2021 ◽  
Author(s):  
Nicole B. Coggins ◽  
Henriette O’Geen ◽  
Paul C. Lott ◽  
David J. Segal ◽  
Luis Carvajal Carmona
Keyword(s):  
Risk Allele ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Growth Factor Signaling ◽  
Cellular Models ◽  
Genome Wide ◽  
Potential Biomarker ◽  
Increased Risk ◽  
Hct 116

Abstract Genome-wide association studies have identified numerous loci associated with increased risk for colorectal cancer (CRC), including 8q24.21 which contains a known enhancer of proto-oncogene MYC . However, the role of candidate functional SNP rs6983267 within this locus remains unclear. Here, we generate isogenic cellular models of risk SNP rs6983267 in human CRC line, HCT-116. Comprehensive molecular characterization reveals risk allele-G drives enhancer DNA contacts with downstream regions that include MYC . Absence of risk allele leads to activation of lncRNA CCAT2 . Rather than changes in MYC expression, we observe activation of alternative growth factor signaling pathways with loss of both risk allele and CCAT2 expression. Analysis of TCGA CRC cases demonstrates low CCAT2 expression combined with non-risk rs6983267 genotype correlate with higher frequency of PI3K mutations in CRC patients displaying WNT dysregulation. Together, these provide a potential biomarker for therapeutically targetable PI3K dysregulation in CRC and application in cancer precision medicine.

scholarly journals Association Analysis of Genetic Variants with Type 2 Diabetes in a Mongolian Population in China

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Haihua Bai ◽  
Haiping Liu ◽  
Suyalatu Suyalatu ◽  
Xiaosen Guo ◽  
Shandan Chu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Large Scale ◽  
Risk Allele ◽  
Association Studies ◽  
Northern China ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide

The large scale genome wide association studies (GWAS) have identified approximately 80 single nucleotide polymorphisms (SNPs) conferring susceptibility to type 2 diabetes (T2D). However, most of these loci have not been replicated in diverse populations and much genetic heterogeneity has been observed across ethnic groups. We tested 28 SNPs previously found to be associated with T2D by GWAS in a Mongolian sample of Northern China (497 diagnosed with T2D and 469 controls) for association with T2D and diabetes related quantitative traits. We replicated T2D association of 11 SNPs, namely, rs7578326 (IRS1), rs1531343 (HMGA2), rs8042680 (PRC1), rs7578597 (THADA), rs1333051 (CDKN2), rs6723108 (TMEM163), rs163182 and rs2237897 (KCNQ1), rs1387153 (MTNR1B), rs243021 (BCL11A), and rs10229583 (PAX4) in our sample. Further, we showed that risk allele of the strongest T2D associated SNP in our sample, rs757832 (IRS1), is associated with increased level of TG. We observed substantial difference of T2D risk allele frequency between the Mongolian sample and the 1000G Caucasian sample for a few SNPs, including rs6723108 (TMEM163) whose risk allele reaches near fixation in the Mongolian sample. Further study of genetic architecture of these variants in susceptibility of T2D is needed to understand the role of these variants in heterogeneous populations.

scholarly journals SLC6A14, an amino acid transporter, modifies the primary CF defect in fluid secretion

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Saumel Ahmadi ◽  
Sunny Xia ◽  
Yu-Sheng Wu ◽  
Michelle Di Paola ◽  
Randolph Kissoon ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Amino Acid ◽  
Association Studies ◽  
Genetic Modifier ◽  
Fluid Secretion ◽  
Amino Acid Transporter ◽  
Genome Wide Association Studies ◽  
Primary Defect ◽  
Acid Transporter

The severity of intestinal disease associated with Cystic Fibrosis (CF) is variable in the patient population and this variability is partially conferred by the influence of modifier genes. Genome-wide association studies have identified SLC6A14, an electrogenic amino acid transporter, as a genetic modifier of CF-associated meconium ileus. The purpose of the current work was to determine the biological role of Slc6a14, by disrupting its expression in CF mice bearing the major mutation, F508del. We found that disruption of Slc6a14 worsened the intestinal fluid secretion defect, characteristic of these mice. In vitro studies of mouse intestinal organoids revealed that exacerbation of the primary defect was associated with reduced arginine uptake across the apical membrane, with aberrant nitric oxide and cyclic GMP-mediated regulation of the major CF-causing mutant protein. Together, these studies highlight the role of this apical transporter in modifying cellular nitric oxide levels, residual function of the major CF mutant and potentially, its promise as a therapeutic target.

scholarly journals The role of TGFbetal as modifier gene in Italian cystic fibrosis patients

2008 ◽  
Vol 7 ◽  
pp. S2
Author(s):  
M.D. Bettin ◽  
C. Bombieri ◽  
G. Malerba ◽  
L. Xumerle ◽  
F. Belpinati ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Modifier Gene

scholarly journals A ROLE OF MODIFIER GENE TCF7L2 FOR DEVELOPMENT OF DIABETES IN ADULT PATIENTS WITH CYSTIC FIBROSIS

2014 ◽  
pp. 33-39
Author(s):  
V. A. Samoylenko ◽  
N. V. Petrova ◽  
G. Yu. Babadzhanova ◽  
A. B. Nagornyy ◽  
S. A. Krasovskiy ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Modifier Gene ◽  
Adult Patients

MicroRNAs as Biomarker for Breast Cancer

2020 ◽  
Vol 20 (10) ◽  
pp. 1597-1610 ◽  
Author(s):  
Taru Aggarwal ◽  
Ridhima Wadhwa ◽  
Riya Gupta ◽  
Keshav Raj Paudel ◽  
Trudi Collet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Association Studies ◽  
Large Family ◽  
Breast Cancer Diagnosis ◽  
Cell Multiplication ◽  
Cell Physiology ◽  
Gene Transcript ◽  
Genome Wide Association Studies ◽  
Non Coding Rnas

Regardless of advances in detection and treatment, breast cancer affects about 1.5 million women all over the world. Since the last decade, genome-wide association studies (GWAS) have been extensively conducted for breast cancer to define the role of miRNA as a tool for diagnosis, prognosis and therapeutics. MicroRNAs are small, non-coding RNAs that are associated with the regulation of key cellular processes such as cell multiplication, differentiation, and death. They cause a disturbance in the cell physiology by interfering directly with the translation and stability of a targeted gene transcript. MicroRNAs (miRNAs) constitute a large family of non-coding RNAs, which regulate target gene expression and protein levels that affect several human diseases and are suggested as the novel markers or therapeutic targets, including breast cancer. MicroRNA (miRNA) alterations are not only associated with metastasis, tumor genesis but also used as biomarkers for breast cancer diagnosis or prognosis. These are explained in detail in the following review. This review will also provide an impetus to study the role of microRNAs in breast cancer.

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