NEJM -- Variants of DENND1B Associated with Asthma in Children

Published at www.nejm.org December 23, 2009 (10.1056/NEJMoa0901867)
Variants of DENND1B Associated with Asthma in Children

Patrick M.A. Sleiman, Ph.D., James Flory, Ph.D., Marcin Imielinski, M.D., Ph.D., Jonathan P. Bradfield, B.S., Kiran Annaiah, M.Sc., Saffron A.G. Willis-Owen, Ph.D., Kai Wang, Ph.D., Nicholas M. Rafaels, M.S., Sven Michel, Ph.D., Klaus Bonnelykke, M.D., Ph.D., Haitao Zhang, Ph.D., Cecilia E. Kim, B.A., Edward C. Frackelton, B.A., Joseph T. Glessner, M.Sc., Cuiping Hou, M.Sc., F. George Otieno, M.Sc., Erin Santa, B.A., Kelly Thomas, B.A., Ryan M. Smith, B.A., Wendy R. Glaberson, B.A., Maria Garris, B.A., Rosetta M. Chiavacci, B.S.N., Terri H. Beaty, Ph.D., Ingo Ruczinski, Ph.D., Jordan M. Orange, M.D., Ph.D., Julian Allen, M.D., Jonathan M. Spergel, M.D., Ph.D., Robert Grundmeier, M.D., Ph.D., Rasika A. Mathias, Sc.D., Jason D. Christie, M.D., Erika von Mutius, M.D., William O.C. Cookson, M.D., Michael Kabesch, M.D., Miriam F. Moffatt, Ph.D., Michael M. Grunstein, M.D., Ph.D., Kathleen C. Barnes, Ph.D., Marcella Devoto, Ph.D., Mark Magnusson, M.D., Hongzhe Li, Ph.D., Struan F.A. Grant, Ph.D., Hans Bisgaard, M.D., and Hakon Hakonarson, M.D., Ph.D.


ABSTRACT

Background Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown.

Methods We carried out a genomewide association study involving children with asthma. The sample included 793 North American children of European ancestry with persistent asthma who required daily inhaled glucocorticoid therapy and 1988 matched controls (the discovery set). We also tested for genomewide association in an independent cohort of 917 persons of European ancestry who had asthma and 1546 matched controls (the replication set). Finally, we tested for an association between 20 single-nucleotide polymorphisms (SNPs) at chromosome 1q31 and asthma in 1667 North American children of African ancestry who had asthma and 2045 ancestrally matched controls.

Results In our meta-analysis of all samples from persons of European ancestry, we observed an association, with genomewide significance, between asthma and SNPs at the previously reported locus on 17q21 and an additional eight SNPs at a novel locus on 1q31. The SNP most strongly associated with asthma was rs2786098 (P=8.55x10–9). We observed replication of the association of asthma with SNP rs2786098 in the independent series of persons of European ancestry (combined P=9.3x10–11). The alternative allele of each of the eight SNPs on chromosome 1q31 was strongly associated with asthma in the children of African ancestry (P=1.6x10–13 for the comparison across all samples). The 1q31 locus contains DENND1B, a gene that is expressed by natural killer cells and dendritic cells and that encodes a protein that interacts with the tumor necrosis factor receptor.

Conclusions We have identified a locus containing DENND1B on chromosome 1q31.3 that is associated with susceptibility to asthma.

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NEJM -- Variants of DENND1B Associated with Asthma in Children