Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency

Background: The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2). We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency. Methods The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2 were selected for genotyping. Fev$_1$ percent of predicted and Fev$_1$/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication set, general linear models were used for quantitative phenotypes and logistic regression models were used for the presence/absence of emphysema or COPD. Results: Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with pre-bronchodilator Fev$_1$ percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator Fev$_1$ percent of predicted and pre-bronchodilator Fev$_1$/FVC ratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly associated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed. Conclusions: IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact

PTCH mutations and deletions in patients with typical nevoid basal cell carcinoma syndrome and in patients with a suspected genetic predisposition to basal cell carcinoma: a French study

The patched (PTCH) mutation rate in nevoid basal cell carcinoma syndrome (NBCCS) reported in various studies ranges from 40 to 80%. However, few studies have investigated the role of PTCH in clinical conditions suggesting an inherited predisposition to basal cell carcinoma (BCC), although it has been suggested that PTCH polymorphisms could predispose to multiple BCC (MBCC). In this study, we therefore performed an exhaustive analysis of PTCH (mutations detection and deletion analysis) in 17 patients with the full complement of criteria for NBCCS (14 sporadic and three familial cases), and in 48 patients suspected of having a genetic predisposition to BCC (MBCC and/or age at diagnosis ⩽40 years and/or familial BCC). Eleven new germline alterations of the PTCH gene were characterised in 12 out of 17 patients harbouring the full complement of criteria for the syndrome (70%). These were frameshift mutations in five patients, nonsense mutations in five patients, a small inframe deletion in one patient, and a large germline deletion in another patient. Only one missense mutation (G774R) was found, and this was in a patient affected with MBCC, but without any other NBCCS criterion. We therefore suggest that patients harbouring the full complement of NBCCS criteria should as a priority be screened for PTCH mutations by sequencing, followed by a deletion analysis if no mutation is detected. In other clinical situations that suggest genetic predisposition to BCC, germline mutations of PTCH are not common

Circulating polymers in α1-antitrypsin deficiency.

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Depoliticisation, the management of money and the renewal of social democracy: New Labour's Keynesianism and the political economy of ‘discretionary constraint’

Pointing to its radical underpinnings in so-called ‘Open Marxism’ and its theory of the state (one that subsumes the state in the capital relation), this article critically scrutinises Peter Burnham's thesis of ‘depoliticisation’ as a dominant accumulation strategy and regime. The article identifies ambiguities around Burnham's depiction of New Labour in power as committed to depoliticisation. It addresses these by drawing a distinction between regime of accumulation and mode of regulation, characterising New Labour's political economy in terms of the latter as a form of depoliticised Keynesianism framed by ‘discretionary constraint’. Contra-Burnham, the article points to the continued efficacy of Keynesian and social democratic political agency in the context of a dialectic of depoliticisation and repoliticisation focused on the role and power of the state. This dialectic is symptomatic of the contested regulation of capitalism around the defence of the value of money, on the one hand, and its broader management and redistribution, on the other

Beyond 'third wave' globalisation analysis: a critical review of structural dependency theory in international political economy

Abstrac

From 'embedded liberalism' to 'negotiated openness': British trade unions and the European Union from the 1960s - a world-order approach

This article is primarily concerned with the political economy of British trade union policy towards the European Community (EC) in the 1960s and 1970s. Its aim is to reassess union engagement with the EC in this period &om a viewpoint informed by the now established perspective of world-order analysis in international political economy (Cox, 1981; Lipietz, 1992; Gamble 81 Payne, 1996; Payne, 2005). The article is specifically concerned with the re-evaluation in this light of two notable but contrasting and substantially contradictory perspectives on British unions and Europe: Dorfman (1977) and Teague (1985, 1989, later incorporated into Teague & Grahl, 1992). In its concluding section, the article briefly considers the implications of this reassessment for British union policy in relation to the contemporary EU

Globalisation, regionalism and Labour interests in the new international political economy

This article has two main objectives. First, it provides a critical appraisal of the theoretical accounts of globalisation/regionalisation provided by the left structuralist or ‘hyperglobalist’ approach and the new constitutionalist version of the neo-Gramscian approach. It is argued that both approaches have been essentially negative in their evaluation of the role and position of organised labour in the changing IPE. Such pessimism is particularly marked (perhaps not surprisingly) in the left structuralist approach, but nevertheless (and more surprisingly) still pervades the new constitutionalism. I argue that in both cases pessimism is to a significant degree misplaced and I seek to show the various points at which, in my view, each approach has gone wrong. Generally speaking, however, I would suggest that the problems highlighted have rather less to do with the general theoretical perspectives deployed (for both left structuralism and neo-Gramscian analysis have a great deal to offer the study of IPE) than with the specific treatments of these approaches critiqued here. Briefly stated, these treatments suffer from a common failure to conceptualise changing world orders in terms of the dialectic of structure and agency. Second, the article focuses on a more empirical analysis of (mainly British) labour movement agency within the context of European integration since the mid 1980s, concentrating particularly, although not exclusively, on trade union responses to and understandings of economic and monetary union (EMU). This is designed partly as a corrective to the new constitutionalists’ emphasis on elite agency. I argue that the evidence indicates a significant galvanisation of labour agency at the European Union (EU) level. This needs to be understood partly in terms of a (negative/defensive) response to economic globalisation but also as a positive engagement with the globalisation/regionalism, structure/agency dialectic which reveals broader and more positive trade union purposes and objectives grounded in what Robert Cox has called ‘critical theory’ and directed at forms of social transformation.4 This engagement has, in turn, been partly facilitated by the EU’s own determination of the structure/agency dialectic evident in the changing and politically contested (as opposed to elite-determined) governance structures of the EU. I argue that the starting theoretical assumptions of European labour movement agency are positive in their assertion of feasible alternatives to neoliberal economic governance at the EU level. This corresponds to the more optimistic version of neo-Gramscianism that has informed the work of Alain Lipiet