Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes

Aims/hypothesis: An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes. 
 Methods: The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1 diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value <10^{−4 were followed up in 3,750 additional patients with type 1 diabetes from seven studies.} 
 Results: The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p < 5 × 10^{−8). In the replication group, a nominally significant association (p = 0.035) was observed between albuminuria and rs1564939 in GLRA3, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic association observed at the common variants in GLRA3. The strongest replication (p = 0.026) was obtained for rs2410601 between the PSD3 and SH2D4A genes. Pathway analysis highlighted natural killer cell mediated immunity processes.} 
 Conclusions/interpretation: This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.

Obesity and kidney disease in type 1 and 2 diabetes: an analysis of the National Diabetes Audit

Background: Obesity is increasingly prevalent in many countries. Obesity is a major risk factor for the development of type 2 diabetes but its relationship with diabetic kidney disease (DKD) remains unclear. Some studies have suggested that the metabolic syndrome (including obesity) may be associated with DKD in type 1 diabetes. Aim: To investigate the association between obesity and DKD. Design: Retrospective cross-sectional study. Methods: National Diabetes Audit data were available for the 2007–08 cycle. Type 1 and 2 diabetes patients with both a valid serum creatinine and urinary albumin:creatinine ratio were included. DKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2, albuminuria or both. Logistic regression was used to analyse associations of obesity (body mass index ≥30 kg/m2) and other variables including year of birth, year of diagnosis, ethnicity and stage of kidney disease. Results: A total of 58 791 type 1 and 733 769 type 2 diabetes patients were included in the analysis. After adjustment, when compared with type 1 diabetes patients with normal renal function those with DKD were up to twice as likely to be obese. Type 2 DKD patients were also more likely to be obese. For example, type 2 diabetes patients with an eGFR <15 ml/min/1.73 m2 and normoalbuminuria, microalbuminuria or macroalbuminuria were all more likely to be obese; odds ratios (95% CI) 1.65 (1.3–2.1), 1.56 (1.28–1.92) and 1.27 (1.05–1.54), respectively. Conclusions: This study has highlighted a strong association between obesity and kidney disease in type 1 diabetes and confirmed their association in type 2 diabetes.

The influence of market deregulation on fast food consumption and body mass index:A cross-national time series analysis

Objective
To investigate the effect of fast food consumption on mean population body mass index (BMI) and explore the possible influence of market deregulation on fast food consumption and BMI.

Methods
The within-country association between fast food consumption and BMI in 25 high-income member countries of the Organisation for Economic Co-operation and Development between 1999 and 2008 was explored through multivariate panel regression models, after adjustment for per capita gross domestic product, urbanization, trade openness, lifestyle indicators and other covariates. The possible mediating effect of annual per capita intake of soft drinks, animal fats and total calories on the association between fast food consumption and BMI was also analysed. Two-stage least squares regression models were conducted, using economic freedom as an instrumental variable, to study the causal effect of fast food consumption on BMI.

Findings
After adjustment for covariates, each 1-unit increase in annual fast food transactions per capita was associated with an increase of 0.033 kg/m2 in age-standardized BMI (95% confidence interval, CI: 0.013–0.052). Only the intake of soft drinks – not animal fat or total calories – mediated the observed association (β: 0.030; 95% CI: 0.010–0.050). Economic freedom was an independent predictor of fast food consumption (β: 0.27; 95% CI: 0.16–0.37). When economic freedom was used as an instrumental variable, the association between fast food and BMI weakened but remained significant (β: 0.023; 95% CI: 0.001–0.045).

Conclusion
Fast food consumption is an independent predictor of mean BMI in high-income countries. Market deregulation policies may contribute to the obesity epidemic by facilitating the spread of fast food.

No evidence that runs of homozygosity are associated with schizophrenia in an Irish genome-wide association dataset

Runs of homozygosity (ROH), regions of the genome containing many consecutive homozygous SNPs, may represent two copies of a haplotype inherited from a common ancestor. A rare variant on this haplotype could thus be present in a homozygous and potentially recessive state. To detect rare risk variants for schizophrenia, we performed an ROH analysis in a homogeneous Irish genome wide association study (GWAS) dataset consisting of 1606 cases and 1794 controls. There was no genome-wide excess of ROH in cases compared to controls (p=0.7986). No consensus ROH at individual loci showed association with schizophrenia after genome-wide correction.

Job strain and the risk of severe asthma exacerbations: A meta-analysis of individual-participant data from 100 000 European men and women

Background: Many patients and healthcare professionals believe that work-related psychosocial stress, such as job strain, can make asthma worse, but this is not corroborated by empirical evidence. We investigated the associations between job strain and the incidence of severe asthma exacerbations in working-age European men and women. Methods: We analysed individual-level data, collected between 1985 and 2010, from 102 175 working-age men and women in 11 prospective European studies. Job strain (a combination of high demands and low control at work) was self-reported at baseline. Incident severe asthma exacerbations were ascertained from national hospitalization and death registries. Associations between job strain and asthma exacerbations were modelled using Cox regression and the study-specific findings combined using random-effects meta-analyses. Results: During a median follow-up of 10 years, 1 109 individuals experienced a severe asthma exacerbation (430 with asthma as the primary diagnostic code). In the age- and sex-adjusted analyses, job strain was associated with an increased risk of severe asthma exacerbations defined using the primary diagnostic code (hazard ratio, HR: 1.27, 95% confidence interval, CI: 1.00, 1.61). This association attenuated towards the null after adjustment for potential confounders (HR: 1.22, 95% CI: 0.96, 1.55). No association was observed in the analyses with asthma defined using any diagnostic code (HR: 1.01, 95% CI: 0.86, 1.19). Conclusions: Our findings suggest that job strain is probably not an important risk factor for severe asthma exacerbations leading to hospitalization or death.

A Posteriori Dietary Patterns Are Related to Risk of Type 2 Diabetes: Findings from a Systematic Review and Meta-Analysis

Our review and meta-analysis examined the association between a posteriori–derived dietary patterns (DPs) and risk of type 2 diabetes mellitus. MEDLINE and EMBASE were searched for articles published up to July 2012 and data were extracted by two independent reviewers. Overall, 19 cross-sectional, 12 prospective cohort, and two nested case-control studies were eligible for inclusion. Results from cross-sectional studies reported an inconsistent association between DPs and measures of insulin resistance and/or glucose abnormalities, or prevalence of type 2 diabetes. A meta-analysis was carried out on nine prospective cohort studies that had examined DPs derived by principle component/factor analysis and incidence of type 2 diabetes risk (totaling 309,430 participants and 16,644 incident cases). Multivariate-adjusted odds ratios were combined using a random-effects meta-analysis. Two broad DPs (Healthy/Prudent and Unhealthy/Western) were identified based on food factor loadings published in original studies. Pooled results indicated a 15% lower type 2 diabetes risk for those in the highest category of Healthy/Prudent pattern compared with those in the lowest category (95% CI 0.80 to 0.91; P<0.0001). Compared with the lowest category of Unhealthy/Western DP, those in the highest category had a 41% increased risk of type 2 diabetes (95% CI 1.32 to 1.52; P<0.0001). These results provide evidence that DPs are consistently associated with risk of type 2 diabetes even when other lifestyle factors are controlled for. Thus, greater adherence to a DP characterized by high intakes of fruit, vegetables, and complex carbohydrate and low intakes of refined carbohydrate, processed meat, and fried food may be one strategy that could have a positive influence on the global public health burden of type 2 diabetes.

Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States

Objective: To investigate the association between serum 25-hydroxyvitamin D concentrations (25(OH)D) and mortality in a large consortium of cohort studies paying particular attention to potential age, sex, season, and country differences.

Design: Meta-analysis of individual participant data of eight prospective cohort studies from Europe and the US.

Setting: General population.

Participants: 26 018 men and women aged 50-79 years

Main outcome measures: All-cause, cardiovascular, and cancer mortality.

Results: 25(OH)D concentrations varied strongly by season (higher in summer), country (higher in US and northern Europe) and sex (higher in men), but no consistent trend with age was observed. During follow-up, 6695 study participants died, among whom 2624 died of cardiovascular diseases and 2227 died of cancer. For each cohort and analysis, 25(OH)D quintiles were defined with cohort and subgroup specific cut-off values. Comparing bottom versus top quintiles resulted in a pooled risk ratio of 1.57 (95% CI 1.36 to 1.81) for all-cause mortality. Risk ratios for cardiovascular mortality were similar in magnitude to that for all-cause mortality in subjects both with and without a history of cardiovascular disease at baseline. With respect to cancer mortality, an association was only observed among subjects with a history of cancer (risk ratio, 1.70 (1.00 to 2.88)). Analyses using all quintiles suggest curvilinear, inverse, dose-response curves for the aforementioned relationships. No strong age, sex, season, or country specific differences were detected. Heterogeneity was low in most meta-analyses.

Conclusions: Despite levels of 25(OH)D strongly varying with country, sex, and season, the association between 25(OH)D level and all-cause and cause-specific mortality was remarkably consistent. Results from a long term randomised controlled trial addressing longevity are being awaited before vitamin D supplementation can be recommended in most individuals with low 25(OH)D levels.

Depression and mortality: Artifact of measurement and analysis?

Background: Previous research demonstrates various associations between depression, cardiovascular disease (CVD) incidence and mortality, possibly as a result of the different methodologies used to measure depression and analyse relationships. This analysis investigated the association between depression, CVD incidence (CVDI) and mortality from CVD (MCVD), smoking related conditions (MSRC), and all causes (MALL), in a sample data set, where depression was measured using items from a validated questionnaire and using items derived from the factor analysis of a larger questionnaire, and analyses were conducted based on continuous data and grouped data.

Methods: Data from the PRIME Study (N=9798 men) on depression and 10-year CVD incidence and mortality were analysed using Cox proportional hazards models.

Results: Using continuous data, both measures of depression resulted in the emergence of positive associations between depression and mortality (MCVD, MSRC, MALL). Using grouped data, however, associations between a validated measure of depression and MCVD, and between a measure of depression derived from factor analysis and all measures of mortality were lost.

Limitations: Low levels of depression, low numbers of individuals with high depression and low numbers of outcome events may limit these analyses, but levels are usual for the population studied.

Conclusions: These data demonstrate a possible association between depression and mortality but detecting this association is dependent on the measurement used and method of analysis. Different findings based on methodology present clear problems for the elucidation and determination of relationships. The differences here argue for the use of validated scales where possible and suggest against over-reduction via factor analysis and grouping.

The role of adiposity in cardiometabolic traits:a Mendelian randomization analysis

The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

The student experience in Objective Structured Clinical Examinations (OSCEs): phenomenological analysis

Background and purpose
The dominant psychometric discourse of OSCEs may lead to unexpected problems, such as a checklist-based student performance1 which under emphasises the clinical relationship with student and standardised patient (SP). Such encounters can be dehumanising for SPs2 and have implications for what students learn about relational skills through the assessment process. In this study we explore medical students’ experiences of undertaking OSCEs using a phenomenological frame.
Methodology
Interpretative phenomenological analysis is a form of qualitative methodology which has strong resonance with existentialism and focuses on the lived experience without significant reference to external political or discursive
forces.
Six 4th year undergraduate medical students from Queen’s University Belfast were recruited in December 2013. Maximum variation sampling was used. Students were interviewed by a researcher in the week prior to the
OSCE and then again in the week following the OSCE in Jan 2014. Interviews were minimally structured in order to be open to respondents, rather than adhering to a fixed topic guide, but focussed on participants’ experiences, thoughts and feelings about taking part in OSCEs. Interviews were audio-recorded and
transcribed. Students were also asked to complete a short diary entry in the days prior to the OSCEs and another immediately following. Diary entries were written, emailed or audio-recorded at student’s preference.
Results
Transcripts are currently being analysed by interpretative phenomenological analysis. Preliminary analysis has demonstrated the significance of students’ relationships within the OSCE triad (student, SP and examiner); the effect of the immediate examination environment; realism versus roleplay; students’ perceptions of the purpose of assessment; and coping mechanisms.
Full results will be available by the time of the conference.
Conclusion and Discussion
Understanding the student experience in OSCEs is a crucial step in understanding the complex construction of relationships within the OSCE triad. The focus in OSCEs is typically on standardisation and reliability, but in exploring social interactions we may refocus attention on their inherent potential for learning and effects on both students and patients.
References
1. Hodges B. Medical education and the maintenance of incompetence. Med Teach 2006;28(8):690-6
2. Johnston JL, Lundy G, McCullough M, Gormley GJ. The view from over there: reframing the OSCE through the experience of standardised patient
raters. Med Educ 2013;47(9):899-909

Alcohol and the Risk of Barrett's Esophagus: A Pooled Analysis from the International BEACON Consortium

OBJECTIVES: Results from studies examining the association between alcohol consumption and the risk of Barrett's esophagus have been inconsistent. We assessed the risk of Barrett's esophagus associated with total and beverage-specific alcohol consumption by pooling individual participant data from five case–control studies participating in the international Barrett's and Esophageal Adenocarcinoma Consortium.
METHODS: For analysis, there were 1,282 population-based controls, 1,418 controls with gastroesophageal reflux disease (GERD), and 1,169 patients with Barrett's esophagus (cases). We estimated study-specific odds ratios (ORs) and 95% confidence intervals (95% CI) using multivariable logistic regression models adjusted for age, sex, body mass index (BMI), education, smoking status, and GERD symptoms. Summary risk estimates were obtained by random-effects models. We also examined potential effect modification by sex, BMI, GERD symptoms, and cigarette smoking.
RESULTS: For comparisons with population-based controls, although there was a borderline statistically significant inverse association between any alcohol consumption and the risk of Barrett's esophagus (any vs. none, summary OR=0.77, 95% CI=0.60–1.00), risk did not decrease in a dose-response manner (Ptrend=0.72). Among alcohol types, wine was associated with a moderately reduced risk of Barrett's esophagus (any vs. none, OR=0.71, 95% CI=0.52–0.98); however, there was no consistent dose–response relationship (Ptrend=0.21). We found no association with alcohol consumption when cases were compared with GERD controls. Similar associations were observed across all strata of BMI, GERD symptoms, and cigarette smoking.
CONCLUSIONS: Consistent with findings for esophageal adenocarcinoma, we found no evidence that alcohol consumption increases the risk of Barrett's esophagus.

Genome-wide association study identifies novel loci associated with resistance to bovine tuberculosis

Tuberculosis (TB) caused by Mycobacterium bovis is a re-emerging disease of livestock that is of major economic importance worldwide, as well as being a zoonotic risk there is significant heritability for host resistance to bovine TB (bTB) in dairy cattle. To identify resistance loci for bTB, we undertook a genome-wide association study in female Holstein-Friesian cattle with 592 cases and 559 age-matched controls from case herds. Cases and controls were categorised into distinct phenotypes: skin test and lesion positive vs skin test negative on multiple occasions, respectively these animals were genotyped with the Illumina BovineHD 700K BeadChip. Genome-wide rapid association using linear and logistic mixed models and regression (GRAMMAR), regional heritability mapping (RHM) and haplotype-sharing analysis identified two novel resistance loci that attained chromosome-wise significance, protein tyrosine phosphatase receptor T (PTPRT; P=4.8 × 10 -7) and myosin IIIB (MYO3B; P=5.4 × 10 -6). We estimated that 21% of the phenotypic variance in TB resistance could be explained by all of the informative single-nucleotide polymorphisms, of which the region encompassing the PTPRT gene accounted for 6.2% of the variance and a further 3.6% was associated with a putative copy number variant in MYO3B the results from this study add to our understanding of variation in host control of infection and suggest that genetic marker-based selection for resistance to bTB has the potential to make a significant contribution to bTB control.

Fruit and vegetable consumption and muscle strength and power during adolescence: a cross-sectional analysis of the Northern Ireland Young Hearts Project 1999-2001

Objectives: To examine the association between fruit and vegetable (FV) consumption and muscle strength and power in an adolescent population. Methods: We conducted a cross-sectional analysis among 1019 boys and 998 girls, aged 12 and 15 years, who participated in The Young Hearts Project. FV consumption (excluding potatoes) was assessed by 7-d diet history. Grip strength and jump power was assessed with a dynamometer and Jump-MD meter, respectively. Associations between FV consumption and strength and power were assessed by regression modelling. Results: Boys and girls with the highest FV intakes (>237.71 g/d and >267.57 g/d, respectively, based on the highest tertile) had significantly higher jump power than those with the lowest intakes (<135.09 g/d and <147.43 g/d, respectively), after adjustment for confounding factors. Although girls with the highest FV intakes had higher grip strength than those with the lowest intakes, no significant independent associations were evident between FV intake and grip strength in boys or girls. Similar findings were observed when FV were analysed separately.Conclusions: Higher FV consumption in this group of adolescents was positively associated with muscle power. There was no independent association between higher FV consumption and muscle strength. Intervention studies are required to determine whether muscle strength and power can be improved through increased FV consumption.