Recent Drug-Repurposing-Driven Advances in the Discovery of Novel Antibiotics.

Curr Med Chem. 2018 Jul 05;:

Authors: Konreddy AK, Rani GU, Lee K, Choi Y

Abstract
Drug repurposing is a safe and successful pathway to speed up the novel drug discovery and development processes compared with de novo drug discovery approaches. Drug repurposing uses FDA-approved drugs and drugs that failed in clinical trials, which have detailed information of potential toxicity, formulation, and pharmacology. Technical advancements in the informatics, genomics, and biological sciences account for the major success of drug repurposing in identifying secondary indications of existing drugs. Drug repurposing is playing a vital role in filling the gap in the discovery of potential antibiotics. Bacterial infections emerged as an ever increasing global public health threat by dint of multidrug resistance to existing drugs. This raises the urgent need of development of new antibiotics that can effectively fight multidrug-resistant bacterial infections (MDRBIs). The present review describes the key role of drug repurposing in the development of antibiotics during 2016-2017 and of the details of recently FDA-approved antibiotics, pipeline antibiotics, and antibacterial properties of various FDA-approved drugs of anti-cancer, anti-fungal, anti-hyperlipidemia, anti-inflammatory, anti-malarial, anti-parasitic, anti-viral, genetic disorder, immune modulator, etc. Further, in view of combination therapies with the existing antibiotics, their potential for new implications for MDRBIs is discussed. The current review may provide essential data for the development of quick, safe, effective, and novel antibiotics for current needs and suggest acuity into its effective implications for inhibiting MDRBIs by repurposing existing drugs.

PMID: 29984648 [PubMed - as supplied by publisher]

Creating longitudinal datasets and cleaning existing data identifiers in a cystic fibrosis registry using a novel Bayesian probabilistic approach from astronomy.

PLoS One. 2018;13(7):e0199815

Authors: Hurley PD, Oliver S, Mehta A

Abstract
Patient registry data are commonly collected as annual snapshots that need to be amalgamated to understand the longitudinal progress of each patient. However, patient identifiers can either change or may not be available for legal reasons when longitudinal data are collated from patients living in different countries. Here, we apply astronomical statistical matching techniques to link individual patient records that can be used where identifiers are absent or to validate uncertain identifiers. We adopt a Bayesian model framework used for probabilistically linking records in astronomy. We adapt this and validate it across blinded, annually collected data. This is a high-quality (Danish) sub-set of data held in the European Cystic Fibrosis Society Patient Registry (ECFSPR). Our initial experiments achieved a precision of 0.990 at a recall value of 0.987. However, detailed investigation of the discrepancies uncovered typing errors in 27 of the identifiers in the original Danish sub-set. After fixing these errors to create a new gold standard our algorithm correctly linked individual records across years achieving a precision of 0.997 at a recall value of 0.987 without recourse to identifiers. Our Bayesian framework provides the probability of whether a pair of records belong to the same patient. Unlike other record linkage approaches, our algorithm can also use physical models, such as body mass index curves, as prior information for record linkage. We have shown our framework can create longitudinal samples where none existed and validate pre-existing patient identifiers. We have demonstrated that in this specific case this automated approach is better than the existing identifiers.

PMID: 29985939 [PubMed - in process]

A Protein Microarray Assay for Serological Determination of Antigen-specific Antibody Responses Following Clostridium difficile Infection.

J Vis Exp. 2018 Jun 15;(136):

Authors: Negm OH, Hamed M, Monaghan TM

Abstract
We provide a detailed overview of a novel high-throughput protein microarray assay for the determination of anti-Clostridium difficile antibody levels in human sera and in separate preparations of polyclonal intravenous immunoglobulin (IVIg). The protocol describes the methodological steps involved in sample preparation, printing of arrays, assay procedure, and data analysis. In addition, this protocol could be further developed to incorporate diverse clinical samples including plasma and cell culture supernatants. We show how protein microarray can be used to determine a combination of isotype (IgG, IgA, IgM), subclass (IgG1, IgG2, IgG3, IgG4, IgA1, IgA2), and strain-specific antibodies to highly purified whole C. difficile toxins A and B (toxinotype 0, strain VPI 10463, ribotype 087), toxin B from a C. difficile toxin-B-only expressing strain (CCUG 20309), a precursor form of a B fragment of binary toxin, pCDTb, ribotype-specific whole surface layer proteins (SLPs; 001, 002, 027), and control proteins (tetanus toxoid and Candida albicans). During the experiment, microarrays are probed with sera from individuals with C. difficile infection (CDI), individuals with cystic fibrosis (CF) without diarrhea, healthy controls (HC), and from individuals pre- and post-IVIg therapy for the treatment of CDI, combined immunodeficiency disorder, and chronic inflammatory demyelinating polyradiculopathy. We encounter significant differences in toxin neutralization efficacies and multi-isotype specific antibody levels between patient groups, commercial preparations of IVIg, and sera before and following IVIg administration. Also, there is a significant correlation between microarray and enzyme-linked immunosorbent assay (ELISA) for antitoxin IgG levels in serum samples. These results suggest that microarray could become a promising tool for profiling antibody responses to C.difficile antigens in vaccinated or infected humans. With further refinement of antigen panels and a reduction in production costs, we anticipate that microarray technology may help optimize and select the most clinically useful immunotherapies for C. difficile infection in a patient-specific manner.

PMID: 29985307 [PubMed - in process]

Recent Advancements in Our Understanding of the Ergogenic Effect of Respiratory Muscle Training in Healthy Humans: A Systematic Review.

J Strength Cond Res. 2018 Jul 04;:

Authors: Shei RJ

Abstract
Shei, R-J. Recent advancements in our understanding of the ergogenic effect of respiratory muscle training in healthy humans: a systematic review. J Strength Cond Res XX(X): 000-000, 2018-Respiratory muscle training (RMT) has been shown to be an effective ergogenic aid for sport performance. Respiratory muscle training has been documented to improve performance in a wide range of exercise modalities including running, cycling, swimming, and rowing. The physiological effects of RMT that may explain the improvements in performance have been proposed to include diaphragm hypertrophy, muscle fiber-type switching, improved neural control of the respiratory muscles, increased respiratory muscle economy, attenuation of the respiratory muscle metaboreflex, and decreases in perceived breathlessness and exertion. This review summarizes recent studies on the ergogenicity and mechanisms of RMT since 2013 when the topic was last systematically reviewed. Recent evidence confirms the ergogenic effects of RMT and explores different loading protocols, such as concurrent exercise and RMT (i.e., "functional" RMT). These studies suggest that adapting new training protocols may have an additive improvement effect, but evidence of the efficacy of such an approach is conflicting thus far. Other recent investigations have furthered our understanding of the mechanisms underpinning RMT-associated improvements in performance. Importantly, changes in ventilatory efficiency, oxygen delivery, cytokine release, motor recruitment patterns, and respiratory muscle fatigue resistance are highlighted as potential mechanistic factors linking RMT with performance improvements. It is suggested that future investigations focus on development of sport-specific RMT loading protocols, and that further work be undertaken to better understand the mechanistic basis of RMT-induced performance improvements.

PMID: 29985221 [PubMed - as supplied by publisher]

Clinical utility of surveillance computed tomography scans in infants with cystic fibrosis.

Pediatr Pulmonol. 2018 Jul 08;:

Authors: Newbegin K, Pilkington K, Shanthikumar S, Ranganathan S

Abstract
BACKGROUND: In cystic fibrosis (CF), irreversible lung disease arises in early life, and is often asymptomatic and unrecognised. Chest computed tomography (CT) scans have been used to detect asymptomatic lung disease in research; however, the clinical utility of chest CT is unknown. This study aimed to determine the effect of surveillance CT in early life on the clinical management of patients with CF.
WORKING HYPOTHESIS: Surveillance CT in early life changes the management of patients with CF.
METHODS: A medical record review of patients in the AREST-CF cohort who had chest CT at 1 and 3 years of age was performed. Information extracted included CT scan findings and the effect of CT results on clinical management.
RESULTS: The chest CT scans and records of 50 subjects with CF were reviewed. The majority of CT scans (n = 75; 75%) were abnormal. N = 31 (31%) of scans overall led to a direct change in management. The number of CT scans needed to be performed to lead to a treatment change was 3.2. The majority (n = 18, 58%) of changes in management were prompted by the finding of bronchiectasis.
CONCLUSION: To the authors knowledge, this is the first study to highlight that early life surveillance CT frequently results in changes in clinical management, and hence may have a role beyond research and in routine care. If this can be shown to contribute to improved outcomes (such as reduced rates of bronchiectasis), then, as radiation doses diminish, chest CT could have an important clinical role.

PMID: 29984485 [PubMed - as supplied by publisher]

Italian and North American dietary intake after ivacaftor treatment for Cystic Fibrosis Gating Mutations.

J Cyst Fibros. 2018 Jul 05;:

Authors: Sainath NN, Schall J, Bertolaso C, McAnlis C, Stallings VA

Abstract
BACKGROUND: In patients with cystic fibrosis (CF), ivacaftor treatment results in significant weight gain and the impact on diet has not been explored.
METHODS: A study in 22 subjects (6.1-61.6 years) compared diet, energy balance, weight gain, and body composition, before and after three months of treatment in Italians and North Americans with CFTR gating mutations.
RESULTS: With no differences between groups in energy or macronutrient intake at baseline, fat intake increased in all subjects, and both fat and energy intake increased in Italians. Height, weight, BMI, lean and fat mass, and % body fat increased and resting energy expenditure decreased after treatment. Weight gain was associated with energy and fat intake.
CONCLUSIONS: Fat intake increased with treatment, possibly due to the recommendation to take ivacaftor with high fat meals. Increased energy and fat intake correlated with weight gain. Regional dietary patterns differed.

PMID: 29983355 [PubMed - as supplied by publisher]

Sequence heterogeneity of the PenA carbapenemase in clinical isolates of Burkholderia multivorans.

Diagn Microbiol Infect Dis. 2018 Jun 18;:

Authors: Becka SA, Zeiser ET, Marshall SH, Gatta JA, Nguyen K, Singh I, Greco C, Sutton GG, Fouts DE, LiPuma JJ, Papp-Wallace KM

Abstract
Multidrug-resistant gram-negative pathogens are a significant health threat. Burkholderia spp. encompass a complex subset of gram-negative bacteria with a wide range of biological functions that include human, animal, and plant pathogens. The treatment of infections caused by Burkholderia spp. is problematic due to their inherent resistance to multiple antibiotics. The major β-lactam resistance determinant expressed in Burkholderia spp. is a class A β-lactamase of the PenA family. In this study, significant amino acid sequence heterogeneity was discovered in PenA (37 novel variants) within a panel of 48 different strains of Burkholderia multivorans isolated from individuals with cystic fibrosis. Phylogenetic analysis distributed the 37 variants into 5 groups based on their primary amino acid sequences. Amino acid substitutions were present throughout the entire β-lactamase and did not congregate to specific regions of the protein. The PenA variants possessed 5 to 17 single amino acid changes. The N189S and S286I substitutions were most prevalent and found in all variants. Due to the sequence heterogeneity in PenA, a highly conserved peptide (18 amino acids) within PenA was chosen as the antigen for polyclonal antibody production in order to measure expression of PenA within the 48 clinical isolates of B. multivorans. Characterization of the anti-PenA peptide antibody, using immunoblotting approaches, exposed several unique features of this antibody (i.e., detected <500 pg of purified PenA, all 37 PenA variants in B. multivorans, and Pen-like β-lactamases from other species within the Burkholderia cepacia complex). The significant sequence heterogeneity found in PenA may have occurred due to selective pressure (e.g., exposure to antimicrobial therapy) within the host. The contribution of these changes warrants further investigation.

PMID: 29983287 [PubMed - as supplied by publisher]

Results of the Andalusian Cystic Fibrosis Neonatal Screening Program, 5 Years After Implementation.

Arch Bronconeumol. 2018 Jul 05;:

Authors: Delgado Pecellín I, Pérez Ruiz E, Álvarez Ríos AI, Delgado Pecellín C, Yahyaoui Macías R, Carrasco Hernández L, Marcos Luque I, Caro Aguilera P, Moreno Valera MJ, Quintana Gallego ME

Abstract
INTRODUCTION: Cystic fibrosis neonatal screening (CFNS), based on double determination of immunoreactive trypsinogen ([IRT] [IRT1/IRT2]), has been available in Andalusia since May 2011. If screening is positive, a sweat test is performed, and if that is positive or inconclusive, genetic testing is requested.
OBJECTIVE: To analyze CFNS, based on results from the first 4.5 years of the program.
MATERIALS AND METHODS: Prospective descriptive study of neonates undergoing CFNS. IRT levels, sweat chloride, and mutations were recorded. Statistical analysis was performed using SPSS 12.0.
RESULTS: Between May 2011 and December 2016, 474,953 neonates underwent CFNS. Of these, 1,087 (0.23%) had elevated IRT2. Since CFNS was introduced, 73 cases of cystic fibrosis were diagnosed; 60 were diagnosed by positive CFNS, and 13 were diagnosed by other means. In one case, the patient developed a typical clinical picture of cystic fibrosis, but had not undergone CFNS at the decision of the parents; the remaining 12 had a negative CFNS (false negatives). Of these, one patient was diagnosed before symptoms developed, as his twin brother had a positive CFNS result; another had chloride at the upper limit of normal, and was subsequently diagnosed with genetic testing before symptoms appeared; and 10 patients developed clinical signs and symptoms. Excluding patients with meconium ileus, sensitivity and specificity of the CFNS program were 85.71% and 99.78%, respectively. The incidence of the disease in Andalusia is 1/6,506 live births.
CONCLUSION: These results are a basis for reflection on possible areas for improvement of the CFNS algorithm, and thought may be given to the introduction of genetic studies to increase sensitivity and reduce false positives.

PMID: 29983195 [PubMed - as supplied by publisher]

Human airway mucus alters susceptibility of Pseudomonas aeruginosa biofilms to tobramycin, but not colistin.

J Antimicrob Chemother. 2018 Jul 05;:

Authors: Müller L, Murgia X, Siebenbürger L, Börger C, Schwarzkopf K, Sewald K, Häussler S, Braun A, Lehr CM, Hittinger M, Wronski S

Abstract
Objectives: In the context of cystic fibrosis, Pseudomonas aeruginosa biofilms often develop in the vicinity of airway mucus, which acts as a protective physical barrier to inhaled matter. However, mucus can also adsorb small drug molecules administered as aerosols, including antibiotics, thereby reducing their bioavailability. The efficacy of antibiotics is typically assessed by determining the MIC using in vitro assays. This widespread technique, however, does not consider either bacterial biofilm formation or the influence of mucus, both of which may act as diffusion barriers, potentially limiting antibiotic efficacy.
Methods: We grew P. aeruginosa biofilms in the presence or absence of human tracheal mucus and tested their susceptibility to tobramycin and colistin.
Results: A significant reduction of tobramycin efficacy was observed when P. aeruginosa biofilms were grown in the presence of mucus compared with those grown in the absence of mucus. Diffusion of tobramycin through mucus was reduced; however, this reduction was more pronounced in biofilm/mucus mixtures, suggesting that biofilms in the presence of mucus respond differently to antibiotic treatment. In contrast, the influence of mucus on colistin efficacy was almost negligible and no differences in mucus permeability were observed.
Conclusions: These findings underline the important role of mucus in the efficacy of anti-infective drugs.

PMID: 29982453 [PubMed - as supplied by publisher]

Epidemiology of nontuberculous mycobacteria infection in children and young people with cystic fibrosis: analysis of UK Cystic Fibrosis Registry.

Clin Infect Dis. 2018 Jul 05;:

Authors: Gardner AI, McClenaghan E, Saint G, McNamara PS, Brodlie M, Thomas MF

Abstract
Background: Infection with nontuberculous mycobacteria (NTM) is of growing clinical concern in people with cystic fibrosis (CF). The epidemiology of infection in children and young people remains poorly understood. We wished to investigate the epidemiology of NTM infection in the paediatric age-group using data from the United Kingdom CF Registry.
Methods: Data from 2010-2015 for children and young people aged <16 years (23,200 observations from 5,333 unique individuals) were obtained. Univariate analysis of unique individuals comparing all key clinical factors and health outcomes to NTM status was performed. Identified significant factors were used to generate a multivariate logistic regression model, which following step-wise removal generated a final parsimonious model.
Results: The prevalence of individuals with a NTM positive respiratory culture increased every year from 2010 (45 [1.3%]) to 2015 (156 [3.8%]). Allergic bronchopulmonary aspergillosis (OR 2.66, P = 5.0x10-8), age (OR 1.08, P = 3.4x10-10) and intermittent Pseudomonas aeruginosa infection (OR 1.51, P = 0.004) were significantly associated with NTM infection.
Conclusions: NTM infection is of increasing prevalence in the UK paediatric CF population. This study highlights the urgent need for work to establish effective treatment and prevention strategies for NTM infection in young people with CF.

PMID: 29982302 [PubMed - as supplied by publisher]

U.S. patient-centered research priorities and roadmap for bronchiectasis.

Chest. 2018 Jul 05;:

Authors: Henkle E, Aksamit TR, Daley CL, Griffith DE, O'Donnell AE, Quittner AL, Malanga E, Prieto D, Leitman A, Winthrop KL

Abstract
Non-cystic fibrosis bronchiectasis ("bronchiectasis") is an increasingly common chronic lung disease that is difficult to manage due to a lack of evidence on which to base treatment decision-making. We sought to develop a practical list of U.S.-based patient-centered research priorities and an associated roadmap to guide bronchiectasis research. We designed and administered a web-based patient needs assessment survey to establish broad research priorities; convened three stakeholder webinars to confirm the top priorities; obtained written stakeholder feedback; and completed a final consensus survey of objectives. The stakeholder panel consisted of clinical research experts in bronchiectasis, a 7-member Patient Advisory Panel, and representatives from the two key patient advocacy organizations: COPD Foundation and NTM Info & Research (NTMir). Based on survey results from 459 bronchiectasis patients, the stakeholder panel identified 27 patient-centered research priorities for bronchiectasis in the areas of bronchiectasis treatment and prevention of exacerbations, improving treatment of exacerbations and infections, improving health-related quality of life, predictors of poor prognosis, understanding the impact of underlying conditions, and conducting patient-centered clinical trials. These priorities should further inform the development and evaluation of both new and previously unproven therapies, with particular attention to the inclusion of patient-reported outcomes. We anticipate a great deal of progress will be made in the field of bronchiectasis in the next decade.

PMID: 29981718 [PubMed - as supplied by publisher]

PharmGKB summary: ivacaftor pathway, pharmacokinetics/pharmacodynamics.

Pharmacogenet Genomics. 2017 01;27(1):39-42

Authors: Fohner AE, McDonagh EM, Clancy JP, Whirl Carrillo M, Altman RB, Klein TE

PMID: 27636560 [PubMed - indexed for MEDLINE]

CF end point commentary.

J Cyst Fibros. 2016 07;15(4):424

Authors: Durmowicz AG

PMID: 27324552 [PubMed - indexed for MEDLINE]

[Significance of whole exome sequencing in the diagnostics of rare neurological diseases - own experiences through a case presenting with ataxia].

Orv Hetil. 2018 Jul;159(28):1163-1169

Authors: Balicza P, Grosz Z, Bencsik R, Illés A, Gál A, Gézsi A, Molnár MJ

Abstract
Next generation sequencing (NGS) technologies reshape the diagnostics of rare neurological diseases. In the background of certain neurological symptoms, such as ataxia, many acquired and genetic causes may be present. Variations in a given gene can present with variable phenotypes, too. Because of this phenomenon, the conventional one gene sequencing approach often fails to identify the genetic background of a disease. Next generation sequencing panels allow to sequence 50-100 genes simultaneously, and if the disease stratification is not possible based on the clinical symptoms, whole exome sequencing can help in the diagnostic of genetic disorders with atypical presentation. This case study is about the exome sequencing of a patient with cerebellar ataxia. Genetic investigations identified rare variants in the SPG11 gene in association with the clinical phenotype, which gene was originally described in the background of hereditary spastic paraparesis. Our article highlights that in certain cases the variability of the leading presenting symptom makes it hard to select the correct gene panel. In our case the variants in the gene, formerly associated to hereditary spastic paraparesis, resulted in cerebellar ataxia initially, so even an ataxia NGS gene panel would not detect those. Orv Hetil. 2018; 159(28): 1163-1169.

PMID: 29983107 [PubMed - in process]

Whole-Exome Sequencing Identifies Novel Recurrent Somatic Mutations in Sporadic Parathyroid Adenomas.

Endocrinology. 2018 Jul 03;:

Authors: Wei Z, Sun B, Wang ZP, He JW, Fu WZ, Fan YB, Zhang ZL

Abstract
Primary hyperparathyroidism is commonly casused by excess production of parathyroid hormone from sporadic parathyroid adenomas. However, the genetic architecture of sporadic primary hyperparathyroidism remains largely uncharacterized, especially in the Chinese population. To identify novel genetic abnormalities that may be involved in the etiology of sporadic parathyroid adenomas and to determine the mutation frequency of previously identified genes in the Chinese population, we performed whole-exome sequencing of 22 blood-tumor pairs from sporadic parathyroid adenomas. The most important finding is the recurrently mutated gene, ASXL3, which has never been reported in parathyroid tumors before. Moreover, we identified two different somatic mutations in the CDC73 gene and one somatic mutation in the EZH2 gene. The Y54X mutation in the CDC73 gene was previously identified in parathyroid carcinomas, which proved that parathyroid adenomas and carcinomas might possess similar molecular signatures. No mutations in the MEN1 or CCND1 genes were observed in our study. Thus, our data provide new insights into the genetic pathogenesis of sporadic parathyroid adenomas and are valuable for the development of diagnostic and therapeutic approaches for sporadic primary hyperparathyroidism.

PMID: 29982334 [PubMed - as supplied by publisher]

Early onset developmental delay and epilepsy in pediatric patients with WDR45 variants.

Eur J Med Genet. 2018 Jul 05;:

Authors: Chen H, Qian Y, Yu S, Xiao D, Guo X, Wang Q, Hao L, Lu Y, Dong X, Yan K, Zhou W, Wu B, Wang H

Abstract
BACKGROUND: Developmental delay (DD) is a neurological disorder that presents with defects in gross motor, fine motor, language and cognition functions. WD repeat domain 45 (WDR45) is one of the disease-causing genes of DD. Previously, WDR45 de novo mutations were reported in certain adult and pediatric patients due to iron accumulation.
CLINICAL REPORT: We report five pediatric female patients with DD and epilepsy. Their ages were below 3 years at the first consultation, and precise diagnoses were difficult based on the available clinical information and phenotype.
METHODS: Children with DD and/or epilepsy presenting to the molecular diagnostic center of Children's Hospital of Fudan University between May 2016 and May 2017 were enrolled. The patients and their parents were subjected to whole-exome sequencing (WES), and we characterized the phenotypes of the patients carrying WDR45 variants. Furthermore, we overexpressed the candidate variants in HeLa cells and evaluated their effect on autophagy through Western blot and immunofluorescence staining with confocal microscopy.
RESULTS: Five WDR45 de novo mutations, namely, c.19C > T (p.Arg7*), c.401G > C (p.Arg134Pro), c.503G > A (p.Gly168Glu), c.700C > T (p.Arg234*), and c.912delT (p.Ala305Leufs*25), were detected in 623 enrolled pediatric patients (274 females; 487 patients younger than 6 years). All five patients with WDR45 variants presented with DD and epilepsy. Compared with the control HeLa cells, the cells with the p. Arg134Pro and p. Gly168Glu missense mutations showed accumulation of LC3-containing autophagic structures and an abnormally enlarged cell volume, and Western blotting revealed a significant increase in LC3II/GAPDH.
CONCLUSION: The identification of WDR45 mutations provides further evidence that WES plays an important role in the diagnosis of neurological disorders with common phenotypes and that WDR45 mutations are associated with neurological disorders and are not very rare in Chinese female pediatric patients with DD and/or epilepsy. The diagnosis of patients with WDR45 mutations would enable more precise genetic counseling for the parents of these children.

PMID: 29981852 [PubMed - as supplied by publisher]

Genomic determinants of long-term cardiometabolic complications in childhood acute lymphoblastic leukemia survivors.

BMC Cancer. 2017 Nov 10;17(1):751

Authors: England J, Drouin S, Beaulieu P, St-Onge P, Krajinovic M, Laverdière C, Levy E, Marcil V, Sinnett D

Abstract
BACKGROUND: While cure rates for childhood acute lymphoblastic leukemia (cALL) now exceed 80%, over 60% of survivors will face treatment-related long-term sequelae, including cardiometabolic complications such as obesity, insulin resistance, dyslipidemia and hypertension. Although genetic susceptibility contributes to the development of these problems, there are very few studies that have so far addressed this issue in a cALL survivorship context.
METHODS: In this study, we aimed at evaluating the associations between common and rare genetic variants and long-term cardiometabolic complications in survivors of cALL. We examined the cardiometabolic profile and performed whole-exome sequencing in 209 cALL survivors from the PETALE cohort. Variants associated with cardiometabolic outcomes were identified using PLINK (common) or SKAT (common and rare) and a logistic regression was used to evaluate their impact in multivariate models.
RESULTS: Our results showed that rare and common variants in the BAD and FCRL3 genes were associated (p<0.05) with an extreme cardiometabolic phenotype (3 or more cardiometabolic risk factors). Common variants in OGFOD3 and APOB as well as rare and common BAD variants were significantly (p<0.05) associated with dyslipidemia. Common BAD and SERPINA6 variants were associated (p<0.05) with obesity and insulin resistance, respectively.
CONCLUSIONS: In summary, we identified genetic susceptibility loci as contributing factors to the development of late treatment-related cardiometabolic complications in cALL survivors. These biomarkers could be used as early detection strategies to identify susceptible individuals and implement appropriate measures and follow-up to prevent the development of risk factors in this high-risk population.

PMID: 29126409 [PubMed - indexed for MEDLINE]

ANGPTL3 serum concentration and rare genetic variants in Finnish population.

Scand J Clin Lab Invest. 2017 Dec;77(8):601-609

Authors: Tikka A, Metso J, Jauhiainen M

Abstract
Genetic variants of angiopoietin-like protein 3 (ANGPTL3) are associated with serum triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) concentration in GWASs. ANGPTL3 deficiency causes declined TG, total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (apoB) and apolipoprotein A-I (apoA-I) serum concentration, a phenotype defined as familial combined hypolipidaemia (FHBL2). Our aim is to establish whether ANGPTL3 serum protein concentration correlates with lipoproteins and lipids in hyper- or hypolipidaemic subjects, and whether ANGPTL3 sequence variants are associated with untypical lipid profiles. Additionally, 10 subjects with very low lipoprotein concentrations were sequenced for ANGPTL3 for possible loss-of-function (LOF) variants. Study subjects were selected from Finnish FINRISK and Health 2000 surveys. ANGPTL protein concentrations were measured by ELISA method. As a result, ANGPTL3 serum concentration correlated positively with age, phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP) activities, but not with any of the lipid or lifestyle attributes. No ANGPTL3 variants were found among sequenced samples. Subjects who carried ANGPTL3 sequence variants rs12563308 (n = 4) and rs199772471 (n = 1) had abnormally high TC and LDL-C concentrations. Whole exome sequencing data of these five subjects were further analyzed for rare and deleterious missense variants in genes associated with cholesterol metabolism. In conclusion, ANGPTL3 serum protein concentration did not predict lipid concentrations, unlike apolipoprotein C-III (apoC-III) which positively correlated with most of the lipid attributes. ANGPTL3 variant screen yielded five carriers with abnormally high TC concentration; the actual genetic causality, however, could not be verified.

PMID: 28972399 [PubMed - indexed for MEDLINE]

Genetic causes of MCPH in consanguineous Pakistani families.

Clin Genet. 2016 06;89(6):744-5

Authors: Kraemer N, Picker-Minh S, Abbasi AA, Fröhler S, Ninnemann O, Khan MN, Ali G, Chen W, Kaindl AM

PMID: 26548919 [PubMed - indexed for MEDLINE]