Volume 125, Issue 1 , Pages 170-174.e2, January 2010
Chromosome 11q13.5 variant associated with childhood eczema: An effect supplementary to filaggrin mutations
Background
Atopic eczema is a common inflammatory skin disease with multifactorial etiology. The genetic basis is incompletely understood; however, loss of function mutations in the filaggrin gene (FLG) are the most significant and widely replicated genetic risk factor reported to date. The first genome-wide association study in atopic eczema recently identified 2 novel genetic variants in association with eczema susceptibility: a single nucleotide polymorphism on chromosome 11q13.5 (rs7927894) and a single nucleotide polymorphism (rs877776) within the gene encoding hornerin on chromosome 1q21.
Objective
To test the association of these 2 novel variants with pediatric eczema and to investigate their interaction with FLG null mutations.
Methods
Case-control study to investigate the association of rs7927894, rs877776 and the 4 most prevalent FLG null mutations with moderate-severe eczema in 511 Irish pediatric cases and 1000 Irish controls. Comprehensive testing for interaction between each of the loci was also performed.
Results
The association between rs7927894 and atopic eczema was replicated in this population (P = .0025, χ2 test; odds ratio, 1.27; 95% CI, 1.09-1.49). The 4 most common FLG null variants were strongly associated with atopic eczema (P = 1.26 × 10−50; combined odds ratio, 5.81; 95% CI, 4.51-7.49). Interestingly, the rs7927894 association was independent of the well-established FLG risk alleles and may be multiplicative in its effect. There was no significant association between rs877776 and pediatric eczema in this study.
Conclusion
Single nucleotide polymorphism rs7927894 appears to mark a genuine eczema susceptibility locus that will require further elucidation through fine mapping and functional analysis.
Key words: Allergy, atopic dermatitis, atopy, inflammatory skin disease, skin barrier
Abbreviations used: AIC, Akaike information criterion, BIC, Bayesian information criterion, FLG, Filaggrin gene, HRNR, Hornerin gene, OR, Odds ratio, SNP, Single nucleotide polymorphism
G.M.O'R. and A.D.I. are supported by the Children's Medical and Research Foundation, Our Lady's Children's Hospital, Crumlin, Dublin, who funded the establishment of this case collection. H.J.C. is supported by a Wellcome Trust Senior Fellowship (reference 074524). Filaggrin research in the McLean Laboratory is supported by grants from the British Skin Foundation, the National Eczema Society, and the Medical Research Council (reference G0700314) and donations from anonymous families affected by eczema in the Tayside Region of Scotland. S.J.B. is supported by a Wellcome Trust Intermediate Clinical Fellowship (reference 086398).
Disclosure of potential conflict of interest: G. M. O'Regan has received research support from the Children's Research Center. W. H. I. McLean has received research grants from the Medical Research Council and DebRA UK. S. J. Brown has received research support from the Wellcome Trust. A. D. Irvine has received research support from the Children's Medical and Research Foundation, Crumlin, and the Health Research Board, Ireland. H. J. Cordell has received research support from The Wellcome Trust, the European Commission, and the British Heart Foundation. The other author has declared that she has no conflict of interest. I. McLean has filed patents relating to genetic testing and therapy development aimed at the filaggrin gene.
PII: S0091-6749(09)01612-1
doi:10.1016/j.jaci.2009.10.046
© 2010 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Volume 125, Issue 1 , Pages 170-174.e2, January 2010
