Genetic analysis of chromosomal regions 2q33, 7q32 and 19q13 in multiple sclerosis susceptibility

Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system (CNS) affecting 0.1-0.2% of Northern European descent population. MS is considered to be a multifactorial disease, both environment and genetics play a role in its pathogenesis. Despite several decades of intense research, the etiological and pathogenic mechanisms underlying MS remain still largely unknown and no curative treatment exists. The genetic architecture underlying MS is complex with multiple genes involved. The strongest and the best characterized predisposing genetic factors for MS are located, as in other immune-mediated diseases, in the major histocompatibility complex (MHC) on chromosome 6. In humans MHC is called human leukocyte antigen (HLA). Alleles of the HLA locus have been found to associate strongly with MS and remained for many years the only consistently replicable genetic associations. However, recently other genes located outside the MHC region have been proposed as strong candidates for susceptibility to MS in several studies. In this thesis a new genetic locus located on chromosome 7q32, interferon regulatory factor 5 (IRF5), was identified in the susceptibility to MS. In particular, we found that common variation of the gene was associated with the disease in three different populations, Spanish, Swedish and Finnish. We also suggested a possible functional role for one of the risk alleles with impact on the expression of the IRF5 locus. Previous studies have pointed out a possible role played by chromosome 2q33 in the susceptibility to MS and other autoimmune disorders. The work described here also investigated the involvement of this chromosomal region in MS predisposition. After the detection of genetic association with 2q33 (article-1), we extended our analysis through fine-scale single nucleotide polymorphism (SNP) mapping to define further the contribution of this genomic area to disease pathogenesis (article-4). We found a trend (p=0.04) for association to MS with an intronic SNP located in the inducible T-cell co-stimulator (ICOS) gene, an important player in the co-stimulatory pathway of the immune system. Expression analysis of ICOS revealed a novel, previously uncharacterized, alternatively spliced isoform, lacking the extracellular domain that is needed for ligand binding. The stability of the newly-identified transcript variant and its subcellular localization were analyzed. These studies indicated that the novel isoform is stable and shows different subcellular localization as compared to full-length ICOS. The novel isoform might have a regulatory function, but further studies are required to elucidate its function. Chromosome 19q13 has been previously suggested as one of the genomic areas involved in MS predisposition. In several populations, suggestive linkage signals between MS predisposition and 19q13 have been obtained. Here, we analysed the role of allelic variation in 19q13 by family based association analysis in 782 MS families collected from Finland. In this dataset, we were not able to detect any statistically significant associations, although several previously suggested markers were included to the analysis. Replication of the previous findings on the basis of linkage disequilibrium between marker allele and disease/risk allele appears notoriously difficult because of limitations such as allelic heterogeneity. Re-sequencing based approaches may be required for elucidating the role of chromosome 19q13 with MS. This thesis has resulted in the identification of a new MS susceptibility locus (IRF5) previously associated with other inflammatory or autoimmune disorders, such as SLE. IRF5 is one of the mediators of interferons biological function. In addition to providing new insight in the possible pathogenetic pathway of the disease, this finding suggests that there might be common mechanisms between different immune-mediated disorders. Furthermore the work presented here has uncovered a novel isoform of ICOS, which may play a role in regulatory mechanisms of ICOS, an important mediator of lymphocyte activation. Further work is required to uncover its functions and possible involvement of the ICOS locus in MS susceptibility.

Varities of National Metonymy in Media Accounts of International Mergers and Acquisitions

International mergers and acquisitions (M&As) often invoke national identification and national cultural differences. We argue that metonymy is a central linguistic resource through which national cultural identities and differences are reproduced in media accounts of international M&As. In this paper, we focus on two revealing cases: the acquisition of American IBM Personal Computer Division (PCD) by the Chinese company Lenovo and the acquisition of American Anheuser-Busch (A-B) by the Belgian-Brazilian company InBev. First, we identify the forms, functions and frequencies of national metonymy in media accounts of these cases. We present a typology that classifies varieties of national metonymy in international M&As. Second, we demonstrate how these metonyms combine with metaphor to generate evocative imagery, engaging wit, and subversive irony. Our findings show that national metonymy contributes to the construction of emotive frames, stereotypes, ideological differences, and threats. Combinations of national metonymy with metaphor also provide powerful means to construct cultural differences. However, combinations of metonymy with wit and irony enable the play on meanings that overturns and resists national and cultural stereotypes. This is the first study to unpack the deployment of metonymy in accounts of international M&As. In doing so, it also opens up new avenues for research into international management and the analysis of tropes in management and organization.

Public opinion on useful languages in Europe

This article analyses the results of five Eurobarometer surveys (of 1995, 1997, 1998, 2000 and 2005) designed to measure which languages Europeans consider most useful to know. Most Europeans are of the opinion that English is the most useful, followed by French and German. During the last decade the popularity of French and German as useful languages has been decreasing significantly, while English has remained universally favoured as the most useful language. French and German have lost their popularity especially among those who do not speak them as a foreign language. On the other hand, Spanish, Russian and other languages (often these include languages of neighbouring countries, minority languages or a second official language of the country in question) have kept and even increased their former level of popularity. Opinions about useful languages vary according to a respondent’s knowledge of languages, education and profession. This article analyses these differences and discusses their impact on the study of foreign languages and the future of the practice of foreign languages in Europe.