The influence of genetic variation on complex diseases is potentially mediated through a range of highly dynamic epigenetic processes exhibiting temporal variation during development and later life. ...Here we present a catalogue of the genetic influences on DNA methylation (methylation quantitative trait loci (mQTL)) at five different life stages in human blood: children at birth, childhood, adolescence and their mothers during pregnancy and middle age.
We show that genetic effects on methylation are highly stable across the life course and that developmental change in the genetic contribution to variation in methylation occurs primarily through increases in environmental or stochastic effects. Though we map a large proportion of the cis-acting genetic variation, a much larger component of genetic effects influencing methylation are acting in trans. However, only 7 % of discovered mQTL are trans-effects, suggesting that the trans component is highly polygenic. Finally, we estimate the contribution of mQTL to variation in complex traits and infer that methylation may have a causal role consistent with an infinitesimal model in which many methylation sites each have a small influence, amounting to a large overall contribution.
DNA methylation contains a significant heritable component that remains consistent across the lifespan. Our results suggest that the genetic component of methylation may have a causal role in complex traits. The database of mQTL presented here provide a rich resource for those interested in investigating the role of methylation in disease.
Maternal smoking during pregnancy has been found to influence newborn DNA methylation in genes involved in fundamental developmental processes. It is pertinent to understand the degree to which the ...offspring methylome is sensitive to the intensity and duration of prenatal smoking. An investigation of the persistence of offspring methylation associated with maternal smoking and the relative roles of the intrauterine and postnatal environment is also warranted. In the Avon Longitudinal Study of Parents and Children, we investigated associations between prenatal exposure to maternal smoking and offspring DNA methylation at multiple time points in approximately 800 mother-offspring pairs. In cord blood, methylation at 15 CpG sites in seven gene regions (AHRR, MYO1G, GFI1, CYP1A1, CNTNAP2, KLF13 and ATP9A) was associated with maternal smoking, and a dose-dependent response was observed in relation to smoking duration and intensity. Longitudinal analysis of blood DNA methylation in serial samples at birth, age 7 and 17 years demonstrated that some CpG sites showed reversibility of methylation (GFI1, KLF13 and ATP9A), whereas others showed persistently perturbed patterns (AHRR, MYO1G, CYP1A1 and CNTNAP2). Of those showing persistence, we explored the effect of postnatal smoke exposure and found that the major contribution to altered methylation was attributed to a critical window of in utero exposure. A comparison of paternal and maternal smoking and offspring methylation showed consistently stronger maternal associations, providing further evidence for causal intrauterine mechanisms. These findings emphasize the sensitivity of the methylome to maternal smoking during early development and the long-term impact of such exposure.
Prenatal exposure to maternal cigarette smoking (prenatal smoke exposure) had been associated with altered DNA methylation (DNAm) at birth.
We examined whether such alterations are present from birth ...through adolescence.
We used the Infinium HumanMethylation450K BeadChip to search across 473,395 CpGs for differential DNAm associated with prenatal smoke exposure during adolescence in a discovery cohort (n = 132) and at birth, during childhood, and during adolescence in a replication cohort (n = 447).
In the discovery cohort, we found five CpGs in MYO1G (top-ranking CpG: cg12803068, p = 3.3 × 10-11) and CNTNAP2 (cg25949550, p = 4.0 × 10-9) to be differentially methylated between exposed and nonexposed individuals during adolescence. The CpGs in MYO1G and CNTNAP2 were associated, respectively, with higher and lower DNAm in exposed versus nonexposed adolescents. The same CpGs were differentially methylated at birth, during childhood, and during adolescence in the replication cohort. In both cohorts and at all developmental time points, the differential DNAm was in the same direction and of a similar magnitude, and was not altered appreciably by adjustment for current smoking by the participants or their parents. In addition, four of the five EWAS (epigenome-wide association study)-significant CpGs in the adolescent discovery cohort were also among the top sites of differential methylation in a previous birth cohort, and differential methylation of CpGs in CYP1A1, AHRR, and GFI1 observed in that study was also evident in our discovery cohort.
Our findings suggest that modifications of DNAm associated with prenatal maternal smoking may persist in exposed offspring for many years-at least until adolescence.
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Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
There are many single-gene causes of steroid-resistant nephrotic syndrome (SRNS) and the list continues to grow rapidly. Prompt comprehensive diagnostic testing is key to realising the clinical ...benefits of a genetic diagnosis. This report describes a bespoke-designed, targeted next-generation sequencing (NGS) diagnostic gene panel assay to detect variants in 37 genes including the ability to identify copy number variants (CNVs).
This study reports results of 302 patients referred for SRNS diagnostic gene panel analysis. Phenotype and clinical impact data were collected using a standard proforma. Candidate variants detected by NGS were confirmed by Sanger sequencing/Multiplex Ligation-dependent Probe Amplification with subsequent family segregation analysis where possible.
Clinical presentation was nephrotic syndrome in 267 patients and suspected Alport syndrome (AS) in 35. NGS panel testing determined a likely genetic cause of disease in 44/220 (20.0%) paediatric and 10/47 (21.3%) adult nephrotic cases, and 17/35 (48.6%) of haematuria/AS patients. Of 71 patients with genetic disease, 32 had novel pathogenic variants without a previous disease association including two with deletions of one or more exons of
or
.
Gene panel testing provides a genetic diagnosis in a significant number of patients presenting with SRNS or suspected AS. It should be undertaken at an early stage of the care pathway and include the ability to detect CNVs as an emerging mechanism for genes associated with this condition. Use of clinical genetic testing after diagnosis of SRNS has the potential to stratify patients and assist decision-making regarding management.
Bohring-Opitz syndrome (BOS) is a rare genetic disorder characterised by a recognisable craniofacial appearance and a typical 'BOS' posture. BOS is caused by sporadic mutations of
. However, several ...typical patients with BOS have no molecular diagnosis, suggesting clinical and genetic heterogeneity.
To expand the phenotypical spectrum of autosomal recessive variants of
, reported as causing Crisponi syndrome/cold-induced sweating syndrome type 1 (CS/CISS1)-like syndrome.
We performed whole-exome sequencing in two families with a suspected recessive mode of inheritance. We used the Matchmaker Exchange initiative to identify additional patients.
Here, we report six patients with microcephaly, facial dysmorphism, including exophthalmos, nevus flammeus of the glabella and joint contractures with a suspected BOS posture in five out of six patients. We identified autosomal recessive truncating mutations in the
gene.
encodes a BTB-kelch protein implicated in the cell cycle and in protein degradation by the ubiquitin-proteasome pathway. Recently, biallelic mutations in the
gene were reported in four families and associated with CS/CISS1, characterised by clinical features overlapping with our patients.
We have expanded the clinical spectrum of
autosomal recessive variants by describing a syndrome with features overlapping CS/CISS1 and BOS.
A recent English government-funded study has suggested that optometrists are not best suited to screening for diabetic retinopathy. This is surprising given the level of training of optometrists and ...their aptitude in detecting other conditions such as glaucoma and cataract. The need to screen for diabetic retinopathy is discussed. The major unresolved issue concerns the choice of screening modality, i.e. who should perform screening, when and how. A literature search is reported. Given the available evidence, to make conclusions about the relative performance of optometrists with other screeners would be inappropriate. Unresolved controversies could be addressed by new prospective studies of optometrists, and others, in screening. A pragmatic design, mirroring the current environment of care, may be important. In particular, the manner in which diabetics currently present to the health service would make screening by one modality of limited use. If thoughtfully applied, shared care concepts may achieve a broader coverage of patients with diabetics mellitus. Smaller trials investigating sub-issues, and surveys of patients and potential screeners may produce a valuable backdrop in designing appropriate studies. Issues for the development of screening schemes are considered, including the role of training, the development of protocols for care and sharing data, reimbursement and audit.
Aim
To examine the feedback given by nurse educators and clinicians on the quality of communication skills of nurses in interactions with simulated patients.
Background
The quality of communication ...in interactions between nurses and patients has a major influence on patient outcomes. To support the development of effective nursing communication in clinical practice, a good understanding of what constitutes effective communication is helpful.
Design
An exploratory design was used involving individual interviews, focus groups and written notes from participants and field notes from researchers to investigate perspectives on nurse–patient communication.
Methods
Focus groups and individual interviews were held between August 2010–September 2011 with a purposive sample of 15 nurse educators and clinicians who observed videos of interactions between nurses and simulated patients. These participants were asked to give oral feedback on the quality and content of these interactions. Verbatim transcriptions were undertaken of all data collected. All written notes and field notes were also transcribed. Thematic analysis of the data was undertaken.
Findings
Four major themes related to nurse–patient communication were derived from the educators' and clinicians' feedback: approach to patients and patient care, manner towards patients, techniques used for interacting with patients and generic aspects of communication.
Conclusion
This study has added to previous research by contributing grounded evidence from a group of nurse educators and clinicians on the aspects of communication that are relevant for effective nurse–patient interactions in clinical practice.
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