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1.
Pharmacogenet Genomics ; 29(9): 207-215, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31568131

RESUMO

OBJECTIVES: The MinION nanopore sequencing device opens the opportunity to cost-effective and point-of-care DNA sequencing. As a proof of principle, we developed a multiplex assay targeting pharmacogenetic variants related to clopidogrel and warfarin, the two commonly used drugs that show response variability due to genetic polymorphisms. METHODS: Six reference and 78 clinical DNA samples were amplified by PCR to generate 15 amplicons targeting 27 key variants. These products were then barcoded to enable sample multiplexing in one sequencing run. Four variant calling tools (marginCaller, VarScan 2, nanopolish, Clairvoyante) were used to compare genotyping accuracy. RESULTS: In our cohort, 81 out of 84 samples were successfully sequenced and genotyped. Using nanopolish as the variant calling tool achieved accuracy >95% for all except two variants. A known single base deletion (CYP2C9*6) was successfully detected. CONCLUSION: While minor misgenotyping issues exist, this work demonstrates that drug-specific or broad pharmacogenetic screening assays using small PCR amplicons are possible on the MinION sequencing device.

2.
Pharmacogenomics ; 20(14): 1033-1047, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31559921

RESUMO

Aim: Long read sequencing offers the promise of overcoming some of the challenges in accurate genotyping of complex genes, along with the advantage of straightforward variant phasing. We have established methods for sequencing and haplotyping of the whole CYP2D6 gene using nanopore sequencing. Materials and methods: 32 samples covering various haplotypes including gene duplication were sequenced on the GridION platform. Results: Haplotypes of 52 alleles matched accurately to known star (*) allele subvariants, with the remaining 12 being assigned as new alleles, or new subvariants of known alleles. Duplicated alleles could be detected by analyzing the allelic balance. Conclusion: Nanopore sequencing of CYP2D6 offers a high throughput method for accurate haplotyping, detection of new variants and determination of duplicated alleles.

3.
Clin Pharmacol Ther ; 2019 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-31544239

RESUMO

The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human CYP2D6 gene locus. CYP2D6 genetic variation impacts the metabolism of numerous drugs and thus can impact drug efficacy and safety. This GeneReview provides a comprehensive overview and summary of CYP2D6 genetic variation and describes how the information provided by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

4.
Sci Rep ; 9(1): 12108, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31431677

RESUMO

Natriuretic Peptides (NP) are important in maintaining normal cardiac and metabolic status and have been used to predict cardiovascular events. Whether plasma concentrations of NP products within the normal range reflect cardio-metabolic health is unknown. Plasma NTproANP, NTproBNP and NTproCNP and their bioactive counterparts were measured in a random sample of 348 community dwellers aged 49-51 yr without heart disease and associations sought with established vascular risk factors, echocardiographic indices and a genetic variant previously linked with BNP. Stratified by sex, each of ten vascular risk factors were positively associated with NTproCNP whereas associations with NTproBNP and NTproANP were all negative. In both sexes, higher plasma NTproCNP was associated with higher arterial elastance, lower LV stroke volume and lower LV end diastolic volume. Exactly opposite associations were found with plasma NTproBNP or NTproANP. Sex specific differences were identified: positive association of NTproBNP with LV end systolic volume and the negative association with LV elastance were found only in males. The genetic variant rs198358 was independently associated with NTproBNP but not with NTproANP. In conclusion, higher NTproCNP is likely to be an adaptive response to impaired LV relaxation whereas genetic factors likely contribute to higher NTproBNP and improved cardio-metabolic health at midlife.

5.
Sci Rep ; 9(1): 10128, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300667

RESUMO

It has been widely hypothesized that both diet and the microbiome play a role in the regulation of attention-deficit/hyperactivity disorder (ADHD) behaviour. However, there has been very limited scientific investigation into the potential biological connection. We performed a 10-week pilot study investigating the effects of a broad spectrum micronutrient administration on faecal microbiome content, using 16S rRNA gene sequencing. The study consisted of 17 children (seven in the placebo and ten in the treatment group) between the ages of seven and 12 years, who were diagnosed with ADHD. We found that micronutrient treatment did not drive large-scale changes in composition or structure of the microbiome. However, observed OTUs significantly increased in the treatment group, and showed no mean change in the placebo group. The differential abundance and relative frequency of Actinobacteria significantly decreased post- micronutrient treatment, and this was largely attributed to species from the genus Bifidobacterium. This was compensated by an increase in the relative frequency of species from the genus Collinsella. Further research is required to establish the role that Bifidobacterium contribute towards neuropsychiatric disorders; however, these findings suggest that micronutrient administration could be used as a safe, therapeutic method to modulate Bifidobacterium abundance, which could have potential implications for modulating and regulating ADHD behaviour. Our pilot study provides an initial observation into this area of research, and highlights an interesting avenue for further investigation in a larger cohort. Furthermore, these novel results provide a basis for future research on the biological connection between ADHD, diet and the microbiome.

6.
BMJ Open ; 9(5): e025253, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-31061024

RESUMO

OBJECTIVES: In takotsubo syndrome, QTc prolongation is a measure of risk of potentially fatal arrhythmia. It is not known how this risk, or derangement of other markers, differs across the echo variants of takotsubo syndrome. Therefore, we sought to explore whether apical takotsubo syndrome differs from the variants of the syndrome in more ways than just regional wall motion pattern. As the region of affected myocardium is usually larger, we hypothesised that patients with the classic apical ballooning form of takotsubo syndrome would have more severe derangement of their markers. DESIGN: Observational study of patients gathered from a prospective database (2010-2018) and by retrospective review (2006-2009). SETTING: The sole tertiary hospital from a New Zealand region in which case clusters of takotsubo syndrome were precipitated by large earthquakes in 2010, 2011 and 2016. PARTICIPANTS: A total of 222 patients who met a modified version of the Mayo criteria for takotsubo syndrome were included. All patients had digitally archived echocardiograms that were over-read by a second echocardiologist blinded to the clinical report. PRIMARY OUTCOME MEASURES: Ejection fraction, peak troponin and QTc interval. RESULTS: Patients with the apical form were older (p=0.011), had a lower initial left ventricular ejection fraction (35% vs 44%, p<0.0001) and a higher peak high-sensitivity troponin I (hsTnI) (p=0.01) than those with variant forms. There was no difference in the electrical abnormalities between the variants (QTc interval, heart rate, PR interval, QRS duration or T-wave axis). There was also no correlation between any of peak hsTnI, peak QTc and ejection fraction. QTc interval increased on day 2 and peaked on day 3 before falling steeply (p<0.0001). CONCLUSIONS: The variants of takotsubo syndrome differ in more ways than just their echo pattern but do not differ in their electrical abnormalities. There is a dissociation between the structural and electrical abnormalities. QTc peaks on day 3 and then falls steeply.

7.
Physiol Genomics ; 51(2): 43-50, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30576260

RESUMO

Valproic acid (VPA) and lithium are widely used in the treatment of bipolar disorder. However, the underlying mechanism of action of these drugs is not clearly understood. We used RNA-Seq analysis to examine the global profile of gene expression in a rat serotonergic cell line (RN46A) after exposure to these two mood stabilizer drugs. Numerous genes were differentially regulated in response to VPA (log2 fold change ≥ 1.0; i.e., odds ratio of ≥2, at false discovery rate <5%), but only two genes ( Dynlrb2 and Cdyl2) showed significant differential regulation after exposure of the cells to lithium, with the same analysis criteria. Both of these genes were also regulated by VPA. Many of the differentially expressed genes had functions of potential relevance to mood disorders or their treatment, such as several serpin family genes (including neuroserpin), Nts (neurotensin), Maob (monoamine oxidase B), and Ap2b1, which is important for synaptic vesicle function. Pathway analysis revealed significant enrichment of Gene Ontology terms such as extracellular matrix remodeling, cell adhesion, and chemotaxis. This study in a cell line derived from the raphe nucleus has identified a range of genes and pathways that provide novel insights into potential therapeutic actions of the commonly used mood stabilizer drugs.

8.
Clin Exp Allergy ; 49(2): 142-154, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30537422

RESUMO

Angioedema is a rare adverse effect of the commonly used angiotensin-converting enzyme inhibitors (ACEi) and is reported to occur with a prevalence of 0.1%-0.7%. Although most ACEi-induced angioedema (ACEi-A) cases are mild, severe cases requiring intensive care and even resulting in death have been reported in the literature. The mechanisms underlying ACEi-A are not yet fully understood, but bradykinin and/or substance P accumulation resulting from inhibition of ACE is believed to play a crucial role. ACEi-A occurs at variable frequencies across different racial groups, suggesting a genetic association with the development of ACEi-A. To date, one genome-wide association study and several candidate gene studies have been published on the association of genetic variation with ACEi-A. Genetic associations reported have been attributed to several distinct mechanisms: (a) genes coding for alternative enzymes responsible for the degradation of bradykinin and/or substance P in the diminution of ACE activity (b) ACE gene function, (c) bradykinin receptor genes, (d) genes implicated in immune and inflammation regulation and (e) genes in the fibrinolytic and coagulation pathway. Despite several plausible genetic associations, there are currently no genetic variants with sufficient effect to be clinically useful. The low incidence of ACEi-A suggests that a combination of genomic approaches with the capability to detect potentially important variants might be required to shed light on the mechanism of this adverse reaction. Additionally, many non-genetic risk factors associated with ACEi-A suggest the potential contribution of epigenetic dysregulation.

9.
Artigo em Inglês | MEDLINE | ID: mdl-30217770

RESUMO

BACKGROUND: Intent-to-treat analyses from a randomized controlled trial showed significant between-group differences favouring micronutrient treatment on the Clinical Global Impression-Improvement, but no group differences on clinician, parent and teacher ratings of overall ADHD symptoms. There was an advantage of micronutrients over placebo in improving overall function, emotional regulation, aggression, and reducing impairment as well as improving inattention based on clinician but not parent observation. No group differences were observed on hyperactive-impulsive symptoms. We investigated predictors of response defined by pre-treatment variables. METHOD: We conducted analyses of data from a clinical trial of children (7-12 years) with ADHD, whereby participants were randomized to receive micronutrients or placebo for 10 weeks followed by a 10 week open-label (OL) phase. We included only children who had been exposed to micronutrients for a full 10 week period and demonstrated satisfactory adherence, either in RCT phase (n = 40) or OL phase (those who received placebo during RCT phase; n = 31). Seven outcomes were examined: change in ADHD symptoms (clinician/parent), ADHD responder, overall responder, change in mood, change in functioning, and change in aggression. Demographic, developmental variables, current clinical and physical characteristics, MTHFR genotype at two common variants, and pre-treatment serum/plasma levels (vitamin D, B12, folate, zinc, copper, iron, ferritin, potassium, calcium, magnesium, and homocysteine) were all considered as putative predictors. RESULTS: Substantial nutrient deficiencies pre-treatment were observed only for vitamin D (13%) and copper (15%), otherwise most children entered the trial with nutrient levels falling within expected ranges. Regression analyses showed varying predictors across outcomes with no one predictor being consistently identified across different variables. Lower pre-treatment folate and B12 levels, being female, greater severity of symptoms and co-occurring disorders pre-treatment, more pregnancy complications and fewer birth problems were identified as possible predictors of greater improvement for some but not all outcome measures although predictive values were weak. Lower IQ and higher BMI predicted greater improvement in aggression. CONCLUSIONS: This study replicates Rucklidge et al. (2014b) showing the limited value of using serum nutrient levels to predict treatment response although we cannot rule out that other non-assayed nutrient levels may be more valuable. Additionally, no specific demographic or clinical characteristics, including MTHFR genetic status, were identified that would preclude children with ADHD from trying this treatment approach.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/terapia , Suplementos Nutricionais , Micronutrientes/uso terapêutico , Vitaminas/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/sangue , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Biomarcadores/sangue , Índice de Massa Corporal , Criança , Feminino , Humanos , Inteligência , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Transtornos Nutricionais/sangue , Transtornos Nutricionais/diagnóstico , Transtornos Nutricionais/genética , Transtornos Nutricionais/terapia , Polimorfismo de Nucleotídeo Único , Prognóstico , Índice de Gravidade de Doença
10.
Nat Neurosci ; 21(12): 1656-1669, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30482948

RESUMO

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10-13) and African ancestries (rs2066702; P = 2.2 × 10-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

11.
Artigo em Inglês | MEDLINE | ID: mdl-30345660

RESUMO

BACKGROUND: Isolated cardiac arrhythmia due to a variant in CACNA1C is of recent knowledge. Most reports have been of singleton cases or of quite small families, and estimates of penetrance and expressivity have been difficult to obtain. We here describe a large pedigree, from which such estimates have been calculated. METHODS: We studied a five-generation family, in which a CACNA1C variant c.2573G>A p.Arg858His co-segregates with syncope and cardiac arrest, documenting electrocardiographic data and cardiac symptomatology. The reported patients/families from the literature with CACNA1C gene variants were reviewed, and genotype-phenotype correlations are drawn. RESULTS: The range of phenotype in the studied family is wide, from no apparent effect, through an asymptomatic QT interval prolongation on electrocardiography, to episodes of presyncope and syncope, ventricular fibrillation, and sudden death. QT prolongation showed inconsistent correlation with functional cardiology. Based upon analysis of 28 heterozygous family members, estimates of penetrance and expressivity are derived. CONCLUSIONS: These estimates of penetrance and expressivity, for this specific variant, may be useful in clinical practice. Review of the literature indicates that individual CACNA1C variants have their own particular genotype-phenotype correlations. We suggest that, at least in respect of the particular variant reported here, "arrhythmogenic channelopathy" may be a more fitting nomenclature than long QT syndrome.

12.
Contemp Clin Trials ; 74: 61-69, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30287268

RESUMO

BACKGROUND: Genetic factors contribute to anorexia nervosa (AN); and the first genome-wide significant locus has been identified. We describe methods and procedures for the Anorexia Nervosa Genetics Initiative (ANGI), an international collaboration designed to rapidly recruit 13,000 individuals with AN and ancestrally matched controls. We present sample characteristics and the utility of an online eating disorder diagnostic questionnaire suitable for large-scale genetic and population research. METHODS: ANGI recruited from the United States (US), Australia/New Zealand (ANZ), Sweden (SE), and Denmark (DK). Recruitment was via national registers (SE, DK); treatment centers (US, ANZ, SE, DK); and social and traditional media (US, ANZ, SE). All cases had a lifetime AN diagnosis based on DSM-IV or ICD-10 criteria (excluding amenorrhea). Recruited controls had no lifetime history of disordered eating behaviors. To assess the positive and negative predictive validity of the online eating disorder questionnaire (ED100K-v1), 109 women also completed the Structured Clinical Interview for DSM-IV (SCID), Module H. RESULTS: Blood samples and clinical information were collected from 13,363 individuals with lifetime AN and from controls. Online diagnostic phenotyping was effective and efficient; the validity of the questionnaire was acceptable. CONCLUSIONS: Our multi-pronged recruitment approach was highly effective for rapid recruitment and can be used as a model for efforts by other groups. High online presence of individuals with AN rendered the Internet/social media a remarkably effective recruitment tool in some countries. ANGI has substantially augmented Psychiatric Genomics Consortium AN sample collection. ANGI is a registered clinical trial: clinicaltrials.govNCT01916538; https://clinicaltrials.gov/ct2/show/NCT01916538?cond=Anorexia+Nervosa&draw=1&rank=3.

13.
Epigenomics ; 10(9): 1201-1214, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30182732

RESUMO

Exposure times and dosage required for dietary components to modify DNA methylation patterns are largely unknown. AIM: This exploratory research represents the first genome-wide analysis of DNA methylation changes during a randomized-controlled-trial (RCT) for dietary supplementation with broad spectrum vitamins, minerals and amino acids in humans. METHODS: Genome-wide changes in methylation from paired, peripheral blood samples were assessed using the Infinium Methylation EPIC 850 K array. RESULTS: Methylation increased at 84% of the most significant differentially methylated CpGs; however, none showed significance after adjustment for genome-wide testing. CONCLUSION: Micronutrient supplementation is unlikely to have a substantial biological effect on DNA methylation over 10 weeks; however, the trend toward hypermethylation that we observed is likely to become more marked with longer exposure periods.

14.
BMJ Open ; 8(8): e025212, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30082371

RESUMO

Testicular cancer (TC) is by far the most common cancer to affect young men; however, the exposures that cause this disease are still poorly understood. Our own research has shown that Maori men have the highest rates of this disease in New Zealand-a puzzling observation, since internationally TC is most commonly a disease of men of European ancestry. These trends provide us with a unique opportunity: to learn more about the currently unknown exposures that cause TC, and to explain why Maori have the highest rates of this disease in New Zealand. Using epidemiology and genetics, our experienced research team will conduct a nationwide study which aims to answer these internationally important questions. AIM OF STUDY: The overall aim of the current national case-control study is to identify the key exposures in the development of TC in New Zealand, and explore which factors might explain the difference in the incidence of TC between Maori and non-Maori. METHODS AND ANALYSIS: Outside of our own investigations into cryptorchidism, we still do not know which exposures are driving the significant incidence disparity between ethnic groups in NZ. The aim of the proposed research is to use a population-based case-control study to identify the key exposures in the development of TC in New Zealand. We will recruit 410 TC cases and 410 controls, and collect (1) environmental exposure data, via interview and (2) genetic information, via genome-wide genotyping. ETHICS AND DISSEMINATION: Ethical approval for this study was sought and received from the New Zealand Ministry of Health's Health and Disability Ethics Committee (reference # 17/NTA/248). Following a careful data interpretation process, we will disseminate the findings of this study to a wide and varied audience ranging from general academia, community groups and clinical settings, as well as to the participants themselves.

16.
Leuk Lymphoma ; : 1-6, 2018 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-29741432

RESUMO

Imatinib has been successful in the management of chronic myeloid leukemia (CML) but some patients experience adverse reactions or develop resistance to its use. The roles of some polymorphisms in genes encoding enzymes critical for the biotransformation of imatinib have been previously examined. This study, hence, evaluated some other unstudied functionally significant polymorphisms in CYP1A2, CYP2C8, CYP2C9, and CYP3A5. Trough imatinib blood levels and genotypes were determined in 42 CML patients by an HPLC-UV technique and a Sequenom iPLEX assay, respectively. Statistical analysis of the influence of genetic polymorphisms on standardized trough level detected no significant relationship. However, higher trough levels were observed in two homozygous carriers of CYP2C8*2 while diminished imatinib levels were seen in two homozygous carriers of CYP3A5*7. The study findings suggest that polymorphisms in drug metabolizing enzymes may be significant for imatinib therapy only in instances where all copies of the relevant studied genes are functionally impaired.

17.
Front Genet ; 9: 152, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29760718

RESUMO

The human leukocyte antigen (HLA) system encodes the human major histocompatibility complex (MHC). HLA-B is the most polymorphic gene in the MHC class I region and many HLA-B alleles have been associated with adverse drug reactions (ADRs) and disease susceptibility. The frequency of such HLA-B alleles varies by ethnicity, and therefore it is important to understand the prevalence of such alleles in different population groups. Research into HLA involvement in ADRs would be facilitated by improved methods for genotyping key HLA-B alleles. Here, we describe an approach to HLA-B typing using next generation sequencing (NGS) on the MinION™ nanopore sequencer, combined with data analysis with the SeqNext-HLA software package. The nanopore sequencer offers the advantages of long-read capability and single molecule reads, which can facilitate effective haplotyping. We developed this method using reference samples as well as individuals of New Zealand Maori or Pacific Island descent, because HLA-B diversity in these populations is not well understood. We demonstrate here that nanopore sequencing of barcoded, pooled, 943 bp polymerase chain reaction (PCR) amplicons of 49 DNA samples generated ample read depth for all samples. HLA-B alleles were assigned to all samples at high-resolution with very little ambiguity. Our method is a scaleable and efficient approach for genotyping HLA-B and potentially any other HLA locus. Finally, we report our findings on HLA-B genotypes of this cohort, which adds to our understanding of HLA-B allele frequencies among Maori and Pacific Island people.

18.
Inflamm Bowel Dis ; 24(12): 2606-2612, 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-29788244

RESUMO

Background: Up to 20% of patients with inflammatory bowel disease (IBD) who are refractory to thiopurine therapy preferentially produce 6-methylmercaptopurine (6-MMP) at the expense of 6-thioguanine nucleotides (6-TGN), resulting in a high 6-MMP:6-TGN ratio (>20). The objective of this study was to evaluate whether genetic variability in guanine monophosphate synthetase (GMPS) contributes to preferential 6-MMP metabolizer phenotype. Methods: Exome sequencing was performed in a cohort of IBD patients with 6-MMP:6-TGN ratios of >100 to identify nonsynonymous single nucleotide polymorphisms (nsSNPs). In vitro assays were performed to measure GMPS activity associated with these nsSNPs. Frequency of the nsSNPs was measured in a cohort of 530 Caucasian IBD patients. Results: Two nsSNPs in GMPS (rs747629729, rs61750370) were detected in 11 patients with very high 6-MMP:6-TGN ratios. The 2 nsSNPs were predicted to be damaging by in silico analysis. In vitro assays demonstrated that both nsSNPs resulted in a significant reduction in GMPS activity (P < 0.05). The SNP rs61750370 was significantly associated with 6-MMP:6-TGN ratios ≥100 (odds ratio, 5.64; 95% confidence interval, 1.01-25.12; P < 0.031) in a subset of 264 Caucasian IBD patients. Conclusions: The GMPS SNP rs61750370 may be a reliable risk factor for extreme 6MMP preferential metabolism.

19.
Sci Rep ; 8(1): 7548, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29765130

RESUMO

The pathophysiology of stress cardiomyopathy (SCM), also known as takotsubo syndrome, is poorly understood. SCM usually occurs sporadically, often in association with a stressful event, but clusters of cases are reported after major natural disasters. There is some evidence that this is a familial condition. We have examined three possible models for an underlying genetic predisposition to SCM. Our primary study cohort consists of 28 women who suffered SCM as a result of two devastating earthquakes that struck the city of Christchurch, New Zealand, in 2010 and 2011. To seek possible underlying genetic factors we carried out exome analysis, genotyping array analysis, and array comparative genomic hybridization on these subjects. The most striking finding was the observation of a markedly elevated rate of rare, heterogeneous copy number variants (CNV) of uncertain clinical significance (in 12/28 subjects). Several of these CNVs impacted on genes of cardiac relevance including RBFOX1, GPC5, KCNRG, CHODL, and GPBP1L1. There is no physical overlap between the CNVs, and the genes they impact do not appear to be functionally related. The recognition that SCM predisposition may be associated with a high rate of rare CNVs offers a novel perspective on this enigmatic condition.

20.
Nutr Neurosci ; 21(9): 602-613, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28553986

RESUMO

Many aspects of human development and disease are influenced by the interaction between genetic and environmental factors. Understanding how our genes respond to the environment is central to managing health and disease, and is one of the major contemporary challenges in human genetics. Various epigenetic processes affect chromosome structure and accessibility of deoxyribonucleic acid (DNA) to the enzymatic machinery that leads to expression of genes. One important epigenetic mechanism that appears to underlie the interaction between environmental factors, including diet, and our genome, is chemical modification of the DNA. The best understood of these modifications is methylation of cytosine residues in DNA. It is now recognized that the pattern of methylated cytosines throughout our genomes (the 'methylome') can change during development and in response to environmental cues, often with profound effects on gene expression. Many dietary constituents may indirectly influence genomic pathways that methylate DNA, and there is evidence for biochemical links between nutritional quality and mental health. Deficiency of both macro- and micronutrients has been associated with increased behavioural problems, and nutritional supplementation has proven efficacious in treatment of certain neuropsychiatric disorders. In this review we examine evidence from the fields of nutrition, developmental biology, and mental health that supports dietary impacts on epigenetic processes, particularly DNA methylation. We then consider whether such processes could underlie the demonstrated efficacy of dietary supplementation in treatment of mental disorders, and whether targeted manipulation of DNA methylation patterns using controlled dietary supplementation may be of wider clinical value.

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