Biomedical subjects

Hakon Hakonarson

Publications and source records attributed to Hakon Hakonarson.

30 records · Page 2Linked to original sources

PubMed2004

Genetic approaches to assessing evidence for a T helper type 1 cytokine defect in adult asthma.

Recent evidence suggests that deficiency in the Th1 cytokine pathway may underlie the susceptibility to allergic asthma. This study examined whether (1) single-nucleotide polymorphisms exist in the promoter region of the two interleukin (IL)-12 subunit genes in patients with asthma; (2) messenger RNA and protein expressions of signal transducers and activators of transcription, IL-12, IFN-gamma, and their receptors are altered in asthma; and (3) linkage to genes in the Th1 pathway is present in families with asthma in Iceland. The promoter regions of the IL-12 subunit genes were sequenced in 94 patients with asthma and 94 control subjects without asthma. Linkage was examined in 169 families that included over 570 patients with asthma and 950 of their unaffected relatives. The results demonstrate no evidence of linkage to microsatellite markers in close association with genes within the Th1 pathway, and no polymorphism was detected in the promoter regions of the two IL-12 subunit genes in the cohort with asthma patients. Moreover, we found no differences in the messenger RNA or protein expression signals of genes in the IL-12 pathway between the patients and control subjects. We conclude that decrease in Th1 type cytokine response is unlikely to present a primary event in asthma.

Adolescent↗

PubMed2004

The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke.

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.

5-Lipoxygenase-Activating Proteins↗

PubMed2004

Recent development in genomic and proteomic research for asthma.

PURPOSE OF REVIEW: Asthma is a complex genetic disorder with a heterogeneous phenotype attributed to the interactions among many genes and the environment. This review highlights recent developments in asthma genomic and proteomic research. RECENT FINDINGS: Numerous loci and candidate genes have been reported to show linkage and association of asthma and the asthma-associated phenotypes, atopy, elevated immunoglobulin E (IgE) levels, and bronchial hyperresponsiveness to alleles of microsatellite markers and single nucleotide polymorphisms within specific cytokine/chemokine, and IgE regulating genes. Although many studies reporting these observations are compelling, only a few genes conferring significant risk have been mapped. Although significant progress has been made in the field of asthma genetics in the past decade, the clinical implications of the genetic variations within the numerous candidate asthma genes, which have been found to associate with the expression of the asthmatic phenotype, remain largely undetermined. However, in the past year the scientific community has benefited from postgenomic discoveries, with the recent cloning of two asthma genes, ADAM 33 and PHF11, and this has generated new information that is benefiting others. SUMMARY: The asthma genetics field has advanced considerably in recent years, with new information being generated that has led to improved understanding of the pathobiology underlying this complex disorder. This has also generated interest in the study of gene-gene interaction and how linkage disequilibrium blocks and haplotypes can be used as functional units to pinpoint mutations and capture relative risk of mutated genes in complex disorders.

ADAM Proteins↗

PubMed2004

Association of vitamin D binding protein variants with chronic mucus hypersecretion in Iceland.

BACKGROUND: Previous studies of vitamin D binding protein (VDBP, also known as group-specific component, Gc, encoded by the GC gene) have implicated two gene variants, GC*2 and GC*1F, as possible contributors with chronic obstructive pulmonary disease (COPD) protection and susceptibility, respectively. The objective of this study was to examine the association of VDBP to different subtypes of COPD. STUDY DESIGN: The association of the various GC genotypes to the COPD phenotype was examined in Icelandic COPD patients who were followed by pulmonary physicians at the University Hospital of Iceland. METHODS: All patients were genotyped for the known alleles of the GC gene. The single nucleotide polymorphisms (SNPs) were identified by a restriction fragment length polymorphism procedure. Study power was estimated based on allele frequencies of the variants, and risk ratios were calculated from the prevalence of genotypes in the affected group divided by its prevalence in the control population. Statistical analyses were performed using the 2-tailed Fisher's Exact Test and chi(2) test, where appropriate. PATIENT GROUP: One hundred and two COPD patients and 183 controls, together with 46 asthma patients and 48 patients with chronic mucous hypersecretion (CMH) were examined. MAIN OUTCOME MEASURE AND RESULTS: The results demonstrate similar allele and genotype frequencies of GC in COPD patients overall and healthy controls. However, there was a higher prevalence of genotypes carrying a GC*1F allele and lower prevalence of genotypes with a GC*2 allele in the CMH patients than in controls. This difference was most notable in the homozygous form: 8.3% vs 1.1% for the GC*1F/*1F, and 0.0% vs 7.6% for the GC*2/*2 genotypes, respectively. When controlled for smoking, only the non-smoking CMH patients demonstrated a significantly altered frequency of the GC*1F/*1F genotype (p = 0.0001). The prevalence of the GC*2/*2 genotype was also significantly lower in patients with bronchial hypersecretion with airflow obstruction compared with the control group (2.9% vs 7.6%). Taken together, these results demonstrate that the GC*1F and GC*2 alleles are associated with sputum hypersecretion in individuals who are at increased risk of developing COPD.

Asthma↗

PubMed2004

Population genomics of drug response.

Genetic diversity contributes to both disease susceptibility and variability in response to drugs. However, it has proven difficult to isolate genes that underlie common complex disease, and genetic variations that influence clinical responses to drugs remain largely uncovered. The candidate gene approach to uncover genetic variations that contribute to disease susceptibility or variations in response to common drugs has not met expectations. Although the sib-pair linkage approach has certain theoretical advantages in dealing with common/complex disease, success has been slow in coming. Meanwhile family studies including siblings, cousins and second cousins, and studies in well-defined founder populations, have increasingly gained popularity and enabled scientists to map and isolate genes for common complex disease, such as schizophrenia and asthma. The latter method has generated new hope that this approach may also be effective in mapping genes that regulate drug response. Indeed, there is compelling evidence that corticosteroid sensitivity is a mapable trait in patients with asthma. Collectively, these studies support the value of leveraging information available within population-based data systems to map and isolate genes for common complex disease and drug response.

Animals↗

PubMed2003

Autocrine regulation of airway smooth muscle responsiveness.

Bronchial asthma is characterized by airway inflammation, exaggerated airway narrowing to bronchoconstrictor agonists, and attenuated beta-adrenoceptor-mediated airway relaxation. Various cytokines/chemokines have been implicated in the pathogenesis of the airway inflammatory response, and certain cytokines, most notably including specific Th2-type cytokines and IL-1beta, have been shown to directly regulate airway smooth muscle (ASM) responsiveness. Recent evidence supports the concept that the ASM itself has the capacity to endogenously express a number of these cytokines under specific conditions of ASM sensitization. Moreover, these cytokines were found to act in an autocrine manner on the ASM to evoke the 'pro-asthmatic' phenotype of altered airway responsiveness. This cytokine-driven autocrine signaling mechanism in ASM may be triggered by either Fc receptor activation in the atopic (IgE-mediated) sensitized state or by ASM exposure to specific viral respiratory pathogens, most notably including rhinovirus. Furthermore, the autocrine-induced changes in ASM responsiveness are attributed to altered receptor-coupled transmembrane signaling in the sensitized ASM, resulting in perturbed expression and release of second messenger molecules that regulate ASM contraction and relaxation. Collectively, this evidence identifies mechanisms intrinsic to the ASM itself, including autocrine pro-inflammatory signaling and altered receptor/G protein-coupled second messenger activation, that importantly contribute to phenotypic expression of the changes in ASM responsiveness that characterize the asthmatic state.

Adaptation, Physiological↗

PubMed2003

deCODE genetics, Inc.

deCODE genetics, Inc. has compiled the world's most comprehensive collection of population data on genealogy, genotypes and phenotypes. This combination of resources provides an effective system for identifying key genes linked to common diseases and to the regulation of drug response. deCODE has successfully mapped genes in over 25 common complex diseases and isolated genes in eight of these. The methodology used to map these genes is based upon the company's genealogical database of the Icelandic population, which enables deCODE scientists to efficiently conduct population- and genome-wide linkage studies to identify key genetic factors involved in phenotypes ranging from diseases to drug response. In its growing pharmacogenomics program, deCODE has combined this linkage approach with high-throughput expression profiling to develop accurate tests that can predict individual responsiveness to virtually any drug of interest. deCODE is applying its unrivaled discovery capabilities to bring to market new drugs, DNA-based diagnostic products and pharmacogenomic tests. The company believes that such tests will play a crucial role in delivering personalized medicine - contributing to the development of more effective means of diagnosing and treating disease by matching each patient with the most suitable drug.

Chromosome Mapping↗

PubMed2002

Familial predisposition and cosegregation analysis of adult obstructive sleep apnea and the sudden infant death syndrome.

Previous studies suggest a familial link between adult obstructive sleep apnea syndrome (OSAS) and sudden infant death syndrome (SIDS). However, most of these studies were hampered by the availability of too few cases of SIDS to draw conclusions. To examine the familial nature of this association in Iceland, hospital-based lists of all patients who were diagnosed with OSAS (n = 2,350) and SIDS (n = 58) from 1979 to 1998 were used to separately determine the familial occurrence of OSAS and SIDS and to search for evidence of cosegregation of these conditions in Icelandic families, using a nationwide genealogy database. The risk ratio for a first-degree relative of a patient with OSAS was 2.0 (1.7-2.8, 95% confidence interval). The risk ratio of the more severely affected patients with OSAS was slightly higher (2.3). Likewise, the kinship coefficient (KC) for the OSAS patient group, which determines the relatedness of the patients, was significantly larger than the mean KC of 1,000 matched control groups. Estimation of the KC for the SIDS group showed a trend toward significance when compared with control groups, but after excluding one of the half-siblings in the SIDS group from the analysis, the difference did not show any trend toward significance. Although the results of the analysis of the relatedness between all patients with OSAS and infants who died of SIDS were not significant, a trend toward significance was evident when the data were separately analyzed for the more severely affected patients with OSAS. Collectively, these results demonstrate a strong familial component in OSAS and suggest that infants who died of SIDS may have shared some of the same susceptibility factors with OSAS.

Adolescent↗

PubMed2002

A major susceptibility gene for asthma maps to chromosome 14q24.

Alleles↗

PubMed2002

T lymphocyte-mediated changes in airway smooth muscle responsiveness are attributed to induced autocrine release and actions of IL-5 and IL-1beta.

BACKGROUND: Bidirectional stimulatory cross-talk was recently found to exist between activated T cells and airway smooth muscle (ASM) cells, a process that involves coligation of specific cellular adhesion-costimulatory molecules that results in the induction of proasthmatic-like changes in ASM responsiveness. OBJECTIVE: The present study examined whether the cooperative intercellular signaling between activated T cells and ASM cells is coupled to the induced expression and actions of IL-5 and IL-1beta. METHODS: Agonist-induced constrictor and relaxant responses were examined in rabbit ASM segments exposed to resting and anti-CD3-activated T cells in the absence and presence of either an anti-IL-5 receptor mAb or the recombinant human IL-1 receptor antagonist. In addition, mRNA and protein expression of IL-5 and IL-1beta were assayed under control and anti-CD3-stimulated conditions. RESULTS: Relative to inactive T cells, incubation of ASM tissues with anti-CD3-activated T cells induced proasthmatic-like changes in agonist-mediated ASM responsiveness. This T cell-induced perturbation in ASM responsiveness was ablated by pretreating the tissues with either an anti-IL-5 receptor mAb or IL-1 receptor antagonist. Moreover, exposure of ASM cells to anti-CD3-activated T cells elicited an initial increased mRNA expression and release of IL-5, followed by an enhanced expression and release of IL-1beta, and the induced release of these cytokines was prevented in ASM cells that were pretreated with an anti-IL-5 receptor mAb. CONCLUSION: Collectively, these observations provide new evidence demonstrating that exposure of naive ASM cells to activated T cells induces the sequential release of IL-5 and IL-1beta from the ASM cells and that the latter cytokines act in an autocrine manner to elicit the proasthmatic phenotype of altered ASM responsiveness.

Adult↗

PubMed2002

Advances in the development of genetic markers for the diagnosis of disease and drug response.

Genetic diversity, including single nucleotide polymorphisms, contributes to both disease susceptibility and variability in drug response. Since most genes contain multiple single nucleotide polymorphisms, identifying those that are most relevant with respect to disease or drug response is important and may uncover variants that are predictive of either disease susceptibility or therapeutic response to drugs, both with respect to efficacy and toxic side effects. The candidate gene approach has been widely used to search for the genetic basis of pharmacogenomic traits. Although a few successful examples have emerged from this approach, notably trastuzumab (Herceptin; Genentech), imatinib mesylate (Gleevec (USA), Glivec; Novartis) and certain drugs that demonstrate variable efficacy or adverse effects that are attributed to metabolizing enzymes, for most drugs, the genetic variations that determine their clinical response remain uncovered. Genome-wide linkage approach presents an alternative to the candidate gene approach. The powerful combination of linkage when coupled to ultra-high-throughput genotyping, gene array and proteomics technology, together with innovative bioinformatic resources, provides a focused integrative strategy for pinpointing disease-causing genes that may generate validated drug targets and genes that are responsible for differential drug response. Thus, it is anticipated that genetic research will soon generate new information that can be used to develop novel therapeutic strategies and diagnostic tests that will ultimately lead to safer and more efficacious drugs for all patients. This review addresses recent advances in the development of genetic markers that can be used to diagnose disease or drug response.

Cardiovascular Diseases↗

PubMed2002

Genetic analyses in asthma: current concepts and future directions.

Asthma is a complex genetic disorder with a heterogeneous phenotype, largely attributed to the interactions among many genes and between these genes and the environment. Numerous loci and candidate genes have been reported to show linkage and association of asthma and the asthma-associated phenotypes, atopy, elevated immunoglobulin E (IgE) levels, and bronchial hyper-responsiveness to alleles of microsatellite markers and single nucleotide polymorphisms (SNPs) within specific cytokine/chemokine, and IgE regulating genes. While many studies reporting these observations are compelling, only one asthma gene conferring high risk has been mapped. In this review, we present studies that support linkage and/or associations to the various genetic loci and genes in asthma. The first genome-wide scan for linkage to quantitative traits underlying asthma identified linkage on chromosome 4q, 6, 7, 11q, 13q and 16. A genome scan in American families from three racial groups revealed linkage to chromosome 2q, 5q, 6p, 12q, 13q and 14q. A two-stage scan in Hutterite families from the US found linkage on chromosome 5q, 12q, 19q and 21q. A screen in German families identified linkage to asthma on chromosome 2q, 6p, 9 and 12q and a two-stage genome scan in French families found replicated linkage on chromosomes 1p, 12q and 17q. A study of asthma in Finland showed linkage to high IgE on 7q14. Apart from a European linkage study of 199 families with atopic dermatitis, which demonstrated significant linkage to chromosome 3q21, three other studies have reported linkage results of genome-wide significance, including a linkage study in 175 Icelandic asthma families (14q24), a study in 533 Chinese families with bronchial hyper-responsiveness (chromosome 2) and a study in 47 Japanese families with mite-sensitive atopic asthma (5q31), suggesting that these regions may harbor genes contributing to the development of asthma and allergies. While significant progress has been made in the field of asthma genetics in the past decade, the clinical implications of the genes and genetic variations within the numerous candidate asthma genes that have been found to associate with the expression of the asthmatic phenotype, remain undetermined.

Asthma↗