Genetic and epigenetic variants in the MTHFR gene are not associated with non-Hodgkin lymphoma

The methylenetetrahydrofolate reductase (MTHFR) gene codes for the MTHFR enzyme which plays a key role in the pathway of folate and methionine metabolism. Polymorphisms of genes in this pathway affect its regulation and have been linked to lymphoma. In this study we examined whether we could detect an association between two common non-synonomous MTHFR polymorphisms, 677C>T (rs1801133) and 1298A>C (rs1801131), and susceptibility to non-Hodgkin lymphoma (NHL) in an Australian case-control cohort. We found no significant differences between genotype or allele frequencies for either polymorphisms between lymphoma cases and controls. We also explored whether epigenetic modification of MTHFR, specifically DNA methylation of a CpG island in the MTHFR promoter region, is associated with NHL using blood samples from patients. No difference in methylation levels was detected between the case and control samples suggesting that although hypermethylation of MTHFR has been reported in tumour tissues, particularly in the diffuse large B-cell lymphoma subtype of NHL, methylation of this MTHFR promoter CpG island is not a suitable epigenetic biomarker for NHL diagnosis or prognosis in peripheral blood samples. Further studies into epigenetic variants could focus on genes that are robustly associated with NHL susceptibility.

Serum bilirubin concentration is modified by UGT1A1 Haplotypes and influences risk of type-2 diabetes in the Norfolk Island Genetic Isolate

Background Located in the Pacific Ocean between Australia and New Zealand, the unique population isolate of Norfolk Island has been shown to exhibit increased prevalence of metabolic disorders (type-2 diabetes, cardiovascular disease) compared to mainland Australia. We investigated this well-established genetic isolate, utilising its unique genomic structure to increase the ability to detect related genetic markers. A pedigree-based genome-wide association study of 16 routinely collected blood-based clinical traits in 382 Norfolk Island individuals was performed. Results A striking association peak was located at chromosome 2q37.1 for both total bilirubin and direct bilirubin, with 29 SNPs reaching statistical significance (P < 1.84 × 10−7). Strong linkage disequilibrium was observed across a 200 kb region spanning the UDP-glucuronosyltransferase family, including UGT1A1, an enzyme known to metabolise bilirubin. Given the epidemiological literature suggesting negative association between CVD-risk and serum bilirubin we further explored potential associations using stepwise multivariate regression, revealing significant association between direct bilirubin concentration and type-2 diabetes risk. In the Norfolk Island cohort increased direct bilirubin was associated with a 28 % reduction in type-2 diabetes risk (OR: 0.72, 95 % CI: 0.57-0.91, P = 0.005). When adjusted for genotypic effects the overall model was validated, with the adjusted model predicting a 30 % reduction in type-2 diabetes risk with increasing direct bilirubin concentrations (OR: 0.70, 95 % CI: 0.53-0.89, P = 0.0001). Conclusions In summary, a pedigree-based GWAS of blood-based clinical traits in the Norfolk Island population has identified variants within the UDPGT family directly associated with serum bilirubin levels, which is in turn implicated with reduced risk of developing type-2 diabetes within this population.

Evaluation of a 7-gene genetic profile for athletic endurance phenotype in Ironman championship triathletes

Polygenic profiling has been proposed for elite endurance performance, using an additive model determining the proportion of optimal alleles in endurance athletes. To investigate this model’s utility for elite triathletes, we genotyped seven polymorphisms previously associated with an endurance polygenic profile (ACE Ins/Del, ACTN3 Arg577Ter, AMPD1 Gln12Ter, CKMM 1170bp/985+185bp, HFE His63Asp, GDF8 Lys153Arg and PPARGC1A Gly482Ser) in a cohort of 196 elite athletes who participated in the 2008 Kona Ironman championship triathlon. Mean performance time (PT) was not significantly different in individual marker analysis. Age, sex, and continent of origin had a significant influence on PT and were adjusted for. Only the AMPD1 endurance-optimal Gln allele was found to be significantly associated with an improvement in PT (model p=5.79 x 10-17, AMPD1 genotype p=0.01). Individual genotypes were combined into a total genotype score (TGS); TGS distribution ranged from 28.6 to 92.9, concordant with prior studies in endurance athletes (mean±SD: 60.75±12.95). TGS distribution was shifted toward higher TGS in the top 10% of athletes, though the mean TGS was not significantly different (p=0.164) and not significantly associated with PT even when adjusted for age, sex, and origin. Receiver operating characteristic curve analysis determined that TGS alone could not significantly predict athlete finishing time with discriminating sensitivity and specificity for three outcomes (less than median PT, less than mean PT, or in the top 10%), though models with the age, sex, continent of origin, and either TGS or AMPD1 genotype could. These results suggest three things: that more sophisticated genetic models may be necessary to accurately predict athlete finishing time in endurance events; that non-genetic factors such as training are hugely influential and should be included in genetic analyses to prevent confounding; and that large collaborations may be necessary to obtain sufficient sample sizes for powerful and complex analyses of endurance performance.

Next generation sequencing identifies novel CACNA1A gene mutations in Episodic Ataxia type 2

Episodic Ataxia type 2 (EA2) is a rare autosomal dominantly inherited neurological disorder characterized by recurrent disabling imbalance, vertigo and episodes of ataxia lasting minutes to hours. EA2 is caused most often by loss of function mutations of the calcium channel gene CACNA1A. In addition to EA2, mutations in CACNA1A are responsible for two other allelic disorders: familial hemiplegic migraine type1 (FHM1) and spinocerebellar ataxia type 6 (SCA6). Herein, we have utilised Next Generation Sequencing (NGS) to screen the coding sequence, exon-intron boundaries and UTRs of five genes where mutation is known to produce symptoms related to EA2, including CACNA1A. We performed this screening in a group of 31 unrelated patients with EA2 symptoms. Both novel and known mutations were detected through NGS technology, and confirmed through Sanger sequencing. Genetic testing showed in total 15 mutation bearing patients (48%), of which 9 were novel mutations (6 missense and 3 small frameshift deletion mutations) and six known mutations (4 missense and 2 nonsense).These results demonstrate the efficiency of our NGS-panel for detecting known and novel mutations for EA2 in the CACNA1A gene, also identifying a novel missense mutation in ATP1A2 which is not a normal target for EA2 screening.

Prediction of individual genetic risk to prostate cancer using a polygenic score

BACKGROUND Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction. METHODS We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls. RESULTS The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk. CONCLUSIONS Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction. Prostate 75:1467–1474, 2015. © 2015 Wiley Periodicals, Inc.

When and why threats go undetected: Impacts of event rate and shift length on threat detection accuracy during airport baggage screening

Objective: We aimed to assess the impact of task demands and individual characteristics on threat detection in baggage screeners. Background: Airport security staff work under time constraints to ensure optimal threat detection. Understanding the impact of individual characteristics and task demands on performance is vital to ensure accurate threat detection. Method: We examined threat detection in baggage screeners as a function of event rate (i.e., number of bags per minute) and time on task across 4 months. We measured performance in terms of the accuracy of detection of Fictitious Threat Items (FTIs) randomly superimposed on X-ray images of real passenger bags. Results: Analyses of the percentage of correct FTI identifications (hits) show that longer shifts with high baggage throughput result in worse threat detection. Importantly, these significant performance decrements emerge within the first 10 min of these busy screening shifts only. Conclusion: Longer shift lengths, especially when combined with high baggage throughput, increase the likelihood that threats go undetected. Application: Shorter shift rotations, although perhaps difficult to implement during busy screening periods, would ensure more consistently high vigilance in baggage screeners and, therefore, optimal threat detection and passenger safety.

Genetic analysis of structural brain connectivity using DICCCOL models of diffusion MRI in 522 twins

Genetic and environmental factors affect white matter connectivity in the normal brain, and they also influence diseases in which brain connectivity is altered. Little is known about genetic influences on brain connectivity, despite wide variations in the brain's neural pathways. Here we applied the 'DICCCOL' framework to analyze structural connectivity, in 261 twin pairs (522 participants, mean age: 21.8 y ± 2.7SD). We encoded connectivity patterns by projecting the white matter (WM) bundles of all 'DICCCOLs' as a tracemap (TM). Next we fitted an A/C/E structural equation model to estimate additive genetic (A), common environmental (C), and unique environmental/error (E) components of the observed variations in brain connectivity. We found 44 'heritable DICCCOLs' whose connectivity was genetically influenced (α2>1%); half of them showed significant heritability (α2>20%). Our analysis of genetic influences on WM structural connectivity suggests high heritability for some WM projection patterns, yielding new targets for genome-wide association studies.

Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) is a valid screening tool in chemotherapy outpatients

Purpose In the oncology population where malnutrition prevalence is high, more descriptive screening tools can provide further information to assist triaging and capture acute change. The Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) is a component of a nutritional assessment tool which could be used for descriptive nutrition screening. The purpose of this study was to conduct a secondary analysis of nutrition screening and assessment data to identify the most relevant information contributing to the PG-SGA SF to identify malnutrition risk with high sensitivity and specificity. Methods This was an observational, cross-sectional study of 300 consecutive adult patients receiving ambulatory anti-cancer treatment at an Australian tertiary hospital. Anthropometric and patient descriptive data were collected. The scored PG-SGA generated a score for nutritional risk (PG-SGA SF) and a global rating for nutrition status. Receiver operating characteristic curves (ROC) were generated to determine optimal cut-off scores for combinations of the PG-SGA SF boxes with the greatest sensitivity and specificity for predicting malnutrition according to scored PG-SGA global rating. Results The additive scores of boxes 1–3 had the highest sensitivity (90.2 %) while maintaining satisfactory specificity (67.5 %) and demonstrating high diagnostic value (AUC = 0.85, 95 % CI = 0.81–0.89). The inclusion of box 4 (PG-SGA SF) did not add further value as a screening tool (AUC = 0.85, 95 % CI = 0.80–0.89; sensitivity 80.4 %; specificity 72.3 %). Conclusions The validity of the PG-SGA SF in chemotherapy outpatients was confirmed. The present study however demonstrated that the functional capacity question (box 4) does not improve the overall discriminatory value of the PG-SGA SF.

Review of Diagnostic Screening Instruments for Alcohol and Other Drug Use and Other Psychiatric Disorders

In recent years there has been a growing recognition that many people with drug or alcohol problems are also experiencing a range of other psychiatric and psychological problems. The presence of concurrent psychiatric or psychological problems is likely to impact on the success of treatment services. These problems vary greatly, from undetected major psychiatric illnesses that meet internationally accepted diagnostic criteria such as those outlined in the Diagnostic and Statistical Manual (DSM-IV) of the American Psychiatric Association (1994), to less defined feelings of low mood and anxiety that do not meet diagnostic criteria but nevertheless impact on an individual’s sense of wellbeing and affect their quality of life. Similarly, the presence of a substance misuse problem among those suffering from a major psychiatric illness, often goes undetected. For example, the use of illicit drugs such as cannabis and amphetamine is higher among those individuals suffering from schizophrenia (Hall, 1992) and the misuse of alcohol in people suffering from schizophrenia is well documented (e.g., Gorelick et al., 1990; Searles et al., 1990; Soyka et al., 1993). High rates of alcohol misuse have also been reported in a number of groups including women presenting for treatment with a primary eating disorder (Holderness, Brooks Gunn, & Warren, 1994), individuals suffering from post-traumatic stress disorder (Seidel, Gusman and Aubueg, 1994), and those suffering from anxiety and depression. Despite considerable evidence of high levels of co-morbidity, drug and alcohol treatment agencies and mainstream psychiatric services often fail to identify and respond to concurrent psychiatric or drug and alcohol problems, respectively. The original review was conducted as a first step in providing clinicians with information on screening and diagnostic instruments that may be used to assess previously unidentified co-morbidity. The current revision was conducted to extend the original review by updating psychometric findings on measures in the original review, and incorporating other frequently used measures that were not previously included. The current revision has included information regarding special populations, specifically Indigenous Australians, older persons and adolescents. The objectives were to: ● update the original review of AOD and psychiatric screening/diagnostic instruments, ● recommend when these instruments should be used, by whom and how they should be interpreted, ● identify limitations and provide recommendations for further research, ● refer the reader to pertinent Internet sites for further information and/or purchasing of assessment instruments.

Screening for partner violence among family mediation clients: Differentiating types of abuse

Family mediation is mandated in Australia for couples in dispute over separation and parenting as a first step in dispute resolution, except where there is a history of intimate partner violence. However, validation of effective well-differentiated partner violence screening instruments suitable for mediation settings is at an early phase of development. This study contributes to calls for better violence screening instruments in the mediation context to detect a differentiated range of abusive behaviors by examining the reliability and validity of both established scales, and newly developed scales that measured intimate partner violence by partner and by self. The study also aimed to examine relationships between types of abuse, and between gender and types of abuse. A third aim was to examine associations between types of abuse and other relationship indicators such as acrimony and parenting alliance. The data reported here are part of a larger mixed method, naturalistic longitudinal study of clients attending nine family mediation centers in Victoria, Australia. The current analyses on baseline cross-sectional screening data confirmed the reliability of three subscales of the Conflict Tactics Scale (CTS2), and the reliability and validity of three new scales measuring intimidation, controlling and jealous behavior, and financial control. Most clients disclosed a history of at least one type of violence by partner: 95% reported psychological aggression, 72% controlling and jealous behavior, 50% financial control, and 35% physical assault. Higher rates of abuse perpetration were reported by partner versus by self, and gender differences were identified. There were strong associations between certain patterns of psychologically abusive behavior and both acrimony and parenting alliance. The implications for family mediation services and future research are discussed.