Changes in disease-related knowledge and educational needs of patients with coronary heart disease over a six-month period between hospital discharge and follow-up.

OBJECTIVE: To describe changes in the disease-related knowledge and educational needs of individuals with coronary heart disease (CHD). METHODS: Patients hospitalized for CHD answered questionnaires about disease-related knowledge (Coronary Artery Disease Education Questionnaire-short version (CADE-Q-SV), score 0-20), educational needs (investigator-designed questions), health literacy (Short version of the European Health Literacy Survey Questionnaire (HLS-EU-Q16)), self-care (Self-Care of Coronary Heart Disease Inventory version (SC-CHDI)), and physical activity (Leisure-time Physical Activity Questionnaire) at discharge (T1) and six months later (T2). RESULTS: Participants' (N = 308; mean [M] age=65.5 years [SD=8.7]; 81.5% male) knowledge scores increased from M= 13.8 (SD=3.2) to M= 14.8 (SD=2.8) (p < 0.001). At T1, educational level, age, health literacy, smoking, and self-care maintenance explained 14.5% of knowledge variability. At T2, these variables plus lack of awareness of CHD diagnosis explained 20.3% of the variability. Substantial educational needs were reported at both time points, although 89% received predischarge education. CONCLUSION: The patients' educational needs were unfulfilled despite an increase in disease-related knowledge over time. Improved evidence-based patient education and follow-ups that address diagnosis, treatment, and self-care are needed. PRACTICE IMPLICATIONS: Healthcare professionals can improve care of patients with CHD by providing focused patient education, prioritizing "need-to-know" topics and considering patients' health literacy.

A chromosome-level genome assembly for the Rock Ptarmigan (Lagopus muta).

The Rock Ptarmigan (Lagopus muta) is a cold-adapted, largely sedentary, game bird with a Holarctic distribution. The species represents an important example of an organism likely to be affected by ongoing climatic shifts across a disparate range. We provide here a high-quality reference genome and mitogenome for the Rock Ptarmigan assembled from PacBio HiFi and Hi-C sequencing of a female bird from Iceland. The total size of the genome is 1.03 Gb with a scaffold N50 of 71.23 Mb and a contig N50 of 17.91 Mb. The final scaffolds represent all 40 predicted chromosomes, and the mitochondria with a BUSCO score of 98.6%. Gene annotation resulted in 16,078 protein-coding genes out of a total 19,831 predicted (81.08% excluding pseudogenes). The genome included 21.07% repeat sequences, and the average length of genes, exons, and introns were 33605, 394, and 4265 bp, respectively. The availability of a new reference-quality genome will contribute to understanding the Rock Ptarmigan's unique evolutionary history, vulnerability to climate change, and demographic trajectories around the globe while serving as a benchmark for species in the family Phasianidae (order Galliformes).

Processes discriminating adaptive and maladaptive Internet use among European adolescents highly engaged online.

Today adolescents are highly engaged online. Contrary to common concern, not all highly engaged adolescents develop maladaptive patterns of internet use. The present qualitative study explored the experiences, patterns and impact of use of 124 adolescents (M(age) = 16.0) reporting signs of internet addictive behaviors. The focus was to discern adaptive and maladaptive use patterns, which promote or interfere with adolescents' development, respectively. Semi-structured individual interviews were conducted in seven European countries (Greece, Spain, Poland, Germany, Romania, Netherlands and Iceland) and qualitatively analyzed using grounded theory. Considerable variability emerged in the way adolescents satisfied their personal needs online and offline, in the experienced impact from high online engagement and functional value ascribed to the internet, and in the self-regulatory processes underlying use. Variability in these discriminating processes was linked to adaptive or maladaptive adolescent internet use patterns. The emerged processes can provide direction for designing prevention and intervention programs promoting adaptive use.

A sequence variant on 17q21 is associated with age at onset and severity of asthma.

A sequence variant (rs7216389-T) near the ORMDL3 gene on chromosome 17q21 was recently found to be associated with childhood asthma. We sought to evaluate the effect of rs7216389-T on asthma subphenotypes and its correlation with expression levels of neighboring genes. The association of rs7216389-T with asthma was replicated in six European and one Asian study cohort (N=4917 cases N=34 589 controls). In addition, we found that the association of rs7216389-T was confined to cases with early onset of asthma, particularly in early childhood (age: 0-5 years OR=1.51, P=6.89.10(-9)) and adolescence (age: 14-17 years OR=1.71, P=5.47.10(-9)). A weaker association was observed for onset between 6 and 13 years of age (OR=1.17, P=0.035), but none for adult-onset asthma (OR=1.07, P=0.12). Cases were further stratified by sex, asthma severity and atopy status. An association with greater asthma severity was observed among early-onset asthma cases (P=0.0012), but no association with sex or atopy status was observed among the asthma cases. An association between sequence variants and the expression of genes in the 17q21 region was assessed in white blood cell RNA samples collected from Icelandic individuals (n=743). rs7216389 associated with the expression of GSDMB and ORMDL3 genes. However, other sequence variants showing a weaker association with asthma compared with that of rs7216389 were more strongly associated with the expression of both genes. Thus, the contribution of rs7216389-T to the development of asthma is unlikely to operate only through an impact on the expression of ORMDL3 or GSDMB genes.

Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction.

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

Overview on the current status of asthma genetics.

INTRODUCTION: Asthma is a complex heterogeneous and mutifactorial disease occurring at the interface of multiple genes that interact with various environmental stimuli insulting the immune system at different levels and different times of disease susceptibility. OBJECTIVE: The present paper is a review of the current status of the genetics of asthma. RESULTS: Sequence variants in hundreds of genes have been associated with asthma using both family-based and case control screening methods. CONCLUSION: As the number of genes known to be associated with asthma risk is rapidly growing, it is essential to begin integrating epidemiologic, genetic and genomic strategies to unravel the relationships between genotype and phenotype, and elucidate the pathogenesis of asthma with the goal to make clinical use of these discoveries.

Functional polymorphism and differential regulation of CYSLTR1 transcription in human airway smooth muscle and monocytes.

Cysteinyl leukotrienes play an important role in the pathophysiology of many inflammatory disorders, including asthma. The aim of this study was to characterize the mechanisms underlying transcriptional regulation of the human cysteinyl leukotriene receptor 1 (hCYSLTR1) gene. 5'RACE was performed on human airway smooth muscle (HASM) and peripheral blood mononuclear cells. A1128-bp region of the hCYSLTR1 main putative promoter was screened for polymorphisms by sequencing of 48 individuals. Luciferase reporter gene assays were performed using fragments of the core promoter (232 bp to 1128 bp) in HASM and THP1 cells. Three hCYSLTR1 transcripts were found, one representing 90% of all messenger RNA identified. The genomic location of the transcription start sites suggested there are two putative hCYSLTR1 promoters. The majority of the transcriptional activity of the main putative promoter was detected between -232 and -679 bp. Four singlenucleotide polymorphisms in strong linkage disequilibrium were found in the region studied: -561 (rs7066737), -642 (rs2806489), -781 (rs2637204), and -940 (rs321029), with three haplotypes observed. In THP1 cells, the G allele (-642) caused a twofold decrease in luciferase expression compared to the Aallele. These data suggest that the majority of hCYSLTR1 transcripts in HASM and monocytes arise from a single promoter located immediately upstream of the 5\' untranslated region, although rarer transcripts can also occur. This study also raises the possibility that cell-type-dependent differences in transcriptional activity caused by the presence of specific haplotypes within the main CYSLTR1 promoter may be a predictor of disease risk or treatment response.

Profiling of genes expressed in peripheral blood mononuclear cells predicts glucocorticoid sensitivity in asthma patients.

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.

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.

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.

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.

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.

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.

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.

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

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 to asthma and atopy. Although some studies reporting these observations are compelling, no gene has been mapped that confers a sufficiently high risk of asthma to meet the stringent criteria for genomewide significance. Using 175 extended Icelandic families that included 596 patients with asthma, we performed a genomewide scan with 976 microsatellite markers. The families were identified by cross-matching a list of patients with asthma from the Department of Allergy/Pulmonary Medicine of the National University Hospital of Iceland with a genealogy database of the entire Icelandic nation. We detected linkage of asthma to chromosome 14q24, with an allele-sharing LOD score of 2.66. After we increased the marker density within the locus to an average of one microsatellite every 0.2 cM, the LOD score rose to 4.00. We designate this locus "asthma locus one" (AS1). Taken together, these results provide evidence of a novel susceptibility gene for asthma on chromosome 14q24.