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Browse through the publications and recorded discoveries from deCODE that have appeared in highly regarded journals around the world.

Publications by deCODE scientists in 2005

• Gudbjartsson DF et al. Allegro version 2. In Nat Genet (37(10):1015-6). 2005.
  
• Hakonarson H et al. Profiling of genes expressed in peripheral blood mononuclear cells predicts glucocorticoid sensitivity in asthma patients. In Proc Natl Acad Sci U S A (102(41): 14789-14794). 2005.
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  Gene expression profiles were examined in freshly isolated peripheral blood mononuclear cells (PBMC) from two independent cohorts (training and test sets) of glucocorticoid (GC)-sensitive (n = 64) and GC-resistant (n = 42) asthma patients in search of genes that accurately predict responders and nonresponders to inhaled corticosteroids. A total of 11,812 genes were examined with high-density oligonucleotide microarrays in both resting PBMC (106 patients) and cells treated in vitro with IL-1beta and TNF-alpha combined (88 patients), with or without GC. A total of 5,011 genes were expressed at significant levels in the PBMC, and 1,334 of those were notably up-regulated or down-regulated by IL-1beta/TNF-alpha treatment. The expression changes of 923 genes were significantly reversed in GC responders in the presence of GC. The expression pattern of 15 of these 923 genes that most accurately separated GC responders (n = 26) from the nonresponders (n = 18) in the training set, based on the weighted voting algorithm, predicted the independent test set of equal size with 84% accuracy. The expression accuracy of these genes was confirmed by real-time-quantitative PCR, wherein 11 of the 15 genes predicted GC sensitivity at baseline with 84% accuracy, with one gene predicting at 81% in an independent cohort of 79 patients. We conclude that we have uncovered gene expression profiles in PBMC that predict clinical response to inhaled GC therapy with meaningful accuracy. Upon validation in an independent study, these results support the development of a diagnostic test to guide GC therapy in asthma patients.

• Benedikz J et al. The natural history of untreated multiple sclerosis in Iceland. A total population-based 50 year prospective study. In Clin Neurol Neurosurg (104(3):208-10). 2005.
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  There have been many reports on the natural history.

  of multiple sclerosis (MS) from selected regions of the.

  world [1], but we are not aware of another longitudinal.

  study of the disease over a 50-year period of continuous.

  observation of a stable, secluded and totally accessible.

  population of a nation state. These are the results of.

  such an investigation of Iceland. None of the patients.

  were treated with immunomodulatory drugs.

• Nollert P. Membrane protein crystallization in amphiphile phases: practical and theoretical considerations. In Prog Biophys Mol Biol (88(3):339-57). 2005.
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  Integral membrane proteins are amphiphilic molecules. In order to enablechromatographic purification and crystallization, a complementary amphiphilicmicroenvironment must be created and maintained. Various types of amphiphilicphases have been employed in crystallizations and intricate amphiphilicmicroenvironmental structures have resulted from these and are found insidemembrane protein crystals. In this review the process of crystallization is putinto the context of amphiphile phase transitions. Finally, practical factors areconsidered and a pragmatic way is suggested to pursue membrane proteincrystallization trials.

• Soldevila M et al. Assessing the signatures of selection in PRNP from polymorphism data: results support Kreitman and Di Rienzo's opinion. In Trends Genet (21(7):389-91). 2005.
  
• Duan MS et al. Cyclodextrin solubilization of the antibacterial agents triclosan and triclocarban: formation of aggregates and higher-order complexes. In Int J Pharm (13;297(1-2):213-22). 2005.
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  It is well known that water-soluble cyclodextrins form inclusion complexes with many lipophilic water-insoluble drugs and that such complexation frequently enhances the aqueous solubility of drugs. It is also well known that various excipients, such as water-soluble polymers, organic acids and bases and metal ions can enhance the solubilizing effects of cyclodextrins. However, it is not clear how these excipients enhance the effects. The effects of cyclodextrins, 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) and randomly methylated beta-cyclodextrin (RMbetaCD) on the aqueous solubility of triclosan and triclocarban were investigated. The phase-solubility profiles were all of type A(P) indicating formation of higher-order complexes or complex aggregates. Addition of lysine and other excipients enhanced the RMbetaCD solubilization of triclocarban. NMR spectroscopic studies, including 2D ROESY and 1D gROESY techniques, indicated that HPbetaCD and RMbetaCD, as well as their complexes, form aggregates of two to three cyclodextrin molecules. The critical concentration for the aggregate formation was determined to be 5.4% (w/v). Lysine, polyvinylpyrrolidone and magnesium ions formed non-inclusion complexes resulting in formation of multiple-component cyclodextrin complexes in aqueous solutions with triclocarban.

• Raymond AC et al. Substrate specificity of tyrosyl-DNA phosphodiesterase I (Tdp1). In J Biol Chem (280 (23):22029-35). 2005.
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  Tyrosyl-DNA Phosphodiesterase I (Tdp1)1 hydrolyzes 3'-phosphotyrosyl bonds to generate 3'-phosphate DNA and tyrosine in vitro. Tdp1 is involved in the repair of DNA lesions created by topoisomerase I although the in vivo substrate is not known. Here we study the kinetic and binding properties of hTdp1 to identify appropriate 3'-phosphotyrosyl DNA substrates. Genetic studies argue that Tdp1 is involved in double (DSBR) and single strand break repair (SSBR) pathways, however X-ray crystal structures suggest that Tdp1 can only bind single strand DNA. Separate kinetic and binding experiments show that Human Tdp1 (hTdp1) has a preference for single stranded and blunt ended duplex substrates over nicked and tailed duplex substrate conformations. Based on these results, we present a new model to explain Tdp1/DNA binding properties. These results suggest that Tdp1 only acts upon double strand breaks in vivo, and the roles of Tdp1 in yeast and mammalian cells are discussed.

• Gulcher J et al. Genes contributing to risk for common forms of stroke. In Trends Mol Med (11(5):217-24). 2005.
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  The quest for disease genes that confer risk for stroke is now being undertaken using three complementary approaches. Positional cloning using rare Mendelian phenocopies of stroke has found genes that contribute to rare forms of stroke but, so far, not to the common forms of stroke. Candidate-gene case-control association studies using the common forms of stroke have found suggestive associations of modest effect. However, positional cloning using hundreds of Icelandic families affected by the common forms of stroke has recently found two genes conferring substantial risk for ischemic stroke that have apparently been confirmed in the USA and other European populations. Both genes encode enzymes, phosphodiesterase 4D (PDE4D) and arachidonate 5-lipoxygenase-activating protein (FLAP), which suggest novel treatment strategies for stroke prevention.

• Hakonarson H et al. Effects of a 5-Lipoxygenase¿Activating Protein Inhibitor on Biomarkers Associated With Risk of Myocardial Infarction. In JAMA (293 (18): 2245-2256). 2005.
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  Context Myocardial infarction (MI) is the leading cause of death in the world. Variants in the 5-lipoxygenase¿activating protein (FLAP) gene are associated with risk of MI. .

  Objective To determine the effect of an inhibitor of FLAP on levels of biomarkers associated with MI risk. .

  Design, Setting, and Patients A randomized, prospective, placebo-controlled, crossover trial of an inhibitor of FLAP (DG-031) in MI patients who carry at-risk variants in the FLAP gene or in the leukotriene A4 hydrolase gene. Of 268 patients screened, 191 were carriers of at-risk variants in FLAP (87%) or leukotriene A4 hydrolase (13%). Individuals were enrolled in April 2004 and were followed up by designated cardiologists from a university hospital in Iceland until September 2004. .

  Interventions Patients were first randomized to receive 250 mg/d of DG-031, 500 mg/d of DG-031, 750 mg/d of DG-031, or placebo. After a 2-week washout period, patients received DG-031 if they had received placebo first or placebo if they had received DG-031 first. Treatment periods lasted for 4 weeks. .

  Main Outcome Measures Changes in levels of biomarkers associated with risk of MI. .

  Results In response to 750 mg/d of DG-031, production of leukotriene B4 was significantly reduced by 26% (95% confidence interval [CI], 10%-39%; P = .003) and myeloperoxidase was significantly reduced by 12% (95% CI, 2%-21%; P = .02). The higher 2 doses of DG-031 produced a nonsignificant reduction in C-reactive protein (16%; 95% CI, ¿2% to 31%; P = .07) at 2 weeks. However, there was a more pronounced reduction (25%; 95% CI, 5%-40%; P = .02) in C-reactive protein at the end of the washout period that persisted for another 4 weeks thereafter. The FLAP inhibitor DG-031 was well tolerated and was not associated with any serious adverse events. .

  Conclusion In patients with specific at-risk variants of 2 genes in the leukotriene pathway, DG-031 led to significant and dose-dependent suppression of biomarkers that are associated with increased risk of MI events.

• Blakey J et al. Contribution of ADAM33 polymorphisms to the population risk of asthma. In Thorax (60(4):274-276). 2005.
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  ADAM 33 is the first gene identified as a candidate for asthma by positional cloning techniques, with association studies reaching impressive statistical significance. It has a postulated role in myogenesis, airway modelling, and signalling via protein shedding. Concerns over the methodology of the initial study have led to several attempts at replication, with inconsistent results.Method: To clarify the role of ADAM33 in determining the risk of asthma in the general population, new transmission disequilibrium and case-control studies were undertaken followed by a meta-analysis of all existing data. RESULTS: Studies in Icelandic and UK populations revealed no association when taken in isolation. The meta-analysis, however, showed that the F+1 and ST+7 variants were significantly associated with asthma in both types of study. CONCLUSIONS: The additional risk imparted by this variation would account for 50 000 excess asthma cases in the UK alone. This study also demonstrates the size of study required to investigate such hypotheses adequately.

• Staker BL et al. Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex. In J Med Chem (48(7):2336-45). 2005.
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  Human topoisomerase I (top1) is the molecular target of a diverse set of anticancer compounds, including the camptothecins, indolocarbazoles, and indenoisoquinolines. These compounds bind to a transient top1-DNA covalent complex and inhibit the resealing of a single-strand nick that the enzyme creates to relieve superhelical tension in duplex DNA. (Hertzberg, R. P.; et al. Biochem. 1989, 28, 4629-4638. Hsiang, Y. H.; et al. J. Biol. Chem 1985, 260, 14873-14878. Champoux, J. J. Annu. Rev. Biochem. 2001, 70, 369-413. Stewart, L.; et al. Science 1998, 729, 1534-1541.) We report the X-ray crystal structures of the human top1-DNA complex bound with camptothecin and representative members of the indenoisoquinoline and indolocarbazole classes of top1 poisons. The planar nature of all three structurally diverse classes allows them to intercalate between DNA base pairs at the site of single-strand cleavage. All three classes of compounds have a free electron pair near Arg364, a residue that if mutated confers resistance to all three classes of drugs. The common intercalative binding mode is augmented by unexpected chemotype-specific contacts with amino acid residues Asn352 and Glu356, which adopt alternative side-chain conformations to accommodate the bound compounds. These new X-ray structures explain how very different molecules can stabilize top1-DNA covalent complexes and will aid the rational design of completely novel structural classes of anticancer drugs.

• Stefansson H et al. A common inversion under selection in Europeans. In Nat Genet (37(2):129-37). 2005.
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  A refined physical map of chromosome 17q21.31 uncovered a 900-kb inversion polymorphism. Chromosomes with the inverted segment in different orientations represent two distinct lineages, H1 and H2, that have diverged for as much as 3 million years and show no evidence of having recombined. The H2 lineage is rare in Africans, almost absent in East Asians but found at a frequency of 20% in Europeans, in whom the haplotype structure is indicative of a history of positive selection. Here we show that the H2 lineage is undergoing positive selection in the Icelandic population, such that carrier females have more children and have higher recombination rates than noncarriers.

• Helgadottir A et al. Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population. In Am J Hum Genet (76(3)). 2005.
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  Cardiovascular diseases, including myocardial infarction (MI) and stroke, most often occur on the background of atherosclerosis, a condition attributed to the interactions between multiple genetic and environmental risk factors. We recently reported a linkage and association study of MI and stroke that yielded a genetic variant, HapA, in the gene encoding 5-lipoxygenase-activating protein (ALOX5AP), that associates with both diseases in Iceland. We also described another ALOX5AP variant, HapB, that associates with MI in England. To further assess the contribution of the ALOX5AP variants to cardiovascular diseases in a population outside Iceland, we genotyped seven single-nucleotide polymorphisms that define both HapA and HapB from 450 patients with ischemic stroke and 710 controls from Aberdeenshire, Scotland. The Icelandic at-risk haplotype, HapA,had significantly greater frequency in Scottish patients than in controls. The carrier frequency in patients and controls was 33.4% and 26.4%, respectively, which resulted in a relative risk of 1.36, under the assumption of a multiplicative model (P=.007). We did not detect association between HapB and ischemic stroke in the Scottish cohort. However, we observed that HapB was overrepresented in male patients. This replication of haplotype association with stroke in a population outside Iceland further supports a role for ALOX5AP incardiovascular diseases.

• Helgason A et al. An Icelandic example of the impact of population structure on association studies. In Nat Genet (37(1):90-5). 2005.
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  The impact of population structure on association studies undertaken to identifygenetic variants underlying common human diseases is an issue of growinginterest. Spurious associations of alleles with disease phenotypes may beobtained or true associations overlooked when allele frequencies differ notablyamong subpopulations that are not represented equally among cases and controls.Population structure influences even carefully designed studies and can affectthe validity of association results. Most study designs address this problem bysampling cases and controls from groups that share the same nationality orself-reported ethnic background, with the implicit assumption that nosubstructure exists within such groups. We examined population structure in theIcelandic gene pool using extensive genealogical and genetic data. Our resultsindicate that sampling strategies need to take account of substructure even in arelatively homogenous genetic isolate. This will probably be even more importantin larger populations.

• Foltynie T et al. A genome wide linkage disequilibrium screen in Parkinson's disease. In J Neurol. 2005.
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  Whole genome screening is increasingly used to identify genetic risk factors for complex diseases. In this study, a genome wide linkage disequilibrium (LD) screen was performed in a cohort of Parkinson's disease (PD) patients from the UK (n = 195) using pooled DNA to facilitate efficient genotyping of 5546 microsatellite markers. Allele frequencies were compared with those found in 2 previously typed disease free control populations, and the most interesting markers were selected for multiple repeat testing among the 3 pools. Markers were then individually genotyped in our original PD cohort and one of the original control groups, and independently in a second cohort of UK PD patients (n = 179), and additional controls.Using this 2-stage approach, we have been unable to find evidence for consistent association of any markers with sporadic PD. Subgroup analysis of the most promising marker shows some evidence that microsatellite marker D1S2886 is associated with familial forms of the disease.

• Goodacre S et al. Genetic evidence for a family-based Scandinavian settlement of Shetland and Orkney during the Viking periods. In Heredity. 2005.
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  The Viking age witnessed the expansion of Scandinavian invaders across much of northwestern Europe. While Scandinavian settlements had an enduring cultural impact on North Atlantic populations, the nature and extent of their genetic legacy in places such as Shetland and Orkney is not clear. In order to explore this question further, we have made an extensive survey of both Y-chromosomal and mitochondrial DNA (mtDNA) variation in the North Atlantic region. Our findings indicate an overall Scandinavian ancestry of approximately 44% for Shetland and approximately 30% for Orkney, with approximately equal contributions from Scandinavian male and female subjects in both cases. This contrasts with the situation for the Western Isles, where the overall Scandinavian ancestry is less ( approximately 15%) and where there is a disproportionately high contribution from Scandinavian males. In line with previous studies, we find that Iceland exhibits both the greatest overall amount of Scandinavian ancestry (55%) and the greatest discrepancy between Scandinavian male and female components. Our results suggest that while areas close to Scandinavia, such as Orkney and Shetland, may have been settled primarily by Scandinavian family groups, lone Scandinavian males, who later established families with female subjects from the British Isles, may have been prominent in areas more distant from their homeland.

• Karason A et al. Genetics of Psoriasis in Iceland: Evidence for Linkage of Subphenotypes to Distinct Loci. In J Invest Dermatol. 2005.
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  Psoriasis is a chronic inflammatory skin disease with overlapping subphenotypes. It has a strong complex genetic component, but has been problematic to identifying significant loci. We evaluated 1000 patients with chronic plaque psoriasis and documented several subphenotypes. Here we report results of genome-wide linkage scans for psoriasis genes in 238 Icelandic families with 874 patients. MHC linkage was confirmed with LOD score of 10.9. When the entire cohort was analyzed, two other loci with LOD scores of 2.5 and 1.5 were observed on 16q and 4q, respectively. Stratification into subphenotypes revealed additional loci with LOD scores exceeding or approaching significance. A LOD score of 5.7 appeared on 16q in PsA patients with analysis conditioned on parental inheritance. A LOD score of 3.6 on 4q was detected when disease occurred at or older than 17 y, our median cohort age. This locus was defined by a marker near one reportedly displaying significant linkage in a Chinese psoriasis population and near suggestive linkage in a Caucasian population. A LOD of 3.0 was observed on 10q when disease onset occurred in the scalp. Furthermore, clinical stratification either revealed or increased LOD scores when compared to unstratified analysis and some coincided with previous reports.

• Stewart L, Burgin AB. Whole Gene Synthesis: A Gene-O-Matic Future. In Frontiers in Drug Design and Discovery. Bentham Science Publishers, Ltd, Co-Editors Atta-ur-Rahman, B. A. Springer, G. W. Caldwell. 2005.