Fine mapping and positional candidate studies on chromosome 5p13 identify multiple asthma susceptibility loci - 16/08/11
, Sabine Hoffjan, MD a, , M. Geoffrey Hayes, PhD a, b, , Dan Schneider, BS a, Raluca Nicolae, DDS a, Andrea Heinzmann, MD c, Sylvija P. Jerkic, MD c, Rod Parry, MD d, Nancy J. Cox, PhD a, b, Klaus A. Deichmann, MD c, Carole Ober, PhD a, ⁎ 
Reprint requests: Carole Ober, PhD, Department of Human Genetics, 920 E. 58th Street, CLSC 507C, University of Chicago, Chicago, IL 60637.Chicago, Ill, Freiburg, Germany, and Sioux Falls, SD
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.
Le texte complet de cet article est disponible en PDF.Key words : Asthma, linkage, founder population
Abbreviations used : ADAM33, ADAMTS12, BHR, EP, HWE, IL7R, LD, LIFR, LR, NPR3, PRLR, PTGER4, SNP, TDT, ZFR
Plan
| Supported by National Institutes of Health grants HL66533 to C.O. and DK55889 to N.J.C.; S.H. was supported in part by the Deutsche Forschungsgesellschaft, and M.G.H. was supported by Training in Respiratory Biology grant T32 HL007605. Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest. |
Vol 118 - N° 2
P. 396-402 - août 2006 Retour au numéro
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