G2Cdb::Human Disease report

Disease id
D00000240
Name
Asthma
Nervous system disease
no

Genes (2)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00002531 SNAP25
synaptosomal-associated protein, 25kDa
Y (15753894) Single nucleotide polymorphism (SNP) N
G00000030 NOS1
nitric oxide synthase 1 (neuronal)
Y (10641565) Unknown (?) Y
G00000030 NOS1
nitric oxide synthase 1 (neuronal)
Y (10673365) Microsatellite variation (MSV) Y
G00000030 NOS1
nitric oxide synthase 1 (neuronal)
Y (10833424) Dinucleotide polymorphism (DNP) Y
G00000030 NOS1
nitric oxide synthase 1 (neuronal)
Y (11112111) Dinucleotide polymorphism (DNP) Y
G00000030 NOS1
nitric oxide synthase 1 (neuronal)
Y (11668616) Single nucleotide polymorphism (SNP) Y

References

  • Polymorphisms in SPINK5 are not associated with asthma in a Dutch population.

    Jongepier H, Koppelman GH, Nolte IM, Bruinenberg M, Bleecker ER, Meyers DA, te Meerman GJ and Postma DS

    Department of Pulmonary Rehabilitation, Beatrixoord, The Netherlands.

    Background: Asthma and allergic phenotypes are complex genetic diseases with known linkage to chromosome 5q. This region has many candidate genes, including serine protease inhibitor Kazal type 5 (SPINK5), which has been associated with asthma and atopic dermatitis in family-based studies of children with atopic dermatitis.

    Objective: We sought to investigate whether single nucleotide polymorphisms in SPINK5 are associated with asthma, atopic phenotypes, and atopic dermatitis.

    Methods: We investigated whether single nucleotide polymorphisms in SPINK5 (ie, -785 A/G, Asn368Ser, and Lys420Glu) are associated with asthma, atopic phenotypes, and atopic dermatitis in 200 families ascertained by a proband with asthma (nonaffected spouses served as a matched control population) and an independent set of 252 trios with asthma.

    Results: We found no association with asthma, atopic phenotypes, and atopic dermatitis after correction for multiple testing.

    Conclusion: The negative results in this study suggest that SPINK5 is not associated with asthma or atopic phenotypes in individuals ascertained by a proband with asthma. This is consistent with the finding that SPINK5 is not expressed in the lung. Because our patients were ascertained for asthma, a role of SPINK5 in atopic dermatitis cannot be excluded.

    The Journal of allergy and clinical immunology 2005;115;3;486-92

  • Fine mapping and single nucleotide polymorphism association results of candidate genes for asthma and related phenotypes.

    Immervoll T, Loesgen S, Dütsch G, Gohlke H, Herbon N, Klugbauer S, Dempfle A, Bickeböller H, Becker-Follmann J, Rüschendorf F, Saar K, Reis A, Wichmann HE and Wjst M

    GSF-National Research Center for Environment and Health, Institute of Epidemiology, Neuherberg, Germany. immervoll@gsf.de

    Several genome-wide screens for asthma and related phenotypes have been published to date but data on fine-mapping are scarce. For higher resolution we performed a fine-mapping study with 2 cM average spacing in often discussed asthma candidate regions (2p, 5q, 6p, 7p, 9q, 11p, and 12q) to narrow down the regions of interest. All participants of a Caucasian family study (97 families with at least two affected sib pairs) were genotyped for 49 supplementary polymorphic dinucleotide markers. Our results indicate increased evidence for linkage on chromosome 6p, 9q, and 12q. These candidate regions were further analyzed with SNP polymorphisms in the endothelin 1 (EDN1), lymphotoxin alpha (LTA), and neuronal nitric oxide synthase (NOS1) genes. In addition, IL4 -590C>T and IL10 -592C>A, localized on chromosomes 5q and 1q, respectively, have been analyzed for SNP association. Of the six SNPs tested, four revealed weak association with the examined phenotypes. These are the IL10 -592C>A SNP in the interleukin 10 gene (p=0.036 for eosinophil cell counts), the 4124T>C SNP in EDN1 (p=0.044 for asthma), the 3391C>T SNP in NOS1 with eosinophil cell counts (p=0.0086), and the 5266C>T polymorphism, also in the NOS1 gene, for high IgE levels (p=0.022). In summary, fine mapping data enable us to confine asthma candidate regions, while variants of EDN1 and NOS1, or nearby genes, may play an important role in this context.

    Human mutation 2001;18;4;327-36

  • Exhaled nitric oxide in patients with asthma: association with NOS1 genotype.

    Wechsler ME, Grasemann H, Deykin A, Silverman EK, Yandava CN, Israel E, Wand M and Drazen JM

    Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

    An increased concentration of nitric oxide (NO) in exhaled air (FENO) is now recognized as a critical component of the asthmatic phenotype. When we identified patients with asthma on the basis of a standard case definition alone, we found that they were remarkably heterogeneous with respect to their FENO. However, when we included genotype at a prominent asthma candidate gene (i.e., NOS1) in the case definition, and determined the number of AAT repeats in intron 20, we identified a remarkably homogeneous cohort of patients with respect to FENO. Both mean FENO (p = 0.00008) and variability around the mean (p = 0.000002) were significantly lower in asthmatic individuals with a high number (> or = 12) of AAT repeats at this locus than in those with fewer repeats. These data provide a biologically tenable link between genotype at a candidate gene in a region of linkage, NOS1, and an important component of the asthmatic phenotype, FENO. We show that addition of NOS1 genotype to the case definition of asthma allows the identification of a uniform cohort of patients, with respect to FENO, that would have been indistinguishable by other physiologic criteria. Our isolation of this homogeneous cohort of patients ties together the well-established associations among asthma, increased concentrations of NO in the exhaled air of asthmatic individuals, and variations of trinucleotide repeat sequences as identified in several neurologic conditions.

    Funded by: NHLBI NIH HHS: P50-HL-56383

    American journal of respiratory and critical care medicine 2000;162;6;2043-7

  • A neuronal NO synthase (NOS1) gene polymorphism is associated with asthma.

    Grasemann H, Yandava CN, Storm van's Gravesande K, Deykin A, Pillari A, Ma J, Sonna LA, Lilly C, Stampfer MJ, Israel E, Silverman EK and Drazen JM

    Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.

    Recent family-based studies have revealed evidence for linkage of chromosomal region 12q to both asthma and high total serum immunoglobulin E (IgE) levels. Among the candidate genes in this region for asthma is neuronal nitric oxide synthase (NOS1). We sought a genetic association between a polymorphism in the NOS1 gene and the diagnosis of asthma, using a case-control design. Frequencies for allele 17 and 18 of a CA repeat in exon 29 of the NOS1 gene were significantly different between 490 asthmatic and 350 control subjects. Allele 17 was more common in the asthmatics (0.83 vs 0.76, or 1.49 [95% CI 1.17-1.90], P = 0.013) while allele 18 was less common in the asthmatics (0.06 vs 0.12, or 0.49 [95% CI 0.34-0. 69], P = 0.0004). To confirm these results we genotyped an additional 1131 control subjects and found the frequencies of alleles 17 and 18 to be virtually identical to those ascertained in our original control subjects. Total serum IgE was not associated with any allele of the polymorphism. These findings provide support, from case-control association analysis, for NOS1 as a candidate gene for asthma.

    Funded by: NHLBI NIH HHS: HL-56383

    Biochemical and biophysical research communications 2000;272;2;391-4

  • Variants of NOS1, NOS2, and NOS3 genes in asthmatics.

    Gao PS, Kawada H, Kasamatsu T, Mao XQ, Roberts MH, Miyamoto Y, Yoshimura M, Saitoh Y, Yasue H, Nakao K, Adra CN, Kun JF, Moro-oka S, Inoko H, Ho LP, Shirakawa T and Hopkin JM

    Experimental Medicine Unit, University of Wales Swansea, Swansea, United Kingdom.

    Nitric oxide (NO) gas concentrations are higher in expired air in asthmatics. NO is synthesized by three isoforms of NO synthase (NOS) encoded by three distinct genes, NOS1, NOS2, and NOS3. Genome-wide searches have identified linkages to asthma on chromosomes 7, 12, and 17 where these three genes are localized. No association study, however, has been reported to date. To test whether variants of NOS1, NOS2, and NOS3 relate to asthma, a genetic association study was conducted in a British population (n = 300). Intragenic microsatellite variants of NOS1 were significantly associated with asthma [odds ratio (OR) = 2.08, 95% CI: 1.20-3.57 (95% CI), P = 0.008 (Pc = 0.048)], but not with IgE levels. Neither NOS2 nor NOS3 variants showed any association with asthma nor IgE levels. These findings suggest that NOS1 variants may be a significant contributor to asthma in a British population.

    Biochemical and biophysical research communications 2000;267;3;761-3

  • Neuronal NO synthase (NOS1) is a major candidate gene for asthma.

    Grasemann H, Yandava CN and Drazen JM

    Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

    Asthma is a common, but heterogeneous disease, characterized by reversible airway obstruction, bronchial hyperresponsiveness (BHR); and is commonly associated with atopy. The messenger molecule nitric oxide (NO), that is formed by neuronal NO synthase (NOS1), is known to have a key role in bronchomotor control in animals. In humans the gene for NOS1 is located on chromosome 12q24, in a region that had been shown in family studies to be linked to the diagnosis of asthma. We identified variants of the NOS1 gene, and assessed whether there was a genetic association between these variants of NOS1 and the diagnosis asthma. A total of 410 Caucasian asthma patients and 228 Caucasian controls were screened for three bi-allelic polymorphisms in the NOS1 gene that had been detected by single-stranded conformational polymorphism (SSCP) analysis and confirmed by sequencing. Allele frequencies of a polymorphism in exon 29 of the NOS1 gene were significantly different between asthmatics and controls (P<0.05). These findings suggest that variants of the NOS1 gene may be one source of genetic risk for asthma.

    Funded by: NHLBI NIH HHS: HL-56383

    Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 1999;29 Suppl 4;39-41

Literature (6)

Pubmed - human_disease

  • Polymorphisms in SPINK5 are not associated with asthma in a Dutch population.

    Jongepier H, Koppelman GH, Nolte IM, Bruinenberg M, Bleecker ER, Meyers DA, te Meerman GJ and Postma DS

    Department of Pulmonary Rehabilitation, Beatrixoord, The Netherlands.

    Background: Asthma and allergic phenotypes are complex genetic diseases with known linkage to chromosome 5q. This region has many candidate genes, including serine protease inhibitor Kazal type 5 (SPINK5), which has been associated with asthma and atopic dermatitis in family-based studies of children with atopic dermatitis.

    Objective: We sought to investigate whether single nucleotide polymorphisms in SPINK5 are associated with asthma, atopic phenotypes, and atopic dermatitis.

    Methods: We investigated whether single nucleotide polymorphisms in SPINK5 (ie, -785 A/G, Asn368Ser, and Lys420Glu) are associated with asthma, atopic phenotypes, and atopic dermatitis in 200 families ascertained by a proband with asthma (nonaffected spouses served as a matched control population) and an independent set of 252 trios with asthma.

    Results: We found no association with asthma, atopic phenotypes, and atopic dermatitis after correction for multiple testing.

    Conclusion: The negative results in this study suggest that SPINK5 is not associated with asthma or atopic phenotypes in individuals ascertained by a proband with asthma. This is consistent with the finding that SPINK5 is not expressed in the lung. Because our patients were ascertained for asthma, a role of SPINK5 in atopic dermatitis cannot be excluded.

    The Journal of allergy and clinical immunology 2005;115;3;486-92

  • Exhaled nitric oxide in patients with asthma: association with NOS1 genotype.

    Wechsler ME, Grasemann H, Deykin A, Silverman EK, Yandava CN, Israel E, Wand M and Drazen JM

    Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

    An increased concentration of nitric oxide (NO) in exhaled air (FENO) is now recognized as a critical component of the asthmatic phenotype. When we identified patients with asthma on the basis of a standard case definition alone, we found that they were remarkably heterogeneous with respect to their FENO. However, when we included genotype at a prominent asthma candidate gene (i.e., NOS1) in the case definition, and determined the number of AAT repeats in intron 20, we identified a remarkably homogeneous cohort of patients with respect to FENO. Both mean FENO (p = 0.00008) and variability around the mean (p = 0.000002) were significantly lower in asthmatic individuals with a high number (> or = 12) of AAT repeats at this locus than in those with fewer repeats. These data provide a biologically tenable link between genotype at a candidate gene in a region of linkage, NOS1, and an important component of the asthmatic phenotype, FENO. We show that addition of NOS1 genotype to the case definition of asthma allows the identification of a uniform cohort of patients, with respect to FENO, that would have been indistinguishable by other physiologic criteria. Our isolation of this homogeneous cohort of patients ties together the well-established associations among asthma, increased concentrations of NO in the exhaled air of asthmatic individuals, and variations of trinucleotide repeat sequences as identified in several neurologic conditions.

    Funded by: NHLBI NIH HHS: P50-HL-56383

    American journal of respiratory and critical care medicine 2000;162;6;2043-7

  • A neuronal NO synthase (NOS1) gene polymorphism is associated with asthma.

    Grasemann H, Yandava CN, Storm van's Gravesande K, Deykin A, Pillari A, Ma J, Sonna LA, Lilly C, Stampfer MJ, Israel E, Silverman EK and Drazen JM

    Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.

    Recent family-based studies have revealed evidence for linkage of chromosomal region 12q to both asthma and high total serum immunoglobulin E (IgE) levels. Among the candidate genes in this region for asthma is neuronal nitric oxide synthase (NOS1). We sought a genetic association between a polymorphism in the NOS1 gene and the diagnosis of asthma, using a case-control design. Frequencies for allele 17 and 18 of a CA repeat in exon 29 of the NOS1 gene were significantly different between 490 asthmatic and 350 control subjects. Allele 17 was more common in the asthmatics (0.83 vs 0.76, or 1.49 [95% CI 1.17-1.90], P = 0.013) while allele 18 was less common in the asthmatics (0.06 vs 0.12, or 0.49 [95% CI 0.34-0. 69], P = 0.0004). To confirm these results we genotyped an additional 1131 control subjects and found the frequencies of alleles 17 and 18 to be virtually identical to those ascertained in our original control subjects. Total serum IgE was not associated with any allele of the polymorphism. These findings provide support, from case-control association analysis, for NOS1 as a candidate gene for asthma.

    Funded by: NHLBI NIH HHS: HL-56383

    Biochemical and biophysical research communications 2000;272;2;391-4

  • Variants of NOS1, NOS2, and NOS3 genes in asthmatics.

    Gao PS, Kawada H, Kasamatsu T, Mao XQ, Roberts MH, Miyamoto Y, Yoshimura M, Saitoh Y, Yasue H, Nakao K, Adra CN, Kun JF, Moro-oka S, Inoko H, Ho LP, Shirakawa T and Hopkin JM

    Experimental Medicine Unit, University of Wales Swansea, Swansea, United Kingdom.

    Nitric oxide (NO) gas concentrations are higher in expired air in asthmatics. NO is synthesized by three isoforms of NO synthase (NOS) encoded by three distinct genes, NOS1, NOS2, and NOS3. Genome-wide searches have identified linkages to asthma on chromosomes 7, 12, and 17 where these three genes are localized. No association study, however, has been reported to date. To test whether variants of NOS1, NOS2, and NOS3 relate to asthma, a genetic association study was conducted in a British population (n = 300). Intragenic microsatellite variants of NOS1 were significantly associated with asthma [odds ratio (OR) = 2.08, 95% CI: 1.20-3.57 (95% CI), P = 0.008 (Pc = 0.048)], but not with IgE levels. Neither NOS2 nor NOS3 variants showed any association with asthma nor IgE levels. These findings suggest that NOS1 variants may be a significant contributor to asthma in a British population.

    Biochemical and biophysical research communications 2000;267;3;761-3

  • Neuronal NO synthase (NOS1) is a major candidate gene for asthma.

    Grasemann H, Yandava CN and Drazen JM

    Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

    Asthma is a common, but heterogeneous disease, characterized by reversible airway obstruction, bronchial hyperresponsiveness (BHR); and is commonly associated with atopy. The messenger molecule nitric oxide (NO), that is formed by neuronal NO synthase (NOS1), is known to have a key role in bronchomotor control in animals. In humans the gene for NOS1 is located on chromosome 12q24, in a region that had been shown in family studies to be linked to the diagnosis of asthma. We identified variants of the NOS1 gene, and assessed whether there was a genetic association between these variants of NOS1 and the diagnosis asthma. A total of 410 Caucasian asthma patients and 228 Caucasian controls were screened for three bi-allelic polymorphisms in the NOS1 gene that had been detected by single-stranded conformational polymorphism (SSCP) analysis and confirmed by sequencing. Allele frequencies of a polymorphism in exon 29 of the NOS1 gene were significantly different between asthmatics and controls (P<0.05). These findings suggest that variants of the NOS1 gene may be one source of genetic risk for asthma.

    Funded by: NHLBI NIH HHS: HL-56383

    Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 1999;29 Suppl 4;39-41

Pubmed - other

  • Fine mapping and single nucleotide polymorphism association results of candidate genes for asthma and related phenotypes.

    Immervoll T, Loesgen S, Dütsch G, Gohlke H, Herbon N, Klugbauer S, Dempfle A, Bickeböller H, Becker-Follmann J, Rüschendorf F, Saar K, Reis A, Wichmann HE and Wjst M

    GSF-National Research Center for Environment and Health, Institute of Epidemiology, Neuherberg, Germany. immervoll@gsf.de

    Several genome-wide screens for asthma and related phenotypes have been published to date but data on fine-mapping are scarce. For higher resolution we performed a fine-mapping study with 2 cM average spacing in often discussed asthma candidate regions (2p, 5q, 6p, 7p, 9q, 11p, and 12q) to narrow down the regions of interest. All participants of a Caucasian family study (97 families with at least two affected sib pairs) were genotyped for 49 supplementary polymorphic dinucleotide markers. Our results indicate increased evidence for linkage on chromosome 6p, 9q, and 12q. These candidate regions were further analyzed with SNP polymorphisms in the endothelin 1 (EDN1), lymphotoxin alpha (LTA), and neuronal nitric oxide synthase (NOS1) genes. In addition, IL4 -590C>T and IL10 -592C>A, localized on chromosomes 5q and 1q, respectively, have been analyzed for SNP association. Of the six SNPs tested, four revealed weak association with the examined phenotypes. These are the IL10 -592C>A SNP in the interleukin 10 gene (p=0.036 for eosinophil cell counts), the 4124T>C SNP in EDN1 (p=0.044 for asthma), the 3391C>T SNP in NOS1 with eosinophil cell counts (p=0.0086), and the 5266C>T polymorphism, also in the NOS1 gene, for high IgE levels (p=0.022). In summary, fine mapping data enable us to confine asthma candidate regions, while variants of EDN1 and NOS1, or nearby genes, may play an important role in this context.

    Human mutation 2001;18;4;327-36

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

Cookies Policy | Terms and Conditions. This site is hosted by Edinburgh University and the Genes to Cognition Programme.