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Laufey T Amundadottir,
Patrick Sulem,
Julius Gudmundsson,
Agnar Helgason,
Adam Baker,
Bjarni A Agnarsson,
Asgeir Sigurdsson,
Kristrun R Benediktsdottir,
Jean-Baptiste Cazier,
Jesus Sainz, [......],
Carole Ober,
Kathleen A Cooney,
Henrik Gronberg,
William J Catalona,
Gudmundur V Einarsson,
Rosa B Barkardottir,
Jeffrey R Gulcher,
Augustine Kong,
Unnur Thorsteinsdottir,
Kari Stefansson
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ABSTRACT: With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.
Nature Genetics 07/2006; 38(6):652-8. · 35.53 Impact Factor
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Hakon Hakonarson,
Unnur S Bjornsdottir,
Eva Halapi,
Jonathan Bradfield,
Florian Zink,
Magali Mouy,
Hildur Helgadottir,
Asta S Gudmundsdottir,
Hjalti Andrason,
Asdis E Adalsteinsdottir,
Kristleifur Kristjansson,
Illugi Birkisson,
Thor Arnason, Margret Andresdottir,
David Gislason,
Thorarinn Gislason,
Jeffrey R Gulcher,
Kari Stefansson
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ABSTRACT: 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.
Proceedings of the National Academy of Sciences 11/2005; 102(41):14789-94. · 9.68 Impact Factor
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Hakon Hakonarson,
Sverrir Thorvaldsson,
Anna Helgadottir,
Daniel Gudbjartsson,
Florian Zink, Margret Andresdottir,
Andrei Manolescu,
David O Arnar,
Karl Andersen,
Axel Sigurdsson, [......],
Kolbeinn Gudmundsson,
Kristleifur Kristjansson,
Thordur Hardarson,
Arni Kristinsson,
Eric J Topol,
Jeffrey Gulcher,
Augustine Kong,
Mark Gurney,
Gudmundur Thorgeirsson,
Kari Stefansson
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ABSTRACT: 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.
To determine the effect of an inhibitor of FLAP on levels of biomarkers associated with MI risk.
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.
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.
Changes in levels of biomarkers associated with risk of MI.
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.
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.
JAMA The Journal of the American Medical Association 06/2005; 293(18):2245-56. · 30.03 Impact Factor
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Anna Helgadottir,
Andrei Manolescu,
Gudmar Thorleifsson,
Solveig Gretarsdottir,
Helga Jonsdottir,
Unnur Thorsteinsdottir,
Nilesh J Samani,
Gudmundur Gudmundsson,
Struan F A Grant,
Gudmundur Thorgeirsson, [......],
Jesus Sainz,
Margret Thorhallsdottir, Margret Andresdottir,
Michael L Frigge,
Eric J Topol,
Augustine Kong,
Vilmundur Gudnason,
Hakon Hakonarson,
Jeffrey R Gulcher,
Kari Stefansson
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ABSTRACT: We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13. A four-marker single-nucleotide polymorphism (SNP) haplotype in this locus spanning the gene ALOX5AP encoding 5-lipoxygenase activating protein (FLAP) is associated with a two times greater risk of myocardial infarction in Iceland. This haplotype also confers almost two times greater risk of stroke. Another ALOX5AP haplotype is associated with myocardial infarction in individuals from the UK. Stimulated neutrophils from individuals with myocardial infarction produce more leukotriene B4, a key product in the 5-lipoxygenase pathway, than do neutrophils from controls, and this difference is largely attributed to cells from males who carry the at-risk haplotype. We conclude that variants of ALOX5AP are involved in the pathogenesis of both myocardial infarction and stroke by increasing leukotriene production and inflammation in the arterial wall.
Nature Genetics 04/2004; 36(3):233-9. · 35.53 Impact Factor
