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- Thorgeirsson, T. E., et al.
(författare)
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A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences
- 2016
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 21:5, s. 594-600
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Tidskriftsartikel (refereegranskat)abstract
- Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency = 0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P = 1.2 x 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P = 4.0 x 10(-4)), chronic obstructive pulmonary disease (COPD; P = 9.3 x 10(-4)), peripheral artery disease (PAD; P = 0.090) and abdominal aortic aneurysms (AAAs; P = 0.12), and the variant associates strongly with the early-onset forms of LC (OR = 4.49, P = 2.2 x 10(-4)), COPD (OR = 3.22, P = 2.9 x 10(-4)), PAD (OR = 3.47, P = 9.2 x 10(-3)) and AAA (OR = 6.44, P = 6.3 x 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P = 6.8 x 10(-5)), particularly for early-onset cases (P = 2.1 x 10(-7)). Our results are in agreement with functional studies showing that the human alpha 4 beta 2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.
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- Honkamaki, J., et al.
(författare)
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Age- and gender-specific incidence of new asthma diagnosis from childhood to late adulthood
- 2019
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Ingår i: Respiratory Medicine. - : Elsevier BV. - 0954-6111 .- 1532-3064. ; 154, s. 56-62
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Tidskriftsartikel (refereegranskat)abstract
- Background: Asthma is currently divided into different phenotypes, with age at onset as a relevant differentiating factor. In addition, asthma with onset in adulthood seems to have a poorer prognosis, but studies investigating age-specific incidence of asthma with a wide age span are scarce. Objective: To evaluate incidence of asthma diagnosis at different ages and differences between child- and adult-diagnosed asthma in a large population-based study, with gender-specific analyzes included. Methods: In 2016, a respiratory questionnaire was sent to 8000 randomly selected subjects aged 20-69 years in western Finland. After two reminders, 4173 (52.3%) subjects responded. Incidence rate of asthma was retrospectively estimated based on the reported age of asthma onset. Adult-diagnosed asthma was defined as a physician-diagnosis of asthma made at >= 18 years of age. Results: Among those with physician-diagnosed asthma, altogether, 63.7% of subjects, 58.4% of men and 67.8% of women, reported adult-diagnosed asthma. Incidence of asthma diagnosis was calculated in 10-year age groups and it peaked in young boys (0-9 years) and middle-aged women (40-49 years) and the average incidence rate during the examined period between 1946 and 2015 was 2.2/1000/year. Adult-diagnosed asthma became the dominant phenotype among those with physician-diagnosed asthma by age of 50 years and 38 years in men and women, respectively. Conclusions: Asthma is mainly diagnosed during adulthood and the incidence of asthma diagnosis peaks in middle-aged women. Asthma diagnosed in adulthood should be considered more in clinical practice and management guidelines.
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- James, Hayley R, et al.
(författare)
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IgE Antibodies to Mammalian Allergens Are a Major Risk Factor for Prevalence, Severity, and Persistence of Asthma in Northern Sweden
- 2015
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 135:2, s. AB22-AB22
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- IgE to mammalian allergens can contribute significantly to asthma risk. Studying the details of the relationship between animal sensitization and asthma is simpler in an environment where mite, fungal, and cockroach allergens make little or no contribution to asthma risk. Methods: Quantitative assays for IgE to eight allergens were carried out on 963 sera from 19-year-olds in a population-based cohort in northern Sweden, and associations with questionnaire data from ages 7, 12, and 19 on asthma symptoms, diagnosis, and treatment were tested. Results: Overall, 79 (53%) of the students with a physician diagnosis of asthma were positive to one or more of the mammalian allergens (cat, dog, or horse danders) tested. Of the allergens assessed, only mammalian allergens, birch, and timothy grass pollen showed a significant relationship with asthma diagnosis. Multivariate analysis showed that high titer (>17.5 IU/ml) IgE to any mammalian allergen had the strongest relationship with asthma at age 19 (odds ratio 5.1 [3.0-8.6]). Furthermore, IgE to mammalian allergens gave an odds ratio of 8.5 [4.9-15] for asthma that started before age 12 and was still present at age 19. Sensitization to Fel d 1 and Fel d 4 was strongly associated with asthma and significantly reduced in cat owners. Conclusions: Sensitization to cat and dog related allergens, and specifically to the components Fel d 1 and Fel d 4, is a major risk factor for the persistence and severity of asthma in an area where these are the only significant perennial allergens.
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- Lawrence, Monica G, et al.
(författare)
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Undetectable Serum IgE Is a Sensitive and Specific Marker of Common Variable Immunodeficiency (CVID)
- 2015
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 135:2, s. AB275-AB275
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Common variable immunodeficiency (CVID) is characterized by antibody deficiency and recurrent infections as well as autoimmunity, lymphoproliferation, and hematologic malignancy. The current diagnostic criteria for CVID include reduction in serum immunoglobulin (Ig)G and either IgA or IgM and failure of antibody production. Serum IgE level is not currently considered in establishing the diagnosis of CVID. Methods: A cohort of 123 subjects from the University of Virginia Health Systems, Medical College of Wisconsin and Mount Sinai School of Medicine were diagnosed with CVID by an experienced immunologist on the basis of currently accepted diagnostic criteria, including clinical history, serum IgG, IgA and IgM, and antibody response to vaccinations. Serum IgE was measured in all of these subjects using the Phadia ImmunoCap system. Serum IgE was also measured in an unbiased control cohort of 963 healthy 17-18 year olds from northern Sweden. Results: The prevalence of undetectable (<2 IU/ml) total serum IgE in our cohort of 123 subjects with CVID was 84.6% and the prevalence of IgE <10 IU/ml was 97.6%. In comparison, IgE <2 IU/ml was found in only 3.8% of controls, in agreement with other published population estimates. Conclusions: The finding of an undetectable (<2 IU/ml) serum IgE has both a high sensitivity of 84.6% and a high specificity of 96.2% for the diagnosis of CVID. Based on this observation, measurement of serum IgE should be included as a part of the routine laboratory work-up for CVID, and an undetectable serum IgE included as a component of the diagnostic criteria.
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- Matsson, H., et al.
(författare)
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Targeted high-throughput sequencing of candidate genes for chronic obstructive pulmonary disease
- 2016
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Ingår i: Bmc Pulmonary Medicine. - : Springer Science and Business Media LLC. - 1471-2466. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: Reduced lung function in patients with chronic obstructive pulmonary disease (COPD) is likely due to both environmental and genetic factors. We report here a targeted high-throughput DNA sequencing approach to identify new and previously known genetic variants in a set of candidate genes for COPD. Methods: Exons in 22 genes implicated in lung development as well as 61 genes and 10 genomic regions previously associated with COPD were sequenced using individual DNA samples from 68 cases with moderate or severe COPD and 66 controls matched for age, gender and smoking. Cases and controls were selected from the Obstructive Lung Disease in Northern Sweden (OLIN) studies. Results: In total, 37 genetic variants showed association with COPD (p < 0.05, uncorrected). Several variants previously discovered to be associated with COPD from genetic genome-wide analysis studies were replicated using our sample. Two high-risk variants were followed-up for functional characterization in a large eQTL mapping study of 1,111 human lung specimens. The C allele of a synonymous variant, rs8040868, predicting a p.(S45=) in the gene for cholinergic receptor nicotinic alpha 3 (CHRNA3) was associated with COPD (p = 8.8 x 10(-3)). This association remained (p = 0.003 and OR = 1.4, 95 % CI 1.1-1.7) when analysing all available cases and controls in OLIN (n = 1,534). The rs8040868 variant is in linkage disequilibrium with rs16969968 previously associated with COPD and altered expression of the CHRNA5 gene. A follow-up analysis for detection of expression quantitative trait loci revealed that rs8040868-C was found to be significantly associated with a decreased expression of the nearby gene cholinergic receptor, nicotinic, alpha 5 (CHRNA5) in lung tissue. Conclusion: Our data replicate previous result suggesting CHRNA5 as a candidate gene for COPD and rs8040868 as a risk variant for the development of COPD in the Swedish population.
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- Pakkasela, Johanna, et al.
(författare)
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Age at asthma diagnosis in subjects with and without allergic rhinitis
- 2018
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Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 52
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Onset of allergic asthma has a strong association with childhood. Much less is known about adult onset asthma and its association with allergy.Objectives: To assess the proportion of allergic and non-allergic asthma in adulthood in relation to the age at asthma diagnosis.Methods: Postal questionnaires were sent to 8000 randomly selected recipients aged 20-69 years in Finland in 2016. The participation rate was 52% (n=4173). Asthma was classified allergic when a physician-diagnosed asthma and a physician-diagnosed allergic rhinitis were both reported.Results: The prevalence of physician-diagnosed asthma and allergic rhinitis were 11% (n=445) and 18%, respectively. Mean ages at diagnosis of allergic asthma and non-allergic asthma were 19 and 35 years, respectively. Among subjects with asthma diagnosis at ages 0-19, 20-39 and 50-69 years, 67%, 55% and 23%, respectively, were allergic. For non-allergic asthma, the incidence rate of asthma was lowest in children and young adults (0.7/1000/year). It increased after middle age and was highest in older age groups (2.4/1000/year in 50-59 years old).Conclusions: The study results support the well-recognized fact that childhood asthma is mostly allergic. To our knowledge, this is the first study to show that the proportion of allergic asthma steadily declines with advancing age at asthma diagnosis and non-allergic asthma becomes the dominant phenotype with asthma diagnosed in middle age.
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- Perzanowski, Matthew S, et al.
(författare)
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Relevance of specific IgE antibody titer to the prevalence, severity, and persistence of asthma among 19-year-olds in northern Sweden
- 2016
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 138:6, s. 1582-1590
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Although sensitization to indoor allergens is strongly associated with asthma, there are questions as to how this relates to asthma symptoms.OBJECTIVE: We sought to study the relevance of IgE antibodies to cat and dog allergens in an area in which (1) the climate discourages cockroach, fungal, and mite growth and (2) dander allergens are known to be present in schools and houses without animals.METHODS: IgE to 8 allergens was tested in 963 sera from a population-based study on 19-year-olds, and associations with asthma symptoms, diagnosis, and treatment were examined. In positive sera IgE to specific cat and dog allergens was also assayed.RESULTS: IgE specific for animal dander had the highest prevalence and strongest relationship to asthma diagnosis. Furthermore, asthma severity, as judged by the frequency of symptoms and use of treatment, was directly associated with the titer of IgE antibodies to animal dander. Among the 103 subjects who had current asthma at age 19 years, 50 had asthma before age 12 years. Among those 50, the odds ratios for asthma related to any IgE antibodies to animal dander or high-titer IgE antibodies (≥17.5 IU/mL) were 9.2 (95% CI, 4.9-17) and 13 (95% CI, 6.9-25), respectively. In multivariable analysis IgE antibodies to Fel d 1 and Can f 5 were each associated with current asthma.CONCLUSION: High-titer IgE antibodies to cat and dog allergens were strongly associated with the diagnosis, severity, and persistence of asthma; however, a large proportion of patients with current asthma did not live in a house with a cat or dog.
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