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Published ahead of print on March 12, 2004, doi:10.1164/rccm.200302-281OC

Am. J. Respir. Crit. Care Med., Volume 169, Number 11, June 2004, 1217-1223

A more recent version of this article appeared on June 1, 2004
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Submitted on March 18, 2003
Accepted on March 11, 2004

Association of the Interleukin 1 Receptor Antagonist Gene with Asthma

Henning Gohlke1, Thomas Illig1, Margret Bahnweg1, Norman Klopp1, Elisabeth Andre1, Janine Altmuller1, Nicole Herbon1, Monika Werner1, Michael Knapp2, Lydia Pescollderungg3, Attilio Boner4, Giovanni Malerba4, Pier Franco Pignatti4, and Matthias Wjst1*

1 Institute of Epidemiology, GSF- National Research Center for Environment and Health, Neuherberg, Germany, 2 Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany, 3 Department of Pediatrics, Bolzano Hospital, Verona, Italy, 4 Department of Mother and Child, Biology and Genetics, University of Verona, Bolzano, Italy

* To whom correspondence should be addressed. E-mail: m{at}gsf.de.

The interleukin-1 cluster on human chromosome 2q12-2q14 harbours various promising candidate genes for asthma and other inflammatory diseases. We conducted a systematic association study with single nucleotide polymorphisms (SNPs) located in candidate genes situated in this cluster. Single marker, two-locus and three-locus haplotype analysis of SNPs yielded several significant results (p<0.05 to 0.0021) for the human IL1RN gene encoding the IL-1ra protein, an anti-inflammatory cytokine that plays an important role in the maintaining the balance between inflammatory and anti-inflammatory cytokines. These findings were replicated and confirmed in an independent Italian family sample where significant, though weaker, as-sociation with SNPs and asthma was detected. A sequencing approach for the coding region of the human IL1RN gene revealed additional DNA variants, from which a selection was also associated with the disease in the German and the Italian samples. Calculation of the linkage disequilibrium in the human IL1RN gene showed strong LD for nearly all analysed SNPs. Further haplotype analysis indicated that 6 SNPs are sufficient for tagging all haplotypes with a prevalence of > 1%. The most frequent haplotype constructed from these SNPs was 1.4-fold over transmitted in the German families.
Key words: Asthma, Association, SNPs, IL1 cluster




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