scholarly journals Genetic Variation Near chrXq22-q23 Is Linked to Emotional Functioning in Cystic Fibrosis

2020 ◽  
Vol 22 (3) ◽  
pp. 319-325
Author(s):  
Eric Barbato ◽  
Barbara Daly ◽  
Sara Douglas ◽  
Mary Kerr ◽  
Paul Litman ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Emotional Functioning ◽  
Association Studies ◽  
Gastrointestinal Symptoms ◽  
Genome Wide Association Studies ◽  
Genetic Modifiers ◽  
Modifier Locus ◽  
Organ Systems ◽  
Related Quality ◽  
Cf Transmembrane Conductance Regulator

Introduction: Cystic fibrosis (CF) is an autosomal recessive disease that affects many organ systems, most notably the pulmonary and gastrointestinal systems. Through genome-wide association studies, multiple genetic regions modifying CF-related pulmonary and gastrointestinal symptoms have been identified, but translation of these findings to clinical benefit remains elusive. Symptom variation in CF patients has been associated with changes in health-related quality of life (HRQOL), but the relationship between CF symptom-modifying genetic loci and HRQOL has not been explored. The purpose of this study was to determine whether two previously identified genetic modifiers of CF-related pathology also modify the subscales of HRQOL. Methods: HRQOL and genotype data were obtained and analyzed. Linear regressions were used to examine the amount of variance in HRQOL subscales that could be explained by genotype for each modifier locus. Results: A significant regression equation was found between genotype for rs5952223, a variant near chrXq22-q23, and emotional functioning in a sample of 129 CF patients. Discussion: These data suggest that genotype for this single-nucleotide polymorphism is associated with emotional functioning in CF patients and highlight this genetic region as a potential therapeutic target, irrespective of CF transmembrane conductance regulator genotype.

scholarly journals Cystic Fibrosis Disease Modifiers: Complex Genetics Defines the Phenotypic Diversity in a Monogenic Disease

2018 ◽  
Vol 19 (1) ◽  
pp. 201-222 ◽  
Author(s):  
Wanda K. O'Neal ◽  
Michael R. Knowles
Keyword(s):  
Cystic Fibrosis ◽  
Phenotypic Diversity ◽  
Association Studies ◽  
Gene Mutations ◽  
Monogenic Disease ◽  
Genome Wide Association Studies ◽  
Complex Genetics ◽  
Genetic Components ◽  
Significant Gene ◽  
Gene Expression Studies

In many respects, genetic studies in cystic fibrosis (CF) serve as a paradigm for a human Mendelian genetic success story. From recognition of the condition as a heritable pathological entity to implementation of personalized treatments based on genetic findings, this multistep pathway of progress has focused on the genetic underpinnings of CF clinical disease. Along this path was the recognition that not all CFTR gene mutations produce the same disease and the recognition of the complex, multifactorial nature of CF genotype–phenotype relationships. The non- CFTR genetic components (gene modifiers) that contribute to variation in phenotype are the focus of this review. A multifaceted approach involving candidate gene studies, genome-wide association studies, and gene expression studies has revealed significant gene modifiers for multiple CF phenotypes. The bold challenges for the future are to integrate the findings into our understanding of CF pathogenesis and to use the knowledge to develop novel therapies.

Identification of Genetic Modifiers Associated with Risk of Stroke in Children with Sickle Cell Anemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3228-3228
Author(s):  
Jonathan Michael Flanagan ◽  
Heidi Linder ◽  
Vivien Sheehan ◽  
Thad A Howard ◽  
Banu Aygun ◽  
...  
Keyword(s):  
Cerebrovascular Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Conflicts Of Interest ◽  
Association Studies ◽  
Snp Markers ◽  
Genome Wide Association Studies ◽  
Genetic Modifiers ◽  
Sibling Pairs ◽  
Synonymous Mutations

Abstract Abstract 3228 Introduction: Stroke is one of the most catastrophic acute complications of sickle cell anemia (SCA), occurring in 11% of patients before 20 years of age. A further 20 to 30% of children with SCA will develop less clinically overt cerebrovascular disease events such as transient ischemic attacks (TIA) and silent infarcts. There is a definite need for biomarkers that could determine the cause of these irreversible cerebrovascular events and which might predict children at greatest risk. Previous studies of sibling pairs have shown that there is a genetic component to cerebrovascular disease development but few genetic modifiers have been validated as having a substantial effect on risk of stroke. The aim of this study was to perform an unbiased whole genome search for genetic modifiers of stroke risk in SCA. Methods: Pediatric patients with SCA and documented primary stroke (n=177) were compared to a pediatric control non-stroke group with SCA (n=335). All control patients were over 5 years old and without previous clinical stroke prior to beginning any clinical treatment. Genome wide association studies (GWAS) were performed using genotype data obtained from Affymetrix SNP6.0 arrays. A pooled DNA approach was used to perform whole exome sequencing (WES) by Illumina next generation sequencing of pooled control (n=104) and pooled stroke (n=120) groups. Results: From the Affymetrix SNP6.0 GWAS data, 139 single nucleotide polymorphisms (SNP) were identified with stroke association. From the WES, 294 non-synonymous mutations were found to be significantly associated with stroke. In combination, 11 mutations identified by WES were located within 250kb of a SNP identified by GWAS (Table 1). These 11 mutations represent key areas of the genome that are targets for further in depth study. To next validate the genetic variants identified by WES with association with risk of stroke, 21 candidate mutations were genotyped in an independent cohort of control (n=231) and stroke (n=57) patients with SCA. One mutation in GOLGB1 (Y1212C) was corroborated as having significant association with lower risk of stroke (p=0.02). Conclusion: This mutation in GOLGB1 is predicted to effect the golgi associated function of the encoded protein and future studies will focus on how this functional mutation may protect against development of cerebrovascular disease in the context of SCA. For all variants with significant association with stroke, the chromosomal position of each variant identified by WES (n=300, p<0.001) was compared to the location of all SNP markers (n=139, p<0.0001). We identified 11 variants by WES where there was at least one SNP marker within 250kb. These variants all represent excellent regions of the genome for future study. The four variants highlighted with a asterisk (*) are variants predicted by PolyPhen2 or SIFT to be deleterious. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome–wide interaction study

2013 ◽  
Vol 20 (6) ◽  
pp. 875-887 ◽  
Author(s):  
Anja Rudolph ◽  
Rebecca Hein ◽  
Sara Lindström ◽  
Lars Beckmann ◽  
Sabine Behrens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fixed Effects ◽  
Association Studies ◽  
Meta Analysis ◽  
Case Control ◽  
Genome Wide Association Studies ◽  
Genetic Modifiers ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 case–control studies. We used a case-only design to assess interactions between single-nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2920 cases (541 lobular) from four genome-wide association studies. The top 1391 SNPs showing P values for interaction (Pint) <3.0×10−3 were selected for replication using pooled case–control data from 11 studies of the Breast Cancer Association Consortium, including 7689 cases (676 lobular) and 9266 controls. Fixed-effects meta-analysis was used to derive combined Pint. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 near POMP (combined Pint≤8.9×10−6), two SNPs in SLC25A21 (combined Pint≤4.8×10−5), and three SNPs in PLCG2 (combined Pint≤4.5×10−5). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined Pint≤2.7×10−5), one SNP in CD80 (combined Pint≤8.2×10−6), three SNPs on chr17 near TMEM132E (combined Pint≤2.2×10−6), and two SNPs on chr18 near SLC25A52 (combined Pint≤4.6×10−5). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling, and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies.

scholarly journals Hyponatremic dehydration and metabolic alkalosis as dominant manifestation in cystic fibrosis infants with mild phenotype - a case series

2018 ◽  
Vol 146 (9-10) ◽  
pp. 581-583 ◽  
Author(s):  
Stojka Fustik ◽  
Tatjana Jakovska ◽  
Dijana Plaseska-Karanfilska
Keyword(s):  
Cystic Fibrosis ◽  
Metabolic Alkalosis ◽  
Clinical Symptoms ◽  
Gastrointestinal Symptoms ◽  
Case Series ◽  
Mild Phenotype ◽  
Mean Values ◽  
Sweat Chloride ◽  
Cf Transmembrane Conductance Regulator ◽  
Compound Heterozygotes

Introduction. Due to increased losses of chloride and sodium in the sweat, children with cystic fibrosis (CF) are predisposed to develop episodes of hyponatremic/hypochloremic dehydration with hypokalemia and metabolic alkalosis when they sweat excessively. Even the patients with mild phenotype may have such episodes of dehydration and salt depletion. Outline of cases. Six cases of pancreatic sufficient (PS) CF patients complicated with episodes of severe hyponatremic dehydration with metabolic alkalosis in infancy are presented. The mean age was 6.3 ? 2.16 months at admission. All the cases had no symptoms suggestive of CF before admission. The most common clinical symptoms at the time of hospitalization were vomiting, anorexia, weight loss, dehydration, irritation, or lethargy. Mean values of blood pH, serum bicarbonate, sodium, chloride, and potassium (mmol/l) were as follows: 7.59 ? 0.06, 41.73 ? 5.78, 117.52 ? 2.88, 66.0 ? 11.58 and 2.62 ? 0.37, respectively. Sweat chloride test was pathological and ranged 69?120 mmol/L. The determination of fecal elastase-1 proved that they were PS (values > 200 ?g/g stool). CF transmembrane conductance regulator gene analyses in six cases confirmed the diagnosis of CF; namely, patients were compound heterozygotes for F508del and other rare mutation or compound heterozygotes for two rare mutations. Conclusion. Distinctive about these cases is that they were PS and had very mild presentation of CF. Without these episodes of dehydration, these patients would have remained undiagnosed until later age. CF should be considered in infants and children presenting with hypoelectrolytemia and metabolic alkalosis even in the absence of respiratory or gastrointestinal symptoms.

scholarly journals Genetic modifiers of Huntington’s disease differentially influence motor and cognitive domains

2022 ◽  
Author(s):  
Jong-Min Lee ◽  
Yuan Huang ◽  
Michael Orth ◽  
Tammy Gillis ◽  
Jacqueline Siciliano ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Damage ◽  
Association Studies ◽  
Cag Repeat ◽  
Genome Wide Association Studies ◽  
Genetic Modifiers ◽  
Cognitive Domains ◽  
Somatic Instability ◽  
Dna Maintenance

AbstractGenome-wide association studies (GWAS) of Huntington’s disease (HD) have identified six DNA maintenance gene loci (among others) as modifiers and implicated a two step-mechanism of pathogenesis: somatic instability of the causative HTT CAG repeat with subsequent triggering of neuronal damage. The largest studies have been limited to HD individuals with a rater-estimated age at motor onset. To capitalize on the wealth of phenotypic data in several large HD natural history studies, we have performed algorithmic prediction using common motor and cognitive measures to predict age at other disease landmarks as additional phenotypes for GWAS. Combined with imputation using the Trans-Omics for Precision Medicine reference panel, predictions using integrated measures provided objective landmark phenotypes with greater power to detect most modifier loci. Importantly, substantial differences in the relative modifier signal across loci, highlighted by comparing common modifiers at MSH3 and FAN1, revealed that individual modifier effects can act preferentially in the motor or cognitive domains. Individual components of the DNA maintenance modifier mechanisms may therefore act differentially on the neuronal circuits underlying the corresponding clinical measures. In addition, we identified new modifier effects at the PMS1 and PMS2 loci and implicated a potential new locus on chromosome 7. These findings indicate that broadened discovery and characterization of HD genetic modifiers based on additional quantitative or qualitative phenotypes offers not only the promise of in-human validated therapeutic targets, but also a route to dissecting the mechanisms and cell types involved in both the somatic instability and toxicity components of HD pathogenesis.

scholarly journals Leveraging TOPMed Imputation Server and Constructing a Cohort-Specific Imputation Reference Panel to Enhance Genotype Imputation among Cystic Fibrosis Patients

2021 ◽  
Author(s):  
Quan Sun ◽  
Weifang Liu ◽  
Jonathan D Rosen ◽  
Le Huang ◽  
Rhonda G Pace ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Sample Size ◽  
Association Studies ◽  
Genetic Disorder ◽  
Genome Project ◽  
Genotype Imputation ◽  
Reference Panel ◽  
Effective Sample Size ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies

Cystic fibrosis (CF) is a severe genetic disorder that can cause multiple comorbidities affecting the lungs, the pancreas, the luminal digestive system and beyond. In our previous genome-wide association studies (GWAS), we genotyped ~8,000 CF samples using a mixture of different genotyping platforms. More recently, the Cystic Fibrosis Genome Project (CFGP) performed deep (~30x) whole genome sequencing (WGS) of 5,095 samples to better understand the genetic mechanisms underlying clinical heterogeneity among CF patients. For mixtures of GWAS array and WGS data, genotype imputation has proven effective in increasing effective sample size. Therefore, we first performed imputation for the ~8,000 CF samples with GWAS array genotype using the TOPMed freeze 8 reference panel. Our results demonstrate that TOPMed can provide high-quality imputation for CF patients, boosting genomic coverage from ~0.3 - 4.2 million genotyped markers to ~11 - 43 million well-imputed markers, and significantly improving Polygenic Risk Score (PRS) prediction accuracy. Furthermore, we built a CF-specific CFGP reference panel based on WGS data of CF patients. We demonstrate that despite having ~3% the sample size of TOPMed, our CFGP reference panel can still outperform TOPMed when imputing some CF disease-causing variants, likely due to allele and haplotype differences between CF patients and general populations. We anticipate our imputed data for 4,656 samples without WGS data will benefit our subsequent genetic association studies, and the CFGP reference panel built from CF WGS samples will benefit other investigators studying CF.

scholarly journals Re-imagining cystic fibrosis care: next generation thinking

2020 ◽  
Vol 55 (5) ◽  
pp. 1902443
Author(s):  
Catherine Rang ◽  
Dominic Keating ◽  
John Wilson ◽  
Tom Kotsimbos
Keyword(s):  
Cystic Fibrosis ◽  
Systems Of Care ◽  
Genetic Defect ◽  
Major Advance ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Organ Systems ◽  
Cftr Protein ◽  
Set Up ◽  
Cf Transmembrane Conductance Regulator

Cystic fibrosis (CF) is a common multi-system genetically inherited condition, predominately found in individuals of Caucasian decent. Since the identification of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene in 1989, and the subsequent improvement in understanding of CF pathophysiology, significant increases in life-expectancy have followed. Initially this was related to improvements in the management and systems of care for treating the various affected organ systems. These cornerstone treatments are still essential for CF patients born today. However, over the last decade, the major advance has been in therapies that target the resultant genetic defect: the dysfunctional CFTR protein. Small molecule agents that target this dysfunctional protein via a variety of mechanisms have led to lung function improvements, reductions in pulmonary exacerbation rates and increases in weight and quality-of-life indices. As more patients receive these agents earlier and earlier in life, it is likely that general CF care will increasingly pivot around these specific therapies, although it is also likely that effects other than those identified in the initial trials will be discovered and need to be managed. Despite great excitement for modulator therapies, they are unlikely to be suitable or available for all; whether this is due to a lack of availability for specific CFTR mutations, drug-reactions or the health economic set-up in certain countries. Nevertheless, the CF community must be applauded for its ongoing focus on research and development for this life-limiting disease. With time, personalised individualised therapy would ideally be the mainstay of CF care.

scholarly journals Genetic Modifying Factors of Cystic Fibrosis Phenotype: A Challenge for Modern Medicine

2021 ◽  
Vol 10 (24) ◽  
pp. 5821
Author(s):  
Lăcrămioara Ionela Butnariu ◽  
Elena Țarcă ◽  
Elena Cojocaru ◽  
Cristina Rusu ◽  
Ștefana Maria Moisă ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Association Studies ◽  
Phenotypic Variability ◽  
Genetic Disorders ◽  
Gene Mutations ◽  
Modern Medicine ◽  
Modifier Genes ◽  
Cftr Gene ◽  
Future Research ◽  
Genome Wide Association Studies

Cystic fibrosis (CF) is a monogenic autosomal recessive disease caused by cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. CF is characterized by a high phenotypic variability present even in patients with the same genotype. This is due to the intervention of modifier genes that interact with both the CFTR gene and environmental factors. The purpose of this review is to highlight the role of non-CFTR genetic factors (modifier genes) that contribute to phenotypic variability in CF. We analyzed literature data starting with candidate gene studies and continuing with extensive studies, such as genome-wide association studies (GWAS) and whole exome sequencing (WES). The results of both types of studies revealed that the number of modifier genes in CF patients is impressive. Their identification offers a new perspective on the pathophysiological mechanisms of the disease, paving the way for the understanding of other genetic disorders. In conclusion, in the future, genetic analysis, such as GWAS and WES, should be performed routinely. A challenge for future research is to integrate their results in the process of developing new classes of drugs, with a goal to improve the prognosis, increase life expectancy, and enhance quality of life among CF patients.

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