K Stevens

A genome-wide association study identifies protein quantitative trait loci (pQTLs)

There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts – cis effects, and elsewhere in the genome – trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8×10−57), CCL4L1 (p = 3.9×10−21), IL18 (p = 6.8×10−13), LPA (p = 4.4×10−10), GGT1 (p = 1.5×10−7), SHBG (p = 3.1×10−7), CRP (p = 6.4×10−6) and IL1RN (p = 7.3×10−6) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8×10−40), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways.

Epidemiology of balance and dizziness in a national population: findings from the English Longitudinal Study of Ageing

OBJECTIVE to identify socio-economic, behavioural and disease status risks for impaired balance or self-reported dizziness in older people from a large population-based study. METHODS data were from the English Longitudinal Study of Ageing (ELSA), for 2,925 participants, aged 65+. Multivariate models were used to assess the associations between balance and dizziness and disease status, health behaviours, grip strength and socio-economic markers. RESULTS there were 21.5% (n = 619) participants with impaired balance and 11.1% (n = 375) reported dizziness. Impaired balance was statistically significantly associated with age, diabetes (OR = 1.53), arthritis (OR = 1.33), eyesight (OR = 1.94) and grip strength. The wealthiest 20% of participants were less likely to have impaired balance than the poorest 20% (OR = 0.46). Dizziness problems were not associated with age, gender or wealth, but were significantly associated with an abnormal heart rhythm (OR = 1.85), hearing (OR = 1.81), eyesight (OR = 1.72) and grip strength. CONCLUSION the epidemiology of impaired balance differs from that of dizziness, and risk assessment approaches to prevent falls may need to elicit information on different problem-specific factors. Impaired balance test performance in older people may be added to the many outcomes showing strong socio-economic gradients.

A common variant of the interleukin 6 receptor (IL-6r) gene increases IL-6r and IL-6 levels, without other inflammatory effects

Interleukin-6 (IL-6) is a key inflammatory cytokine, signalling to most tissues by binding to a soluble IL-6 receptor (sIL-6r), making a complex with gp130. We used 1273 subjects (mean age 68 years) from the InCHIANTI Italian cohort to study common variation in the IL-6r locus and associations with interleukin 6 receptor (IL-6r), IL-6, gp130 and a battery of inflammatory markers. The rs4537545 single nucleotide polymorphism (SNP) tags the functional non-synonymous Asp358Ala variant (rs8192284) in IL-6r (r2=0.89, n=343). Individuals homozygous for the rs4537545 SNP minor allele (frequency 40%) had a doubling of IL-6r levels (132.48 pg/ml, 95% CI 125.13–140.27) compared to the common allele homozygous group (68.31 pg/ml, 95% CI 65.35–71.41): in per allele regression models, the rs4537545 SNP accounted for 20% of the variance in sIL-6r, with P=5.1 × 10−62. The minor allele of rs4537545 was also associated with higher circulating IL-6 levels (P=1.9 × 10−4). There was no association of this variant with serum levels of gp130 or with any of the studied pro- and anti-inflammatory markers. A common variant of the IL-6r gene results in major changes in IL-6r and IL-6 serum levels, but with no apparent effect on gp130 levels or on inflammatory status in the general population.

Common genetic variation in the gene encoding interleukin-1-receptor antagonist (IL-1RA) is associated with altered circulating IL-1RA levels.

Interleukin-1-receptor antagonist (IL-1RA) modulates the biological activity of the proinflammatory cytokine interleukin-1 (IL-1) and could play an important role in the pathophysiology of inflammatory and metabolic traits. We genotyped seven single nucleotide polymorphisms (SNPs) that capture a large proportion of common genetic variation in the IL-1RN gene in 1256 participants from the Invecchiare in Chianti study. We identified five SNPs associated with circulating IL-1RA levels with varying degrees of significance (P-value range=0.016–4.9 × 10−5). We showed that this association is likely to be driven by one haplotype, most strongly tagged by rs4251961. This variant is only in weak linkage disequilibrium (r2=0.25) with a previously reported variable number of tandem repeats polymorphism (VNTR) in intron-2 although a second variant, rs579543, that tags the VNTR (r2=0.91), may also be independently associated with IL-1RA levels (P=0.03). We found suggestive evidence that the C allele at rs4251961 that lowers IL-1RA levels is associated with an increased IL-1β (P=0.03) level and may also be associated with interferon -γ (P=0.03), α-2 macroglobulin (P=0.008) and adiponectin (P=0.007) serum levels. In conclusion, common variation across the IL-1RN gene is strongly associated with IL-1RA levels.

Reductions in disability prevalence among the highest income groups of older Brazilians.

OBJECTIVES We sought to identify the income-disability prevalence relationship among older Brazilians. METHODS Data were from 63,985 individuals 60 years and older from the 1998 and 2003 Brazilian National Household Surveys. Generalized additive logistic models with cubic regression splines were used to estimate the disability-income relationships. RESULTS There was a strong linear relationship between increased income and reduced disability prevalence for most of the income distribution. Benefits were still present above the 90th percentile of income but were more modest. Because incomes among the wealthiest few are disproportionately large, odds ratios of disability nevertheless showed marked improvements, even across the very highest income groups. CONCLUSIONS Among older Brazilians, reduced disability is associated with higher income, and these associations are present even above the 90th percentile of income. In addition to understanding mechanisms of disability reduction among impoverished individuals, work is needed to understand these mechanisms in middle- and high-income groups.

Epistaxis 2016: national audit of management

BACKGROUND Epistaxis is a common condition that can be associated with significant morbidity, and it places a considerable burden on our healthcare system. This national audit of management sought to assess current practice against newly created consensus recommendations and to expand our current evidence base. METHODS The management of epistaxis patients who met the inclusion criteria, at 113 registered sites across the UK, was compared with audit standards during a 30-day window. Data were further utilised for explorative analysis. RESULTS Data for 1826 cases were uploaded to the database, representing 94 per cent of all cases that met the inclusion criteria at participating sites. Sixty-two per cent of patients were successfully treated by ENT clinicians within 24 hours. The 30-day recurrent presentation rate across the dataset was 13.9 per cent. Significant event analysis revealed an all-cause 30-day mortality rate of 3.4 per cent. CONCLUSION Audit findings demonstrate a varying alignment with consensus guidance, with explorative analysis countering some previously well-established tenets of management.

Bayesian Wavelet Shrinkage of the Haar-Fisz Transformed Wavelet Periodogram.

It is increasingly being realised that many real world time series are not stationary and exhibit evolving second-order autocovariance or spectral structure. This article introduces a Bayesian approach for modelling the evolving wavelet spectrum of a locally stationary wavelet time series. Our new method works by combining the advantages of a Haar-Fisz transformed spectrum with a simple, but powerful, Bayesian wavelet shrinkage method. Our new method produces excellent and stable spectral estimates and this is demonstrated via simulated data and on differenced infant electrocardiogram data. A major additional benefit of the Bayesian paradigm is that we obtain rigorous and useful credible intervals of the evolving spectral structure. We show how the Bayesian credible intervals provide extra insight into the infant electrocardiogram data.

Assessment of the transmural unipolar electrogram morphology change radius during contact force-guided pulmonary vein isolation using the VISITAG™ Module and CARTOREPLAY™

Aims To investigate the radius of transmural (TM) ablation effect at the left atrial posterior wall (LAPW) during contact force (CF)-guided pulmonary vein isolation (PVI), using pure R unipolar electrogram (UE) morphology change – a histologically validated marker of radiofrequency (RF)-induced TM atrial ablation. Methods Following PVI in 24 consecutive patients (30W, continuous RF), VISITAG™ Module and CARTOREPLAY™ (Biosense Webster Inc.) RF and UE data at left and right-sided LAPW annotated sites 1 and 2 were analysed. Results Acutely durable PVI without spontaneous / dormant recovery was achieved following 15s and 10-11s RF, at sites 1 and 2, respectively (p<0.0001). At site 1, RS UE morphology was noted pre-ablation, with RF-induced pure R UE morphology change in 47/48 (98%). Left and right-sided second RF site annotation was at 5.8mm and 5.2mm from site 1 respectively (p=0.64), yet immediate pure R UE morphology was noted in 35/48 (73%). For second-annotated sites, 30 demonstrated inter-ablation site transition time ≤17ms; pure R UE morphology was noted at annotation onset in 22/30 (73%), with overall median time to pure R morphology change significantly shorter than at site 1 – 0.0s, versus 4.1s and 5.3s, for left and right-sided first-annotated LAPW sites, respectively (p<0.0001). Conclusion When the first and second-annotated LAPW RF sites were within 7mm, 73% second-annotated sites demonstrated immediate pure R UE morphology change. These analyses support a paradigm of shorter RF duration at immediately adjacent sites during continuous RF application, and may usefully inform the further development of “tailored” approaches towards CF-guided PVI. What’s known? The VISITAG™ Module and CARTOREPLAY™ permit investigations into the tissue effects of RF energy delivery in vivo, via objective annotation methodology and retrospective evaluation of histologically validated unipolar electrogram (UE) criteria for transmural (TM) atrial ablation. Greater RF energy effect is seen at left compared to right-sided first-annotated left atrial posterior wall (LAPW) sites during pulmonary vein isolation (PVI). What’s new? Following ∼15s RF delivery at first-annotated LAPW sites and aiming for ≤6mm inter-ablation site distance during continuous RF delivery, 73% second-annotated sites demonstrated immediate TM UE morphology change. At second-annotated sites, ∼10s RF resulted in acutely durable PVI in all. Greater left-sided RF energy effect was observed, not explained by differences in RF duration, mean CF or catheter position stability. The radius of TM RF effect may be determined at the LAPW following CF and VISITAG™ Module-guided PVI.

Transmural unipolar electrogram morphology is achieved within 7s at the posterior left atrial wall during pulmonary vein isolation: VISITAG™ Module-based lesion assessment during radiofrequency ablation

Aims To assess the occurrence of a histologically validated measure of transmural (TM) atrial ablation – pure R unipolar electrogram (UE) morphology change – at first-ablated left atrial posterior wall (LAPW) sites during contact force (CF)-guided pulmonary vein isolation (PVI). Methods and results Exported VISITAG™ Module and CARTOREPLAY™ (Biosense Webster Inc.) UE morphology data was retrospectively analysed in 23 consecutive patients undergoing PVI under general anaesthesia. PVI without spontaneous / dormant recovery was achieved in all, employing 16.3[3.2] minutes (mean [SD]) of temperature-controlled RF at 30W. All first-ablated LAPW sites demonstrated RS UE morphology pre-ablation, with RF-induced pure R UE morphology change in 98%. Time to pure R UE morphology was significantly shorter at left-sided LAPW sites (4.9[2.1] s versus 6.7[2.5] s; p=0.02), with significantly greater impedance drop (median 13.5Ω versus 9.9Ω; p=0.003). Importantly, neither the first-site RF duration (14.9 versus 15.0s) nor the maximum ablation catheter tip distance moved (during RF) were significantly different, yet the mean CF was significantly higher at right-sided sites (16.5g versus 11.2g; p=0.002). Concurrent impedance and objectively annotated bipolar electrogram (BE) data demonstrated ~6-8Ω impedance drop and ~30% BE decrease at the time of first pure R UE morphology change. Conclusion Using objective ablation site annotation, TM UE morphology change was typically achieved within 7s at the LAPW, with significantly greater ablative effect evident at left-sided sites. The methodology described in this report represents a novel and scientifically more rigorous foundation towards future research into the biological effects of RF ablation in vivo. Condensed abstract Through appropriate use of the VISITAG™ Module and CARTOREPLAY™, unipolar electrogram morphology change indicative of histologically confirmed transmural atrial ablation in animal models, was proven to occur typically within 7s, during first-site contact force-guided ablation at the left atrial posterior wall during pulmonary vein isolation.