title: Fine mapping and positional candidate studies on chromosome 5p13 identify multiple asthma susceptibility loci.
abstract: BACKGROUND
  Genome-wide linkage scans to identify asthma susceptibility loci have revealed many linked regions, including a broad region on chromosome 5p.
  
  
  OBJECTIVE
  To identify a 5p-linked asthma or bronchial hyperresponsiveness (BHR) locus.
  
  
  METHODS
  We performed fine mapping and positional candidate studies of this region in the Hutterites and an outbred case-control sample from Germany by genotyping 89 single nucleotide polymorphisms (SNPs) in 22 genes. SNP and haplotype analyses were performed.
  
  
  RESULTS
  Three genes in a distal region (zinc finger RNA binding protein [ZFR], natriuretic peptide receptor C, and a disintegrin and metalloproteinase domain with thrombospondin type 1 motif [ADAMTS12]) were associated with BHR, whereas 4 genes in a proximal region (prolactin receptor, IL-7 receptor [IL7R], leukemia inhibitory factor receptor [LIFR], and prostaglandin E4 receptor [PTGER4]) were associated with asthma symptoms in the Hutterites. Furthermore, nearly the entire original linkage signal in the Hutterites was generated by individuals who had the risk-associated alleles in ZFR3, natriuretic peptide receptor C, ADAMTS12, LIFR, and PTGER4. Variation in ADAMTS12, IL7R, and PTGER4 were also associated with asthma in the outbred Germans, and the frequencies of long-range haplotypes composed of SNPs at ZFR, ADAMTS12, IL7R, LIFR, and PTGER4 were significantly different between both the German and Hutterite cases and controls. There is little linkage disequilbrium between alleles in these 2 regions in either population.
  
  
  CONCLUSIONS
  These results suggest that a broad region on 5p, separated by >9 Mb, harbors at least 2 and possibly 5 asthma or BHR susceptibility loci. These findings are consistent with the hypothesis that regions providing evidence for linkage in multiple populations may, in fact, house more than 1 susceptibility locus, as appears to be the case for the linked region on 5p.
  
  
  CONCLUSIONS
  Identifying asthma or BHR genes could lead to novel therapeutic approaches.
authors.affiliation: Department of Human Genetics, University of Chicago, 920 East 58th Street, Chicago, IL 60637, USA.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Kurz
authors.forename: Sabine
authors.initials: S
authors.lastname: Hoffjan
authors.forename: M Geoffrey
authors.initials: MG
authors.lastname: Hayes
authors.forename: Dan
authors.initials: D
authors.lastname: Schneider
authors.forename: Raluca
authors.initials: R
authors.lastname: Nicolae
authors.forename: Andrea
authors.initials: A
authors.lastname: Heinzmann
authors.forename: Sylvija P
authors.initials: SP
authors.lastname: Jerkic
authors.forename: Rod
authors.initials: R
authors.lastname: Parry
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: Klaus A
authors.initials: KA
authors.lastname: Deichmann
authors.forename: Carole
authors.initials: C
authors.lastname: Ober
mesh_terms: D001249:Asthma / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5; D020022:Genetic Predisposition to Disease; D005858:Germany / Q000453:epidemiology; D006801:Humans; D020641:Polymorphism, Single Nucleotide