Acromegaly has a significant adverse effect on well-being and survival. The predominant determinant of outcome is the final serum GH level following treatment.

Rationale Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective To identify additional AAA risk loci using data from all available genome-wide association studies (GWAS). Methods and Results Through a meta-analysis of 6 GWAS datasets and a validation study totalling 10,204 cases and 107,766 controls we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches we observed no new associations between the lead AAA SNPs and coronary artery disease, blood pressure, lipids or diabetes. Network analyses identified ERG, IL6R and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions The 4 new risk loci for AAA appear to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.

Summary1. Soil resource availability and disturbance are widely recognized as key drivers of plant community structure. However, the relative importance of different plant traits in determining species abundance following shifts in soil resource availability and disturbance remains little studied, particularly in long-term experiments. 2. We studied trait-based plant community assembly in a 27-year grassland experiment where 25 plant species were sown into resident vegetation, after which annual manipulations of soil resource availability (five levels of superphosphate fertilizer; the highest level was also irrigated) and disturbance (three 'mob-grazed' sheep grazing intensity levels: lax, moderate, hard) were applied. We used community assembly through trait selection (CATS) models based on entropy maximization to predict species relative abundances and to quantify the relative importance of each trait in determining abundance. 3. Plant species were primarily differentiated along a trade-off axis corresponding to traits promoting rapid growth (e.g. high leaf [N] and specific leaf area [SLA]) vs. those promoting long leaf life span. Using 12 traits, the CATS model predicted >80% of the variation in the relative abundances of 51 species, suggesting that trait-based filtering was important. 4. Species with leaf attributes that reduce nutrient losses held a long-term advantage under the lowest soil resource availability, whereas those associated with a rapid growth rate became dominant under soil resource addition. Species with thinner leaves were also favoured under greater soil resource availability, which may reflect a strategy to maximize SLA without sacrificing leaf density and thus maintain leaf structural defences under grazing disturbance. Greater leaf [S] and the ability to symbiotically fix atmospheric N were favoured under greater soil resource availability. Greater plant height, thinner leaves and higher leaf [N] were favoured under lower grazing intensity. 5. Synthesis. Our results highlight the importance of species functional differences to understand how plant communities react to increases in soil resource availability and disturbance, two important and inseparable components of land-use change in grasslands world-wide.

ObjectiveNeprilysin (NEP), a zinc metallo-endopeptidase, has a role in blood pressure control and lipid metabolism. The present study tested the hypothesis that NEP is associated with insulin resistance and features of the metabolic syndrome (MetS) in a study of 318 healthy human subjects and in murine obesity and investigated NEP production by adipocytes in-vitro.Methods and ResultsIn 318 white European males, plasma NEP was elevated in the MetS and increased progressively with increasing MetS components. Plasma NEP activity correlated with insulin, homeostasis model assessment and body mass index in all subjects (p<0.01). Quantitative RT-PCR and Western blotting showed that in human pre-adipocytes NEP expression is upregulated 25-30 fold during differentiation into adipocytes. Microarray analysis of mRNA from differentiated human adipocytes confirmed high NEP expression comparable to adiponectin and plasminogen activator inhibitor-1. In a murine model of diet-induced insulin resistance, plasma NEP levels were significantly higher in high fat diet (HFD)-fed compared with normal chow diet (NCD)-fed animals (1642±529 and 820±487 pg/μl, respectively; p<0.01). Tissue NEP was increased in mesenteric fat in HFD compared with NCD-fed mice (p<0.05). NEP knock out mice did not display any changes in insulin resistance, glucose tolerance or body and epididymal fat pad weight compared to wild type mice.ConclusionsIn humans, NEP activity correlated with body mass index and measures of insulin resistance with increasing levels in subjects with multiple cardiovascular risk factors. NEP protein production in human adipocytes increased during cell differentiation and plasma and adipose tissue levels of NEP were increased in obese insulin resistant mice. Our results indicate that NEP associates with cardio-metabolic risk in the presence of insulin resistance and increases in obesity.

QOL deteriorates markedly with increasing lower limb ischaemia. The SF36 would appear to be the most appropriate generic QOL analysis tool for these patients. We recommend its widespread adoption throughout Europe, thus providing a standardised tool for reporting generic QOL.

Abdominal aortic aneurysm (AAA) is a common human disease with a high estimated heritability (0.7); however, only a small number of associated genetic loci have been reported to date. In contrast, over 100 loci have now been reproducibly associated with either blood lipid profile and/or coronary artery disease (CAD) (both risk factors for AAA) in large-scale meta-analyses. This study employed a staged design to investigate whether the loci for these two phenotypes are also associated with AAA. Validated CAD and dyslipidaemia loci underwent screening using the Otago AAA genome-wide association data set. Putative associations underwent staged secondary validation in 10 additional cohorts. A novel association between the SORT1 (1p13.3) locus and AAA was identified. The rs599839 G allele, which has been previously associated with both dyslipidaemia and CAD, reached genome-wide significance in 11 combined independent cohorts (meta-analysis with 7048 AAA cases and 75 976 controls: G allele OR 0.81, 95% CI 0.76-0.85, P = 7.2 × 10(-14)). Modelling for confounding interactions of concurrent dyslipidaemia, heart disease and other risk factors suggested that this marker is an independent predictor of AAA susceptibility. In conclusion, a genetic marker associated with cardiovascular risk factors, and in particular concurrent vascular disease, appeared to independently contribute to susceptibility for AAA. Given the potential genetic overlap between risk factor and disease phenotypes, the use of well-characterized case-control cohorts allowing for modelling of cardiovascular disease risk confounders will be an important component in the future discovery of genetic markers for conditions such as AAA.

Questions Is trait convergence more intense when soil resource availability and disturbance constrain productivity and limit above‐ground competition? Do the effects of productivity and disturbance on functional diversity differ between the local and metacommunity scales? Location Semi‐arid grasslands in New Zealand (43°59′ S, 170°27′ E). Methods We measured trait convergence and divergence in grasslands along gradients of primary productivity and disturbance at local (i.e. 1 m × 1 m) and metacommunity (8 m × 50 m) scales, using long‐term (27‐yr) manipulations of soil resource availability and grazing intensity. We compared trait dispersion metrics to those expected under different null models. Results At the metacommunity scale, we found stronger trait convergence with increasing productivity and grazing intensity, where all short, slow‐growing species were excluded from the potential species pool. However, once this broad‐scale filter on species pool was taken into account, we found that at the local scale, abundance‐weighted functional dispersion of co‐occurring species was stronger than expected under our null model, thereby suggesting limiting similarity. Moreover, trait divergence became stronger at higher productivity and lower grazing intensity, where size‐asymmetric competition for light is likely to have been more intense. Conclusions At the metacommunity scale, environmental filtering led to species with particular traits being excluded from the species pool. In contrast, at the local community scale where individuals interact, there was evidence of limiting similarity. Our results suggest that environmental filtering and limiting similarity are not mutually exclusive and jointly determine community structure, but can operate at different spatial scales.