Nat Genet. 2022 Jun 2. doi: 10.1038/s41588-022-01078-z. Online ahead of print.

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance, including 25 without prior NAFLD or alanine aminotransferase associations, with one additional locus identified in European American-only and two in African American-only analyses (P < 5 × 10-8). External replication in histology-defined NAFLD cohorts (7,397 cases and 56,785 controls) or radiologic imaging cohorts (n = 44,289) replicated 17 single-nucleotide polymorphisms (SNPs) (P < 6.5 × 10-4), of which 9 were new (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH and IFI30). Pleiotropy analysis showed that 61 of 77 multiancestry and all 17 replicated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.

PMID:35654975 | DOI:10.1038/s41588-022-01078-z

Front Pediatr. 2022 May 16;10:881470. doi: 10.3389/fped.2022.881470. eCollection 2022.

ABSTRACT

Cystic fibrosis is the most common life-limiting recessive genetic disorder in Caucasian populations, characterized by the involvement of exocrine glands, causing multisystemic comorbidities. Since the first descriptions of pancreatic and pulmonary involvement in children, technological development and basic science research have allowed great advances in the diagnosis and treatment of cystic fibrosis. The great search for treatments that acted at the genetic level, despite not having found a cure for this disease, culminated in the creation of CFTR modulators, highly effective medications for certain groups of patients. However, there are still many obstacles behind the treatment of the disease to be discussed, given the wide variety of mutations and phenotypes involved and the difficulty of access that permeate these new therapies around the world.

PMID:35652053 | PMC:PMC9149599 | DOI:10.3389/fped.2022.881470

Transpl Int. 2022 May 16;35:10159. doi: 10.3389/ti.2022.10159. eCollection 2022.

ABSTRACT

The MUC5B promoter polymorphism (rs35705950) has been associated with interstitial lung disease (ILD) and with prolonged pre-transplant survival in idiopathic pulmonary fibrosis (IPF), but no information is available regarding its prevalence in other respiratory diseases and its influence on post-transplant outcome. We included the Leuven lung transplantation cohort between 1991 and 2015 (n = 801). We assessed the minor allele frequency (MAF) of the MUC5B variant in the entire study cohort and investigated the influence of recipient MUC5B promoter polymorphism on post-transplant outcome in patients who were transplanted after 2004. MUC5B was successfully genotyped in 746 patients. The MAF was significantly higher in ILD (17.6%) compared to chronic obstructive pulmonary disease (COPD)/emphysema (9.3%), cystic fibrosis (CF)/bronchiectasis (BRECT) (7.5%) and pulmonary hypertension (PHT) (7.4%) (p < 0.001). No association was observed between rs35705950 and chronic lung allograft dysfunction (CLAD)/graft loss in the ILD population [CLAD: HR 1.37 95% CI (0.70-2.68); graft loss: HR 1.02 95% CI (0.55-1.89)], nor the entire study cohort [CLAD: HR 0.96 95% CI (0.69-1.34); graft loss: HR 0.97 95% CI (0.70-1.35)]. The MUC5B promoter polymorphism is a very specific predictive factor for the presence of pulmonary fibrosis as it is only associated with pulmonary fibrosis and not with other chronic respiratory diseases. While the MUC5B promoter variant is associated with better pre-transplant survival among IPF patients, recipient MUC5B promoter variant does not play a role in post-transplant outcome.

PMID:35651878 | PMC:PMC9149783 | DOI:10.3389/ti.2022.10159

J Clin Invest. 2022 Jun 1;132(11):e161483. doi: 10.1172/JCI161483.

NO ABSTRACT

PMID:35642631 | PMC:PMC9151683 | DOI:10.1172/JCI161483

Gene Ther. 2022 Jun 2. doi: 10.1038/s41434-022-00347-0. Online ahead of print.

ABSTRACT

The marketing approval, about ten years ago, of the first disease modulator for patients with cystic fibrosis harboring specific CFTR genotypes (~5% of all patients) brought new hope for their treatment. To date, several therapeutic strategies have been approved and the number of CFTR mutations targeted by therapeutic agents is increasing. Although these drugs do not reverse the existing disease, they help to increase the median life expectancy. However, on the basis of their CFTR genotype, ~10% of patients presently do not qualify for any of the currently available CFTR modulator therapies, particularly patients with splicing mutations (~12% of the reported CFTR mutations). Efforts are currently made to develop therapeutic agents that target disease-causing CFTR variants that affect splicing. This highlights the need to fully identify them by scanning non-coding regions and systematically determine their functional consequences. In this review, we present some examples of CFTR alterations that affect splicing events and the different therapeutic options that are currently developed and tested for splice switching.

PMID:35650428 | DOI:10.1038/s41434-022-00347-0

Nat Microbiol. 2022 Jun;7(6):844-855. doi: 10.1038/s41564-022-01133-9. Epub 2022 Jun 1.

ABSTRACT

DNA-protein interactions are central to fundamental cellular processes, yet widely implemented technologies for measuring these interactions on a genome scale in bacteria are laborious and capture only a snapshot of binding events. We devised a facile method for mapping DNA-protein interaction sites in vivo using the double-stranded DNA-specific cytosine deaminase toxin DddA. In 3D-seq (DddA-sequencing), strains containing DddA fused to a DNA-binding protein of interest accumulate characteristic mutations in DNA sequence adjacent to sites occupied by the DNA-bound fusion protein. High-depth sequencing enables detection of sites of increased mutation frequency in these strains, yielding genome-wide maps of DNA-protein interaction sites. We validated 3D-seq for four transcription regulators in two bacterial species, Pseudomonas aeruginosa and Escherichia coli. We show that 3D-seq offers ease of implementation, the ability to record binding event signatures over time and the capacity for single-cell resolution.

PMID:35650286 | DOI:10.1038/s41564-022-01133-9

J Cyst Fibros. 2022 May 29:S1569-1993(22)00148-5. doi: 10.1016/j.jcf.2022.05.010. Online ahead of print.

ABSTRACT

BACKGROUND: Antibiotics are often changed during treatment of pulmonary exacerbations (PEx) in people with cystic fibrosis (CF) who have a poor clinical response. We aimed to characterize the reasons CF providers change antibiotics and examined the effects of antibiotic changes on lung function recovery.

METHODS: This was a retrospective cohort study using the Toronto CF Database from 2009 to 2015 of adults and children with CF PEx treated with intravenous antibiotics. The co-primary outcome measure was absolute and relative change in forced expiratory lung volume in 1 s (FEV1) at end of treatment and follow-up. Secondary outcome assessed the proportion of patients returning to > 90% or > 100% previous baseline FEV1.

RESULTS: A total of 399 PEx were included of which 105 had antibiotic changes. Reasons for antibiotic changes included change in antibiotic route prior to discharge (26%), drug reactions (20%), poor FEV1 response (25%), targeting additional microbes (16%) and lack of symptom improvement (13%). In our multivariable analysis, among non-responders (< 90% FEV1 recovery to baseline or lack of symptom improvement at the interim time point), a change in antibiotics was not associated with any significant difference in absolute or relative FEV1 at end of treatment or at follow-up. Antibiotic change in non-responders was not associated with improved return to 90% or 100% baseline FEV1 at end of treatment or follow-up.

CONCLUSIONS: Changing antibiotics during CF PEx treatment in those with poor clinical response was not associated with any improved FEV1 response or return to baseline lung function.

PMID:35650003 | DOI:10.1016/j.jcf.2022.05.010

Am J Hum Genet. 2022 May 25:S0002-9297(22)00214-2. doi: 10.1016/j.ajhg.2022.05.008. Online ahead of print.

ABSTRACT

Recent work has found increasing evidence of mitigated, incompletely penetrant phenotypes in heterozygous carriers of recessive Mendelian disease variants. We leveraged whole-exome imputation within the full UK Biobank cohort (n ∼ 500K) to extend such analyses to 3,475 rare variants curated from ClinVar and OMIM. Testing these variants for association with 58 quantitative traits yielded 102 significant associations involving variants previously implicated in 34 different diseases. Notable examples included a POR missense variant implicated in Antley-Bixler syndrome that associated with a 1.76 (SE 0.27) cm increase in height and an ABCA3 missense variant implicated in interstitial lung disease that associated with reduced FEV1/FVC ratio. Association analyses with 1,134 disease traits yielded five additional variant-disease associations. We also observed contrasting levels of recessiveness between two more-common, classical Mendelian diseases. Carriers of cystic fibrosis variants exhibited increased risk of several mitigated disease phenotypes, whereas carriers of spinal muscular atrophy alleles showed no evidence of altered phenotypes. Incomplete penetrance of cystic fibrosis carrier phenotypes did not appear to be mediated by common allelic variation on the functional haplotype. Our results show that many disease-associated recessive variants can produce mitigated phenotypes in heterozygous carriers and motivate further work exploring penetrance mechanisms.

PMID:35649421 | DOI:10.1016/j.ajhg.2022.05.008

Curr Opin Pharmacol. 2022 May 29;65:102238. doi: 10.1016/j.coph.2022.102238. Online ahead of print.

ABSTRACT

While discovery metabolomic studies have identified many potential biomarkers of cystic fibrosis (CF) airways disease, relatively few have been validated. We review the recent literature to identify the most promising metabolomic findings as those repeatedly observed over multiple studies. Reproducible metabolomic findings include increased airway amino acids and small peptides in CF airways, as well as changes in phospholipids and sphingolipids. Other commonly altered pathways include adenosine metabolism, polyamine synthesis, and oxidative stress. These pathways represent potential biomarkers and therapeutic targets, though findings require reevaluation in the era of highly effective modulator therapies. Analysis of airway biomarkers in exhaled breath holds promise for non-invasive detection, though technical challenges will need to be overcome.

PMID:35649321 | DOI:10.1016/j.coph.2022.102238

HGG Adv. 2022 May 12;3(3):100117. doi: 10.1016/j.xhgg.2022.100117. eCollection 2022 Jul 14.

ABSTRACT

CFTR F508del (c.1521_1523delCTT, p.Phe508delPhe) is the most common pathogenic allele underlying cystic fibrosis (CF), and its frequency varies in a geographic cline across Europe. We hypothesized that genetic variation associated with this cline is overrepresented in a large cohort (N > 5,000) of persons with CF who underwent whole-genome sequencing and that this pattern could result in spurious associations between variants correlated with both the F508del genotype and CF-related outcomes. Using principal-component (PC) analyses, we showed that variation in the CFTR region disproportionately contributes to a PC explaining a relatively high proportion of genetic variance. Variation near CFTR was correlated with population structure among persons with CF, and this correlation was driven by a subset of the sample inferred to have European ancestry. We performed genome-wide association studies comparing persons with CF with one versus two copies of the F508del allele; this allowed us to identify genetic variation associated with the F508del allele and to determine that standard PC-adjustment strategies eliminated the significant association signals. Our results suggest that PC adjustment can adequately prevent spurious associations between genetic variants and CF-related traits and are therefore effective tools to control for population structure even when population structure is confounded with disease severity and a common pathogenic variant.

PMID:35647563 | PMC:PMC9136666 | DOI:10.1016/j.xhgg.2022.100117

J Med Life. 2022 Apr;15(4):547-556. doi: 10.25122/jml-2021-0261.

ABSTRACT

Due to progress in infertility etiology, several genetic bases of infertility are revealed today. This study aimed to investigate the distribution of mutations in the CFTR gene, M470V polymorphism, and IVS8 poly T. Furthermore, we aimed to examine the hotspot exons (4, 7, 9, 10, 11, 20, and 21 exons) to find a new mutation in cystic fibrosis transmembrane conductance regulator (CFTR) gene among infertile Iranian men very severe oligozoospermia (<1 million sperm/mL ejaculate fluid). In the present case-control study, 200 very severe oligozoospermia (20-60s) and 200 fertile men (18-65s) were registered. Five common CFTR mutations were genotyped using the ARMS-PCR technique. The M470V polymorphism was checked out by real-time PCR, and poly T and exons were sequenced. The F508del was the most common (4.5%) CFTR gene mutation; G542X and W1282X were detected with 1.5% and 1%, respectively. N1303K and R117H were detected in 0.5% of cases. F508del was seen as a heterozygous compound with G542X in one patient and with W1282X in the other patient. Also, in the case of M470V polymorphism, there are differences between the case and control groups (p=0.013). Poly T assay showed statistical differences in some genotypes. The study showed no new mutation in the exons mentioned above. Our results shed light on the genetic basis of men with very severe oligozoospermia in the Iranian population, which will support therapy decisions among infertile men.

PMID:35646184 | PMC:PMC9126445 | DOI:10.25122/jml-2021-0261

Int J Neonatal Screen. 2022 May 9;8(2):32. doi: 10.3390/ijns8020032.

ABSTRACT

Cystic fibrosis (CF) has been included within the UK national newborn screening programme since 2007. The approach uses measures of immunoreactive trypsin (IRT) in dried blood spot samples obtained at day 5 of life. Samples which reveal IRT results &gt;99.5th centile go on to be tested for a limited panel of CF mutations. While the programme works well and achieves a high level of sensitivity and specificity, it relies upon repeat testing in some cases and identifies probable carriers, both potentially provoking parental anxiety. In addition, the limited CF mutation panel may not fully reflect the ethnic diversity within the UK population. The use of wider genomic screening, made possible by next-generation sequencing to replace more limited panels, can be used to avoid these shortcomings. However, the way in which this approach is employed can either be designed to maximise specificity by limiting reporting to combinations of known pathogenic mutations or can maximise sensitivity by also reporting combinations of pathogenic mutations together with variants of uncertain significance. The latter approach also increases the number of Cystic Fibrosis Screen-Positive Inconclusive Diagnosis (CFSPID) designations reported, resulting in uncertainty for parents. To help consider the design of the programme, a dialogue was commissioned by the UK National Screening Committee (UKNSC) to elicit the views of members of the public without direct experience of CF, to determine if there was a preference for maximising the sensitivity or the specificity of CF screening. The participants initially expressed a clear preference to maximise sensitivity and avoid missing CF cases, but after time to reflect and consider the implications of their choice, a number changed their views so as to tolerate some missed cases if this resulted in greater certainty of outcome; this became the majority view. It is proposed that it may be a generalisable finding that the public, when facing whole-population screening programmes, may require significant time and information to inform and make their choices and may attach great importance to clarity and certainty of outcome in the screening process.

PMID:35645286 | DOI:10.3390/ijns8020032

Arch Bronconeumol. 2022 Mar 11:S0300-2896(22)00180-6. doi: 10.1016/j.arbres.2022.02.009. Online ahead of print.

NO ABSTRACT

PMID:35644710 | DOI:10.1016/j.arbres.2022.02.009

Med Clin (Barc). 2022 May 26:S0025-7753(22)00135-X. doi: 10.1016/j.medcli.2022.02.008. Online ahead of print.

NO ABSTRACT

PMID:35644627 | DOI:10.1016/j.medcli.2022.02.008

Int Forum Allergy Rhinol. 2022 May 29. doi: 10.1002/alr.23036. Online ahead of print.

NO ABSTRACT

PMID:35643960 | DOI:10.1002/alr.23036

Chest. 2022 May 25:S0012-3692(22)01049-2. doi: 10.1016/j.chest.2022.05.021. Online ahead of print.

ABSTRACT

BACKGROUND: Improved methods are needed to risk-stratify patients with cystic fibrosis (CF) and reduced FEV1.

RESEARCH QUESTIONS: What are the predictors of 2-year death or lung transplant (LTx) among CF patients with FEV1 ≤50% predicted? Do these markers similarly predict outcomes among G551D patients taking ivacaftor since 2012?

STUDY DESIGN AND METHODS: CF patients age ≥6 years with FEV1 ≤50% predicted as of December 31, 2014 were identified in a dataset that merged CF Foundation and UNOS registries. Least absolute shrinkage and selection operator (LASSO) was applied to a randomly selected training set to select important prognostic variables. Accuracy and association with 2-year death or LTx of the model was validated via logistic regression on an independent test set. Sensitivity analyses explored predictors for patients with UNOS data.

RESULTS: FEV1% predicted (OR 1.51 for 5% decrease, 95% CI 1.27 - 1.81), number of pulmonary exacerbations treated with intravenous antibiotics (OR 1.35, 95% CI 1.11-1.65), and continuous or nocturnal oxygen (OR 3.71 95% CI 1.81-7.59) were significantly associated with 2-year death or LTx. Our model predicted outcomes with greater sensitivity (rSens 1.26, 95% CI 1.02-1.54), positive predictive value (rPPV 1.25, 95% CI 1.05-1.51), and negative predictive value (rNPV 1.04, 95% CI 1.01-1.07) than FEV1 < 30% predicted. Among those on ivacaftor in 2014, only FEV1 remained associated with death or LTx. For patients with UNOS data, LASSO identified additional covariates of interest, including non-invasive ventilation use, low hemoglobin, pulmonary arterial systolic pressure, supplemental oxygen, mechanical ventilation, FEV1 percent predicted, and cardiac index.

INTERPRETATION: Among individuals with CF and FEV1 ≤50% predicted, FEV1% predicted, oxygen therapy, and number of pulmonary exacerbations predicted 2-year death or LTx. Although limited by small sample size, only FEV1 remained predictive in patients taking highly effective modulator therapy. Additional physiologic variables could improve prognostication in CF.

PMID:35643116 | DOI:10.1016/j.chest.2022.05.021

Hum Mutat. 2022 Jun 1. doi: 10.1002/humu.24418. Online ahead of print.

ABSTRACT

The ATP-binding cassette (ABC) transporter superfamily comprises membrane proteins that efflux various substrates across extra- and intra-cellular membranes. Mutations in ABC genes cause 21 human disorders or phenotypes with Mendelian inheritance, including cystic fibrosis, adrenoleukodystrophy, retinal degeneration, cholesterol, and bile transport defects. To provide tools to study the function of human ABC transporters we compiled data from multiple genomics databases. We analyzed ABC gene conservation within human populations and across vertebrates surveyed phenotypes of ABC gene mutations in mice. Most mouse ABC gene disruption mutations have a phenotype that mimics human disease, indicating they are applicable models. Interestingly several ABCA family genes, whose human function is unknown, have cholesterol level phenotypes in the mouse. Genome-wide association studies confirm and extend ABC traits and suggest several new functions to investigate. Whole exome sequencing of tumors from diverse cancer types demonstrates that mutations in ABC genes are not common in cancer, but specific genes are overexpressed in select tumor types. Finally, an analysis of the frequency of loss-of-function mutations demonstrates that many human ABC genes are essential with a low level of variants, while others have a higher level of genetic diversity. This article is protected by copyright. All rights reserved.

PMID:35642569 | DOI:10.1002/humu.24418

J Med Case Rep. 2022 May 31;16(1):230. doi: 10.1186/s13256-022-03399-3.

ABSTRACT

BACKGROUND: We present the first case to our knowledge of a spontaneous twin pregnancy in a 16-year-old Caucasian patient with cystic fibrosis and systemic lupus erythematosus. Cystic fibrosis is one of the most common autosomal recessive genetic disorders and primarily affects the respiratory and digestive systems. Systemic lupus erythematosus is a chronic inflammatory disease of unknown cause that affects nearly every organ. Patients with cystic fibrosis or systemic lupus erythematosus are progressively having longer life expectancy and better quality of life, which has led a greater number of female patients reporting the desire to become mothers.

CASE PRESENTATION: We present a case of a Caucasian 16-year-old pregnant with twins being treated for both cystic fibrosis and systemic lupus erythematosus. She has two CFTR mutations: p.F508del and 1812_1G>A. In the second trimester, she was admitted for possible preterm labor, which was successfully stopped. The patient's nutritional status worsened, and she had a pulmonary exacerbation as well as a flare of systemic lupus erythematosus. At the 28th gestational week, she presented with a massive hemoptysis episode. The cesarean delivery had no complications, and there were no serious immediate postpartum complications.

DISCUSSION AND CONCLUSIONS: While adolescent pregnancies in and of themselves are considered high risk for both the young mothers and their children, they are further complicated when the mother has two chronic diseases and a twin pregnancy. We achieved positive results using a multidisciplinary approach; however, the risks involved were so high that major efforts are to be taken by our medical community to prevent unplanned pregnancies in all patients with cystic fibrosis, especially when a serious comorbidity like the one in this case is present.

PMID:35641986 | DOI:10.1186/s13256-022-03399-3

J Cyst Fibros. 2022 May;21(3):381-382. doi: 10.1016/j.jcf.2022.05.002.

NO ABSTRACT

PMID:35641034 | DOI:10.1016/j.jcf.2022.05.002

Stem Cells. 2022 May 27:sxac038. doi: 10.1093/stmcls/sxac038. Online ahead of print.

ABSTRACT

Cartilaginous airways of larger mammals and the mouse trachea contain at least three well-established stem cell compartments including basal cells (BC) of the surface airway epithelium (SAE) and ductal and myoepithelial cells of the submucosal glands (SMG). Here we demonstrate that glandular Sox9-expressing progenitors capable of SAE repair decline with age in mice. Notably, Sox9-lineage glandular progenitors produced basal and ciliated cells in the SAE, but failed to produce secretory cells. Lef1 was required for glandular Sox9 lineage contribution to SAE repair and its deletion significantly reduced proliferation following injury. By contrast, in vivo deletion of Sox9 enhanced proliferation in both SAE and SMG progenitors shortly following injury, but these progenitors failed to proliferate in vitro in the absence of Sox9, similar to that previously shown for Lef1 deletion. In cystic fibrosis ferret airways, Sox9 expression inversely correlated with Ki67 proliferative marker expression in SMG and the SAE. Using in vitro and ex vivo models, we demonstrate that Sox9 is extinguished as glandular progenitors exit ducts and proliferate on the airway surface and that Sox9 is required for migration and proper differentiation of SMG, but not SAE, progenitors. We propose a model whereby Wnt/Lef1 and Sox9 signals differentially regulate the proliferative and migratory behavior of glandular progenitors, respectively.

PMID:35639980 | DOI:10.1093/stmcls/sxac038