Fine mapping and positional candidate studies on chromosome 5p13 identify multiple asthma susceptibility loci

Thorsten Kurz, Sabine Hoffjan, M. Geoffrey Hayes, Dan Schneider, Raluca Nicolae, Andrea Heinzmann, Sylvija P. Jerkic, Rod Parry, Nancy J. Cox, Klaus A. Deichmann, Carole Ober*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

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. Conclusion: 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. Clinical implications: Identifying asthma or BHR genes could lead to novel therapeutic approaches.

Original languageEnglish (US)
Pages (from-to)396-402
Number of pages7
JournalJournal of Allergy and Clinical Immunology
Volume118
Issue number2
DOIs
StatePublished - Aug 2006

Keywords

  • Asthma
  • founder population
  • linkage

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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