RESEARCH ARTICLE Fine Mapping and Single Nucleotide Polymorphism Association Results of Candidate Genes for Asthma and Related Phenotypes Thomas Immervoll, 1 * Sabine Loesgen, 1 Gabriele Dütsch, 1 Henning Gohlke, 1 Nicole Herbon, 1 Sabine Klugbauer, 1 Astrid Dempfle, 1 Heike Bickeböller, 1 Johannes Becker-Follmann, 2 Franz Rüschendorf, 2,3 Kathrin Saar, 2 Andre Reis, 2 H.-Erich Wichmann, 1 and Matthias Wjst 1 1 GSFNational Research Center for Environment and Health, Institute of Epidemiology, Neuherberg, Germany 2 Molecular Genetics and Gene Mapping Center, Max-Delbrück-Center, Berlin, Germany 3 Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany Communicated by Pui-Yan Kwok 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 dinucle- otide 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 addi- tion, 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 con- fine asthma candidate regions, while variants of EDN1 and NOS1, or nearby genes, may play an important role in this context. Hum Mutat 18:327336, 2001. © 2001 Wiley-Liss, Inc. KEY WORDS: SNP; association analysis; fine-mapping; asthma; MALDI-TOF MS; EDN1; NOS1; LTA; TNFB; IL4; IL10; multifactorial disease DATABASES: EDN1  OMIM: 131240; GDB: 119861; GenBank: J05008; HGMD: EDN1 NOS1  OMIM: 163731; GDB: 132579; GenBank: XM_006698; HGMD: NOS1 LTA  OMIM: 153440; GDB: 120442; GenBank: Z15026; HGMD: LTA IL4  OMIM: 147780; GDB: 120096; GenBank: M234421; HGMD: IL4 IL10  OMIM: 124092; GDB: 128636; GenBank: X73536; HGMD: IL10 Multifactorial disorders  OMIM: 600807 (asthma); http://cooke.gsf.de/asthmagen/main.cfm (Asthma and Allergy Gene Database); http://genome.ucsc.edu (Human Genome Project Working Draft at UCSC) Received 29 March 2001; accepted revised manuscript 13 July 2001. *Correspondence to: Dr. Thomas Immervoll, GSF–National Research Center for Environment and Health, Institute of Epide- miology, Ingolstaedter Landstrasse 1, D-85764 Neuherberg, Ger- many. E-mail: immervoll@gsf.de Contract grant sponsors: HGF Strategiefond II Genetik Komplexer Erkrankungen; Genome Analysis Center (GAC) of the GSF–National Research Center for Environment and Health. Contract grant sponsor: Deutsche Forschungsgemeinschaft; Con- tract grant number: WI621/5-1.