Genetic Association and Risk Scores in a COPD Meta-Analysis of 16,707 Subjects

The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine 1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD, and 2) the impact of genetic risk scores on COPD. We genotyped 3,346 single nucleotide polymorphisms (SNP) in 2,588 cases (1,803 severe COPD) and 1,782 controls from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 controls. Additionally, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (p=1.28x10-8) and PPP4R4/SERPINA1 (p=1.01x10-8) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (AUC ~0.6), and accounted for a mean 0.9-1.9% lower FEV1 percent-predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest but significant effects on risk of COPD and lung function

The Implementation of Integrating Reporting <IR> in SMEs. Insights from a pioneering experience in Italy

Abstract Purpose – This paper aims to discuss the most critical aspects relative to the “usability” of the International Integrated Reporting Council (IIRC) Framework faced by small and medium-sized enterprises (SMEs) in releasing the integrated report and adapting the Integrated Reporting (IR) principles (i.e. materiality, integrated thinking and connectivity) to their needs and features. Only recently the relevance of IR for SMEs has been internationally acknowledged. Design/methodology/approach – The study is based on both a deductive and inductive approach. The first one is founded on a literature and technical review aimed at tracing the theoretical background and the framework on integrating reporting in SMEs. The second one is empirically constructed and follows the action research approach because it involves the analysis of a single case-study relative to a company – Costa Edutainment Spa that released its pioneering integrated report in 2014 – belonging to the Italian Network on Business Reporting, a working group which has been involved in the pivotal drafting process of a Guidance for IR in SMEs. Findings – Results emphasise the main criticalities faced by an SME in the IR process, namely, the need for the following: clearly defining the relationship between sustainability and integrated reporting; adapting the main IR concepts (such us materiality, integrated thinking and connectivity) and fully understanding the benefits deriving from the implementation of IR. Moreover, results shed light on the usefulness of a simplified and operative guidance for releasing the integrated report within SMEs the effectiveness deriving from the direct involvement in the NIBR working group and the provision of practical examples and suggestions. Research limitations/implications – The main limitations are due to the fact that the empirical analysis is related to a single case study, and it is explorative in nature. Consequently, results are not generalisable. However, the work contributes to nourish the debate on the benefits and critical issues relative to the diffusion of IR among SMEs in a research field which has not been adequately investigated and to develop reflections on the benefits of the diffusion of the IR among SMEs, pointing out the opportunity to follow an evolutionary path which drives the evolution of the entrepreneurial and organisational culture towards monitoring, assessing and reporting the company’s value process creation. Practical implications – The work contributes to triggering the debate on the diffusion of IR among SMEs which represents a research field that remains still under investigated. It points out a fundamental gap on how to implement IR in SMEs and operationalise the IIRC concepts and principles. It develops reflections on the critical issues and benefits of the diffusion of the IR among SMEs. Drawing from a pioneering experience, the work contributes to supporting entrepreneurs by emphasising the possible benefits deriving from the implementation of the IR process. It suggests an evolutionary path through different steps (starting from the business model definition) which are necessary to drive the entrepreneurial and organisational culture towards monitoring, assessing and reporting the SMEs’ value process creation. Originality/value – The work contributes to devoting the attention of both scholars and practitioners to an underestimated research field – the “feasibility of IR in the SMEs context – which has not been yet adequately investigated. Moreover, being empirically based, it helps in supporting the diffusion of the IRframework among SMEs, practitioners and consultants by providing insights aimed to improve the IR Guidance for SMEs and sensitise entrepreneurs by emphasising that a possible step-by-step “IR journey” is possible

Impact of non-linear smoking effects on the identification of gene-by-smoking interactions in COPD genetics studies

BACKGROUND: The identification of gene-by-environment interactions is important for understanding the genetic basis of chronic obstructive pulmonary disease (COPD). Many COPD genetic association analyses assume a linear relationship between pack-years of smoking exposure and forced expiratory volume in 1 s (FEV(1)); however, this assumption has not been evaluated empirically in cohorts with a wide spectrum of COPD severity. METHODS: The relationship between FEV(1) and pack-years of smoking exposure was examined in four large cohorts assembled for the purpose of identifying genetic associations with COPD. Using data from the Alpha-1 Antitrypsin Genetic Modifiers Study, the accuracy and power of two different approaches to model smoking were compared by performing a simulation study of a genetic variant with a range of gene-by-smoking interaction effects. RESULTS: Non-linear relationships between smoking and FEV(1) were identified in the four cohorts. It was found that, in most situations where the relationship between pack-years and FEV(1) is non-linear, a piecewise linear approach to model smoking and gene-by-smoking interactions is preferable to the commonly used total pack-years approach. The piecewise linear approach was applied to a genetic association analysis of the PI*Z allele in the Norway Case-Control cohort and a potential PI*Z-by-smoking interaction was identified (p=0.03 for FEV(1) analysis, p=0.01 for COPD susceptibility analysis). CONCLUSION: In study samples of subjects with a wide range of COPD severity, a non-linear relationship between pack-years of smoking and FEV(1) is likely. In this setting, approaches that account for this non-linearity can be more powerful and less biased than the more common approach of using total pack-years to model the smoking effect

Polymorphisms in the superoxide dismutase-3 gene are associated with emphysema in COPD

Superoxide dismutase-3 (SOD3) is a major extracellular antioxidant enzyme, and previous studies have indicated a possible role of this gene in chronic obstructive pulmonary disease (COPD). We hypothesized that polymorphisms in the SOD3 gene would be associated with COPD and COPD-related phenotypes. We genotyped three SOD3 polymorphisms (rs8192287 (E1), rs8192288 (I1), and rs1799895 (R213G)) in a case-control cohort, with severe COPD cases from the National Emphysema Treatment Trial (NETT, n = 389) and smoking controls from the Normative Aging Study (NAS, n = 472). We examined whether the single nucleotide polymorphisms (SNPs) were associated with COPD status, lung function variables, and quantitative computed tomography (CT) measurements of emphysema and airway wall thickness. Furthermore, we tried to replicate our initial findings in two family-based studies, the International COPD Genetics Network (ICGN, n = 3061) and the Boston Early-Onset COPD Study (EOCOPD, n = 949). In NETT COPD cases, the minor alleles of SNPs E1 and I1 were associated with a higher percentage of emphysema (%LAA950) on chest CT scan (p = .029 and p = .0058). The association with E1 was replicated in the ICGN family study, where the minor allele was associated with more emphysema (p = .048). Airway wall thickness was positively associated with the E1 SNP in ICGN; however, this finding was not confirmed in NETT. Quantitative CT data were not available in EOCOPD. The SNPs were not associated with lung function variables or COPD status in any of the populations. In conclusion, polymorphisms in the SOD3 gene were associated with CT emphysema but not COPD susceptibility, highlighting the importance of phenotype definition in COPD genetics studies