title: Intermediary quantitative traits--an alternative in the identification of disease genes in asthma?
abstract: Intermediary quantitative traits are a possible alternative for the identification of disease genes. This may be particularly relevant when diagnostic criteria are not very well defined as described for asthma. We analyzed serum samples from 944 individuals of 218 asthma families for 17 cytokines (eotaxin, GM-CSF, IFNγ, IL1B, IL1RA, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12(p40), IL-13, IL-17, IL-23, IL-33, TSLP and TNF-α) and determined the heritability. Linked chromosomal regions were identified by a genome-wide analysis using 334 autosomal microsatellite marker and association tested by further 550 SNP marker at genes implicated earlier with immune response. Heritability varied with TNF-α and IL-8 levels having the highest and TSLP having the lowest heritability. Linkage was significantly increased only for IL-12(p40) at D17S949. There were multiple significant single-nucleotide polymorphisms (SNP) associations (P<0.05) as found in the transmission disequilibrium test, whereas only a few replicated in parents or children only. These include SNPs in IL1RN that were associated with IL-33 and TSLP levels, and a SNP in NR3C2 that was associated with eotaxin, IL-13 and IFN-γ levels. Circulating level of serum cytokines exhibits genetic associations with asthma traits that are otherwise not detected using clinical diagnosis or when the clinical details are ambiguous.
authors.affiliation: Institute of Lung Biology and Health (iLBD), Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München, Munich-Neuherberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Sargurupremraj
authors.affiliation: Institute of Lung Biology and Health (iLBD), Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München, Munich-Neuherberg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Pukelsheim
authors.affiliation: Institute of Lung Biology and Health (iLBD), Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München, Munich-Neuherberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Hofer
authors.affiliation: Institute of Lung Biology and Health (iLBD), Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München, Munich-Neuherberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wjst
mesh_terms: D000328:Adult; D001249:Asthma / Q000235:genetics*; D002648:Child; D016207:Cytokines / Q000097:blood / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D016209:Interleukin-8; C561839:NR3C2 protein, human; D018161:Receptors, Mineralocorticoid; D014409:Tumor Necrosis Factor-alpha; D000094632:Thymic Stromal Lymphopoietin